Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 280 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 96 mg of 2-butyn-1-ol, to which 55 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 212 mg of 4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (83)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:15])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:15][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Cc1ccccc1-c1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1-c1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 6-chloro-2′-methyl-biphenyl-2-ol (4.75 g, 21.7 mmol) in DMF (30 mL) was added potassium carbonate (4.5 g, 32.6 mmol) and allyl bromide (3.0 mL, 32.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of O to 30% ethyl acetate in hexanes provided 5.6 g (100%) of 2-allyloxy-6-chloro-2′-methylbiphenyl as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[C:5]([F:22])=[CH:4][N:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[CH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:12]1[O:11][C:10](=[O:21])[NH:9][C@@H:8]1[C:6]1[C:5]([F:22])=[CH:4][N:3]=[C:2]([C:24]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1
Reactant: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2cc(F)ccc2F)O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3ccccc3)ncc2F)[C@@H](c2cc(F)ccc2F)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
In a 1 mL scint vial, a suspension of optically-enriched (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (20 mg, 0.054 mmol), and ethynylbenzene (0.014 mL, 0.129 mmol) in triethyl amine (1.5 mL) was purged with nitrogen for 30 min. Triphenylphosphine (3.7 mg, 0.014 mmol) was added and the suspension stirred for 5 min. To this was added copper (I) iodide (0.408 mg, 2.144 μmol), and bis(triphenylphosphine)palladium(II) chloride (1.8 mg, 2.6 μmol). The vial was purged with nitrogen for an additional 5 min, capped, and immersed in a 90° C. bath for 5 h. The reaction was cooled to room temperature and concentrated. The resulting residue was dissolved in dichloromethane and poured into water. The mixture was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, and concentrated. The material was purified first by reversed phase HPLC (TFA/MeOH/sunfire column) to give an optically enriched mixture of regioisomers. The material was further purified by chiral prep HPLC (Chiralpak AD, A=heptane/0.1% DEA, B=ethanol, 40%→60% over 35 min) to give the title compound (3.4 mg). 1H NMR (CDCl3) δ: 8.52 (d, J=0.9 Hz, 1H), 7.75 (d, J=5.8 Hz, 1H), 7.63 (dd, J=7.3, 2.1 Hz, 2H), 7.38-7.44 (m, 3H), 7.23-7.27 (m, 1H), 7.11-7.17 (m, 2H), 5.79 (br. s., 1H), 5.64 (d, J=5.5 Hz, 1H), 5.08 (d, J=5.5 Hz, 1H). 1H NMR (CDCl3) δ: 8.51 (d, J=0.9 Hz, 1H), 7.73 (d, J=5.5 Hz, 1H), 7.63 (dd, J=7.6, 1.8 Hz, 2H), 7.39-7.46 (m, 3H), 7.23-7.27 (m, 1H), 7.10-7.16 (m, 2H), 5.95 (br. s., 1H), 5.61 (d, J=5.5 Hz, 1H), 5.13 (d, J=5.8 Hz, 1H). Mass spec.: 395.2 (MH)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:46][O:47][C:48]([C:50]1[N:51]=[C:52]([NH2:55])[S:53][CH:54]=1)=[O:49]>C(Cl)Cl>[CH3:46][O:47][C:48]([C:50]1[N:51]=[C:52]([NH:55][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[S:53][CH:54]=1)=[O:49]
Reactant: COC(=O)c1csc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution triphenylphosphine (164 mg, 0.63 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (112 mg, 0.63 mmol) in small portions. The resulting orange reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 54A, 150 mg, 0.52 mmol). The reaction mixture was stirred at 0° C. for an additional 15 min and then allowed to warm to 25° C. The reaction mixture was then treated with 2-aminothiazole-4-carboxylic acid methyl ester (181 mg, 1.15 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) to afford impure (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester. The impure product was diluted with ethyl acetate and then washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide pure (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (92 mg, 41%) as a white solid: mp 143–144° C.; [α]23589=−10.2° (c=0.98, chloroform); EI-HRMS m/e calcd for C19H20Cl2N2O3S (M+) 426.0572, found 426.0562.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:27][N:28]([CH3:46])[CH2:29][CH2:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37](C(O)=O)[NH:38]2)=[CH:34][C:33]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:37]2[NH:38][C:39]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:44][CH3:45])=[C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:27])[CH3:46])[CH:40]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: COc1cc2cc(C(=O)O)[nH]c2cc1OCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc2cc(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)[nH]c2cc1OCCN(C)C
Yield: 47.8 %

Procedure:
Deprotection of 13 (260 mg, 0.72 mmol) as in Example C, and reaction of the product with 6-[2-(dimethylamino)ethoxy]-5-methoxyindole-2-carboxylic acid hydrochloride (230 mg, 0.73 mmol), EDCI.HCl (345 mg, 1.80 mmol) and DMA (3 mL) at 20° C. for 3 h gave a solid. This was shaken with dilute KHCO3 and the resulting gelatinous solid was collected and chromatographed on alumina-90. Elution with EtOAc/MeOH (10:1) provided the crude product which was recrystallised from EtOAc/i-Pr2O, followed by CH2Cl2 /petroleum ether, to give 14f (180 mg, 48%), mp 224-234 (C (dec.). 1H NMR [(CD3)2SO] δ 11.54 (d, J=1.6 Hz, 1 H, NH), 9.17 (s, 1 H, H-4), 8.34 (dd, J=7.5, 2.2 Hz, 1 H, H-6), 8.22 (dd, J=7.1, 1.8 Hz, 1 H, H-9), 7.79-7.69 (m, 2 H, H-7,8), 7.17 (d, J=1.6 Hz, 1 H, H-3'), 7.16 (s, 1 H, H-4' or 7'), 6.99 (s, 1 H, H-4' or 7'), 4.91 (t, J=10.2 Hz, 1 H, H-2), 4.68 (dd, J=10.9, 2.4 Hz, 1 H, H-2), 4.65-4.57 (m, 1 H, H-1), 4.17-4.09 (m, 2 H, CH2Cl), 4.06 (t, J=6.0 Hz, 2 H, OCH2), 3.79 (s, 3 H, OCH3), 2.69 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.26 (s, 6 H, N(CH3)2).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[C:25]([OH:26])=[C:24]([CH3:27])[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:26][C:25]1[C:24]([CH3:27])=[CH:23][CH:22]=[CH:21][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1cccc(N)c1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Yield: 83.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 680 mg of 6-amino-2-methylphenol and 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 6 ml of pyridine and 8 ml of N,N-dimethylformamide. 1.1 g of N-(2-hydroxy-3-methyl phenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2/[CH:13]=[C:14]1/[C:15](=[O:20])[NH:16][C:17](=[S:19])[S:18]/1.[CH3:21]CN(C(C)C)C(C)C.IC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2/[CH:13]=[C:14]1/[C:15](=[O:20])[N:16]=[C:17]([S:19][CH3:21])[S:18]/1
Reactant: COc1ccc2[nH]c(C)c(/C=C3\SC(=S)NC3=O)c2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CI
Product: COc1ccc2[nH]c(C)c(/C=C3\SC(SC)=NC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a room temperature suspension of (Z)-5-[(5-methoxy-2 methyl-1H-indol-3-yl)methylene]-2-thioxo-4-thiazolidinone (1.714 g, 5.63 mmols) in 50 mL of methanol is added Hunig's base (1.15 mL, 6.61 mmols) followed by iodomethane (0.500 mL, 8.03 nmmols). The thick suspension is stirred overnight at room temperature. Filtration washing with ether provides 1.631 g (91%) of (Z)-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-2(methylthio)-4(5H) thiazolone; mp 214-222° C. dec. Calc'd for C15H14N2O2S2 :
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]2)[CH:23]=1
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCCN1CCC[C@H](Nc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((S)-3-aminopiperidin-1-yl)ethyl ester (1.565 g, 6.85 mmol) in DMF (30 mL) was added 2,4-difluoronitrobenzene (1.517 g, 8.92 mmol) and potassium carbonate (1.9 g, 13.8 mmol). The reaction mixture was stirred at RT for 16 h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a yellow oil (2.307 g, 92%). LCMS (Method J): RT 2.34 min [M+H]+ 368.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[I-:16].[Na+].CNCCNC>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[I:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: [I-]
Reactant: Brc1cncc(C#Cc2ccccc2)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Ic1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Heat a mixture of 3-bromo-5-phenylethynylpyridine (5.71 g, 22.12 mmol), (prepared essentially as described in EXAMPLE 9), copper (I) iodide (211 mg, 1.1 mmol), sodium iodide (6.63 g, 44.24 mmol) and N,N′-dimethylethylenediamine (0.24 mL, 2.21 mmol) in 1,4-dioxane (20 mL) at 110° C. for 60 h. Cool to room temperature, dilute with ethyl acetate and wash with a saturated aqueous solution of sodium chloride, and dry (sodium sulfate). Purify the residue by silica gel chromatography, eluting with 15:1 hexanes:ethyl acetate, to give the title compound (5.45 g, 81%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([CH3:18])[CH:20]=1)[CH2:13][CH3:14]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 3-methyl-benzoyl chloride (6.00 ml) was dropwise added, Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.05 g of yellow liquid. MS: m/e 319(M++1), 318(M+″), 273, 259, 244, 226, 199, 182, 119(base), 91, 77.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and benzoyl chloride (4.7 μL, 40 μmole, 1.0 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.32 (t, 1H), 8.18 (s, 1H), 7.77 (d, 2H), 7.47 (t, 1H), 7.37 (m, 4H), 7.25 (d, 2H), 7.18 (t, 1H), 4.40 (s, 2H), 3.30 (water), 2.98 (t, 4H), 2.48 (DMSO), 1.61 (m, 4H), 1.36 (m, 1H), 1.28 (m, 1H), 0.62 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:25]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[CH:6]=1)[CH:24]=[CH2:23]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and allyl bromide with sodium carbonate in acetone there is obtained 1-(5-allyloxy-4-chloro-2-fluorophenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 103°-104° C.;
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:4])=[O:3].[C:19](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH3:19][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)c2cc[nH]c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.2 %

Procedure:
To a mixture of Methyl 4-[(methylsulfonyl)amino]-1H-indole-6-carboxylate (0.6 g) in THF (10 mL) was added potassium carbonate (0.309 g) and iodomethane (0.63 mL). The mixture was stirred at room temperature for 4 h then heated to 40° C. overnight. Iodomethane (0.3 mL) was added and the mixture heated an additional 3 h. The mixture was cooled to room temperature, partitioned between water and diethyl ether, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ether and decolorizing carbon (2 g) was added and the mixture refluxed for 5 minutes then filtered through celite while hot. The ether was removed under reduced pressure to give 0.437 g of the title compound: MS (ESI+) for C12H14 N2 O4 SI m/z 321.1 (M+K).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27]C)=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(OCC2CC2)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cc(CC(=O)O)ccc1OCC1CC1)S(C)(=O)=O
Yield: 94.8 %

Procedure:
To a solution of methyl 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 2.90 mmol) in THF:water=1:1 (35 ml), LiOH (0.695 g, 29.0 mmol) was added, and the mixture was reacted for 30 minutes at RT. THF was evaporated, and the aqueous residue was acidified with HCl 6N (pH=7). The mixture was extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum affording 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetic acid (1.1 g, 2.75 mmol, 95% yield, MS/ESI+ 400.0 [MH]+). This intermediate was used without any additional purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][CH3:21])=[N:3]3)=[CH:15][CH:16]=1
Reactant: Fc1ccc(COc2cccc3nc(Cl)ccc23)cc1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(OCc3ccc(F)cc3)cccc2n1

Procedure:
2-Chloro-5-(4-fluoro-benzyloxy)-quinoline (100 mg, 0.35 mmol) and 2-methoxybenzylamine (144 mg, 1.05 mmol) were stirred in a sealed tube at 150° C. for 16 hours. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). 5-(4-Fluorobenzyloxy)-quinolin-2-yl-(2-methoxy-benzyl)-amine was obtained as a yellow oil (57 mg, 42%), MS: m/e=389.3 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:24]1[C:33]2[N:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.CC1C=CC=C(C)C=1B(O)O>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:34]([C:27]3[C:28]4[N:29]=[CH:30][CH:31]=[N:32][C:33]=4[C:24]([C:18]4[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:16])=[CH:25][CH:26]=3)=[O:35])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Agent: Cc1cccc(C)c1B(O)O
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4c(C)cccc4C)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 2,6-dimethylphenylboronic acid and Pd(PPh3)-4 in Step 1.4. Title compound: ESI-MS: 466.2 [M+H]+; tR=3.74 min (System 3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.C([C:18]1[C:19]([N:27]=[CH:28][N:29]([CH3:31])C)=[N:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=1)#N>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:6]([NH:8][C:31]2[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[N:20][C:19]=3[N:27]=[CH:28][N:29]=2)[CH:7]=1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ncnc2n1
Temperature: 130 °C

Procedure:
The product from Example 5I (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature a solid in the acetic acid solvent appeared which was collected by filtration to provide the title compound as an acetic acid salt (68 mg, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.94 (t, J=7.4 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.35 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 7.18 (m, 5H), 7.23 (m, 2H), 7.37 (s, 1H), 7.51 (d, J=8.1 Hz, 1H), 8.48 (s, 1H), 8.69 (d, J=8.5 Hz, 1H); MS (ESI)+ m/z 387 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1)[CH2:5]2
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CN2CCC1CC2)c1ccc(I)c([N+](=O)[O-])c1
Yield: 22.5 %

Procedure:
A solution of 3.08 g (24.4 mmol) of 3-aminoquinuclidine dihydrochloride, 7.60 g (24.4 mmol) of 4-iodo-3-nitrobenzoyl chloride, 9.88 g (97.6 mmol) of triethylamine in 150 ml of DMF was stirred at room temperature overnight. The solvent was distilled off in a rotary evaporator, the residue was taken up in 200 ml of dichloromethane, and 200 ml of a saturated sodium bicarbonate solution were added. The organic phase was dried over sodium sulfate, and the solvent was distilled off in vacuo. 2.20 g (22.5%) of the desired title compound were obtained.