Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 56.9 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and thiomorpholine (77 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (140 mg, 0.33 mmol, yield 56%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10]Br)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2].[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][S:18][C:19]2[NH:20][C:21]3[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of 2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl bromide (2.71 g), ethyl 2 mercaptobenzimidazole-5-carboxylate (2.00 g) and anhydrous potassium carbonate (1.49 g) in N,N-dimethylformamide (30 ml) was stirred at 80-90 ° C. for 30 minutes. The reaction mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloro-methane-ethyl acetate (10:1), to give ethyl 2-[2-(4-acetyl-3- hydroxy-2-propylphenoxy)ethylthio]benzimidazole-5-carboxylate (2.33 g, 58.5 %) as a yellow oil.
Reaction SMILES: Br[C:2]1([Br:10])[CH:9]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].[Al]>C1(C)C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Ag+]>[Br:10][C:2]1[CH:3]([CH:12]([OH:13])[C:11]([O:15][CH3:16])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=1
Reactant: BrC1(Br)C2CCCCCC21
Reactant: COC(=O)CO
Agent: [Ag+]
Agent: [Al]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(O)C1CCCCCC=C1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Added to a solution of 8,8-dibromobicyclo[5.1.0]octane (2.5 g i.e. 9.3 mmol) and methyl glycolate (6.35 ml, i.e. 83.9 mmol) dissolved in 5 ml of anhydrous toluene in a dry round-bottomed flask, under Ar and protected from the light by aluminium foil, are 3.85 g of silver perchlorate (i.e. 18.6 mmol). The reaction is stirred for 1 h 30 min at room temperature, then the silver salts are filtered over a frit and washed with AcOEt. The solution is concentrated under vacuum to give a viscous brown oil which is purified by silica gel chromatography (2-15% AcOEt in cyclohexane) to obtain the product in the form of a yellow oil having a mass m=1.6 g, i.e. 65% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([CH3:20])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)C=C)CCC.[Li+].[Cl-]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([CH:20]=[CH2:24])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Temperature: 110 °C

Procedure:
Degassed mixture of (R)-2-Benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (50 mg, 0.13 mmol), tributyl(vinyl)tin (64 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (9.1 mg, 0.013 mmol) and LiCl (27.5 mg, 0.65 mmol) in toluene (1 mL) was heated at 110° C. for 18 h to give dark brownish reaction mixture. The mixture was then cooled, diluted with ethyl acetate(10 mL) and filtered through bed of celite and rinsed with more ethyl acetate(20 mL). Filtrate was concentrated and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to give (25 mg, 60%) as a faint yellow oil. MS (ESI) 319 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=O)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[CH:29][N:28]=3)=[O:17])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: Cc1cc(-c2cc(CC(=O)O)ccn2)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(CC(=O)Nc3ccc(-c4cnccn4)cn3)ccn2)ccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′-methyl-2,4′-bipyridin-4-yl)acetic acid 238-3 (46 mg, 0.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (34 mg, 0.2 mmol),1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble and the filtrate was submitted directly for reverse phase HPLC purification to give 2-(2′-methyl-2,4′-bipyridin-4-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 238 as white solid. MS m/z 383.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.30 (d, 1H), 9.11 (dd, 1H), 8.73-8.71 (m, 1H), 8.67 (d, 1H), 8.62 (d, 1H), 8.56 (d, 1H), 8.52 (dd, 1H), 8.21 (d, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.84 (dd, 1H), 7.45 (dd, 1H), 3.95 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.[N:38]1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[CH2:44][NH2:45]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:45][CH2:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][N:38]=1)=[O:25]
Reactant: NCc1cnccn1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2cnccn2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-pyrazin-2-yl-methylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:6]([CH3:16])[CH:5]=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH:22][CH3:23]>O1CCCC1>[CH3:21][N:22]([CH3:23])[S:17]([C:3]1[CH:4]=[CH:5][C:6]([CH3:16])=[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)C)c(C)c1NS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 69.7 %

Procedure:
2,4-Dimethyl-3-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.4 g) was added to tetrahydrofuran (20 ml) containing dimethylamine (0.6 g), and the resultant mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was washed with 5% hydrochloric acid and water in order, dried over anhydrous magnesium sulfate and concentrated to give an oily substance, which was purified by column chromatography with silica gel (150 ml) to give 1.0 g of N,N-dimethyl-2,4-dimethyl-3-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 62) M.P., 70.5°-72° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[N:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[N:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CCOC(=O)CN1CCN(c2ccc(Cl)nn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1

Procedure:
Compound 344 was prepared as a light yellow solid (TFA salt) from compound 4 and compound 345 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.65 (1 H, s), 9.33 (1 H, s), 8.63-8.68 (2 H, m), 8.15 (1 H, d, J=9.8 Hz), 7.94 (1 H, d, J=9.8 Hz), 5.46 (1 H, qt), 4.33 (2 H, q, J=7.1 Hz), 4.11 (2 H, s), 3.98 (4 H, br. s.), 3.46 (4 H, t, J=5.1 Hz), 2.45-2.59 (2 H, m), 2.13-2.31 (4 H, m), 1.84-1.96 (2 H, m), 1.34 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 502.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:43]1([C:49]2[C:53]([C:54](O)=[O:55])=[CH:52][O:51][N:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[C:43]1([C:49]2[C:53]([C:54]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:55])=[CH:52][O:51][N:50]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1conc1-c1ccccc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1conc1-c1ccccc1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (8 mg, 0.06 mmol), TBTU (22 mg, 0.12 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (10 μL, 0.06 mmol) in DMF (0.6 mL) was added to 3-phenylisoxazole-4-carboxylic acid (11 mg, 0.06 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C19H17N3O2: 319.1321, found 319.1326.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=O)[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:31][NH:32][CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:31][N:32]([CH2:22][C:20]1[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1)[CH3:33]
Reactant: CNC
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(CN(C)C)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (100 mg, 0.24 mmol) was dissolved in DCE (4 mL). Dimethylamine (2 M in THF, 0.142 mL, 0.28 mmol) and acetic acid (0.014 mL, 0.24 mmol) were added followed by sodium triacetoxyborohydride (80 mg, 0.38 mmol). The mixture was stirred at rt under nitrogen atmosphere for 1 hour 45 min. Water was added and the mixture was stirred for 3 minutes then the phases were separated. The water phase was extracted by DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on silica then subjected to column chromatography eluting with a gradient of methanol in DCM. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 22 mg (21%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[O:1][CH2:21][C:22]#[N:23]
Reactant: N#CCCl
Reactant: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC#N)cc(N2C(=O)c3ccccc3C2=O)c1
Yield: 88.8 %

Procedure:
59 g (233 mmol) 2-(3-hydroxy-5-methyl-phenyl)-isoindole-1,3-dione, 44 ml (700 mmol) chloroacetonitrile and 96.7 g (700 mmol) potassium carbonate were heated for 4 h to 80° C. in 300 ml dry dimethyl-formamide. It was poured onto 2 l water, filtered and 60.5 g (89%) [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-methyl-phenoxy]-acetonitrile of Fp 156°-157° C. was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6]1([CH3:16])[CH3:15])=[O:4].[NH3:17]>C(O)C>[ClH:1].[NH2:17][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6]1([CH3:16])[CH3:15])=[O:4]
Reactant: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CCl
Reactant: N
Solvent: CCO
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3-(2-chloroacetyl)-2,2-dimethyl-5-oxo-1-imidazolidineacetamide (0.48 g) in 33% ammonia solution (6 ml) was stirred at room temperature for 90 minutes. The clear solution obtained was diluted with dry ethanol (80 ml) and evaporated under reduced pressure. The residue was crystallized from water/acetone to afford 3-(2-aminoacetyl)-2,2-dimethyl-5-oxo-1-imidazolidine acetamide hydrochloride as a white powder, m.p. 292° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:1][C:2]1[N:3]=[C:4]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[N:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Clc1ccc(Br)cc1Cl
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1

Procedure:
4A was prepared from 2-chloro-4-trifluoromethyl-pyrimidine and 3,4-dichlorobromobenzene by the method reported for 1A. (Method A) 1H NMR 1H, (8.29, 8.28, d) 1H, (8.01, 8.00, 7.98, 7.97, dd) 1H, (7.92, s) 1H, (7.66,7.63, d).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[CH3:38]O>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:30]2[CH:29]=[CH:28][C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:19])([F:36])[F:37])=[CH:32][CH:31]=2)=[O:7])[C@H:9]([C:16]([O:18][CH3:38])=[O:17])[CH2:10]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: CO
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C(F)(F)F)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound was isolated as a mixture of two isomers in 86.3% purity by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:16][OH:17])=[C:6]([CH:15]=1)[CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1C=CC=CC=1>[C:18]([O:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:6]=1[CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:20])[CH3:19]
Reactant: OCc1ccc(Cl)cc1C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)OCc1ccc(Cl)cc1C(O)c1ccccc1

Procedure:
To a solution of 97 g. of the compound of Example 1 in 550 ml. of benzene, 75 ml. of acetic anhydride is added and the mixture is gently refluxed for 3 hours. The cooled solution is washed with aqueous sodium bicarbonate, then with water. The organic phase is dried over sodium sulphate and evaporated to dryness. The residue, after trituration with light petroleum, is crystallized from a mixture of ethyl ether and benzol. M.p. 86°-88° C. Yield 60 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[ClH:15].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([Cl:15])=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)C=Cc1cccnc1

Procedure:
To a suspension of 3-(pyridin-3-yl)acrylic acid (1.03 g, 6.9 mmol) in DCM (25 ml) is added oxalyl chloride (2 M in DCM, 17.25 mL, 34.5 mmol) dropwise. With stir, 100 uL of DMF is added and the mixture is stirred at RT for 30 min then heat at reflux for 3 h. The solvent is removed under vacuum and ether is added (40 mL). The suspension is stirred at RT for 30 min then filtered. The solid is washed with ether (20 mL) and dried under vacuum to give the tilted compound as a white solid. (1.22 g, 87%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([O:34][CH3:35])[CH:25]=1)([O-:23])=[O:22].O>C1COCC1>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][C:26]=3[O:34][CH3:35])(=[O:31])=[O:32])[C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCCC2)c2cc(Cl)ccc21
Reaction time: 18 h
Yield: 64.4 %

Procedure:
600 mg of sodium hydride as a 60% dispersion in oil were added in portions, with stirring, to a solution of 3 g of 5-chloro-3-cycloheptyl-1,3-dihydro-2H- benzimidazol-2-one in 30 ml of THF. 3 g of 4-nitro-2- methoxybenzenesulfonyl chloride were then added and the reaction mixture was stirred for 18 hours. The reaction mixture was then poured into a water+ ice mixture, extracted with ethyl acetate and washed with water and the organic phase was dried over sodium sulfate and concentrated to dryness. 3.5 g of the expected product were obtained by crystallization from an iso ether/AcOEt mixture (60/40; v/v). M.p.=193° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH2:14])=[O:13])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:14][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]3)=[O:13])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)c1cc(C(N)=O)oc1C(C)C
Product: CCOC(=O)c1cc2cc(NC(=O)c3cc(C(C)C)c(C(C)C)o3)ccc2[nH]1
Yield: 32.3 %

Procedure:
In the same manner as that of Example 32, 4,5-diisopropylfuran-2-carboxamide (71 mg, 0.364 mmol) and ethyl 5-bromoindole-2-carboxylate (195 mg, 0.728 mmol) were coupled. The reaction mixture was treated in a conventional manner, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (4:1), and 1% methanol-chloroform] and then recrystallized to obtain ethyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]-2-indolecarboxylate (45 mg, 32%) as colorless prisms, together with the collected starting material (39 mg, 55%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:7].[CH3:38][O:39][CH2:40][C@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[ClH:18].[ClH:18].[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:42]2[CH2:43][CH2:44][CH2:45][C@@H:41]2[CH2:40][O:39][CH3:38])[CH2:10][C@H:9]1[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCCl)C[C@H]1Cc1c[nH]c2ccccc12
Reactant: COC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H]1CCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 118.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-(4-chloro-2-butynyl)piperazine (0.25 g), (R)-2-(methoxymethyl)pyrrolidine (0.10 g), potassium carbonate (0.25 g) and potassium iodide (10 mg) in dry N,N-dimethylformamide (5 ml) was stirred for 5 hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[4-[(2R)-2-(methoxymethyl)pyrrolidino]-2-butynyl]piperazine dihydrochloride (0.19 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]=[N+:22]=[N-:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[CH:27]>C1(C)C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[CH:27]=[C:26]([C:25]([CH3:29])([CH3:28])[CH3:24])[N:23]=[N:22]2)[CH2:10][CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN=[N+]=[N-])CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2Cn2cc(C(C)(C)C)nn2)CC1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
In a sealed tube, 4-(2-Azidomethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.366 g, 1.15 mmol) was dissolved in toluene (5 mL). 3,3-dimethyl-1-butyne (0.7 mL, 5.64 mmol) was added and the mixture was heated to reflux for about 48 hours and then cooled to r.t. The mixture was concentrated under reduced pressure and purified using silica chromatography (50% ethyl acetate in hexanes) to give the title compound (0.212 g, 60%) as an oil.