Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:28])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:30][OH:31])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(CC(=O)c2ccncc2)c2c[nH]c3ccccc23)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)c1ccc(C(CC(=NO)c2ccncc2)c2c[nH]c3ccccc23)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(1H-indol-3-yl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.8:1) as a yellow foam, MS (ESI+): m/z=385.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[Li+].[CH3:21]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[CH3:21]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g, 4.0 mmol) in THF (20 ml) was cooled to −78° C. under nitrogen. A solution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) was added over 5 minutes, then after a further 20 minutes, iodomethane (0.63 ml, 10.1 mmol) was added. After 4 hours the reaction was quenched by the addition of saturated ammonium chloride solution and allowed to warm to room temperature then concentrated in vacuo to remove organic solvents. The mixture was diluted with ethyl acetate/petrol 1:4 and washed with saturated ammonium chloride solution then brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with an ethyl acetate/petrol gradient (1% to 2%), to afford the title compound as a colourless oil (210 mg, 17%); LCMS (PS-B3) Rt 4.01 min, No ionisation. 1H NMR (CDCl3) δ 1.88 (3H, s), 3.73 (3H, 5), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:31])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:32]1([C:35](Cl)=[O:36])CC1.CO.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:31])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:36])[CH3:32]
Reactant: O=C(Cl)C1CC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1)c1ncc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(C)c3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28124.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(trifluoromethyl)benzamide (268 mg, 604 μmol) in pyridine (5 mL) were added N,N-dimethylpyridine-4-amine (23.9 mg, 196 μmol) and cyclopropanecarbonyl chloride (200 μL, 2.20 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction solution were added methanol (10 mL) and 2N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 more hr. The reaction solution was concentrated under reduced pressure, and diluted with ethyl acetate (100 mL) and tetrahydrofuran (10 mL). The diluted solution was washed with water (50 mL), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from ethyl acetate and tetrahydrofuran to give the title compound (compound of Example D2) (301 mg, 97%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1nc(Cl)ccc1N

Procedure:
The title compound was prepared in analogy to the procedure described in Step 85.2 using 6-chloro-N-methyl-3-nitropyridin-2-amine (Step 102.1) at RT for 23 hr. The crude material was purified by silica gel column chromatography (25% EtOAc/hexane) to afford a purple solid. tR: 0.64 min (LC-MS 2); ESI-MS: 158 [M+H]+ (LC-MS 2); Rf=0.12 (25% EtOAc/Hexane).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCNC
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, a solution of N-methyl-3-buten-1-amine (6.86 g, 80.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., and triethylamine (17.93 g, 177.2 mmol) and 4-(N,N-dimethylamino)pyridine (207 mg) were added. A solution of benzoyl chloride (11.89 g, 84.6 mmol) in dichloromethane (60 mL) was added dropwise via addition funnel over 1 h at 0-5° C. The resulting turbid mixture was stirred 3 h at 0° C. The mixture was then washed in succession with 1 M HCl solution (3×75 mL), 5% NaHCO3 solution (3×100 mL), and water (100 mL). The organic phase was dried (Na2SO4), filtered, and concentrated on a rotary evaporator to a yellow oil (12.66 g). Vacuum distillation using a 6 in. Vigreaux column and a short path distillation apparatus afforded 8.58 g (56.3%) of a colorless oil, bp 100-103° C. at 0.1 mm Hg.
Reaction SMILES: C1(NC=CP(=O)(OCC)[O:11][CH2:12][CH3:13])CCCCC1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([CH:33]=O)=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:23][CH:22]=1.O.O.C(O)(=O)C(O)=O>O1CCCC1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32](/[CH:33]=[CH:13]/[CH:12]=[O:11])=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:25][CH:26]=1
Reactant: CCOP(=O)(C=CNC1CCCCC1)OCC
Reactant: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1C=O
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
A solution of 11 g (42 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 60 ml of tetrahydrofuran are added dropwise under argon in the course of 10 min to a suspension of 2.52 g (84 mmol) of 80% strength sodium hydride in 60 ml of anhydrous tetrahydrofuran. 9.9 g (35 mmol) of the compound from Example VIII dissolved in 100 ml of tetrahydrofuran are added dropwise at reflux. The mixture is allowed to boil under reflux for 90 min and is cooled, treated with water and extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and concentrated in vacuo. The residue is dissolved in 300 ml of toluene and heated under reflux for 1 h with 22.9 g (182 mmol) of oxalic acid dihydrate in 350 ml of water. The mixture is cooled, the phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue is dissolved in dichloromethane and filtered through 400 g of silica gel 230-400 mesh in a glass suction filter. The mixture is eluted without sucking dry using petroleum ether/ethyl acetate 1:1, the eluate is concentrated in vacuo and the residue is stirred thoroughly in ether.
Reaction SMILES: CO[C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].FC(F)(F)C1C=C(C=CC=1OC)[C:21](O)=[O:22]>>[CH3:21][O:22][C:8]1[CH:9]=[CH:10][C:11]([C:12]([F:13])([F:14])[F:15])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1c(C(=O)O)cccc1C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1C(=O)O

Procedure:
In a similar manner are prepared 2-methoxy-3-trifluoromethylbenzoic acid and 3-trifluoromethyl-4-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH3:14])[C:4]=1[C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH3:14])[C:4]=1[C:15]([Cl:21])=[O:17]
Reactant: COc1cc2ccccc2c(OC)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: COc1cc2ccccc2c(OC)c1C(=O)Cl

Procedure:
The product is prepared from 9.28 g. (40 mmoles) of 1,3-dimethoxy-2-naphthoic acid and 10.15 g. (80 mmoles) of oxalyl chloride by the process of Step 3 of Example 1.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:8]=1)C.[OH-].[Na+].Cl>>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:23])=[O:3])[N:12]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1
Yield: 77.2 %

Procedure:
[4-Chloro-6-(p-chlorobenzylamino)-2-pyrimidinylthio]acetic acid ethyl ester (1.4 g) was heated for 5 minutes with 30 ml. of 30% sodium hydroxide solution on a hot plate. The reaction mixture was then cooled and acidified with concentrated hydrochloric acid solution. The resulting precipitate was removed by filtration, washed with water and recrystallized from ethanol to afford 1.0 g of product, mp. 211°-213°C., decomp.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>CCO.C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
A cooled (0° C.) suspension of 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile (24.2 g, 100 mmol) in EtOH (150 ml) and THF (150 ml) was treated with SnCl22H2O (67.7 g, 300 mmol) and the mixture was stirred to ambient temperature over 12 h. The solvent was removed in vacuo and the residue treated with ice-cold aqueous 2 N NaOH solution (750 ml). The resulting slurry was stirred for 60 min then extracted with CH2Cl2 (2×400 ml). The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated to give a red solid. Crystallisation from toluene gave 5′-amino-2′-fluorobiphenyl-2-carbonitrile as a cream-coloured solid (16 g, 75%): δH (400 MHz, CDCl3 ) 3.65 (2H, br), 6.67-6.73 (2H, m), 7.00 (1H, t, J 9), 7.44-7.49 (2H, m), 7.64 (1H, td, J 9 and 2), 7.75 (1H, dd, J 8 and 2); m/z (ES+) 213 (100%, [MH]+).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[OH:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30]2)=[CH:25][CH:24]=1>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30]3)=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 7-hydroxyflavone in a manner analogous to that described for Example 24, Step B. MS(ES) for C30H26O6[M+H]+:483.2.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:10][N:9]([C:11](=[O:32])[CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][C:15]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]3=[O:31])[CH2:8][C@@H:7]1[CH2:6][CH2:5][CH2:4][N:3]2C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@@:2]12[CH2:10][N:9]([C:11](=[O:32])[CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][C:15]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]3=[O:31])[CH2:8][C@@H:7]1[CH2:6][CH2:5][CH2:4][NH:3]2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CN(C(=O)CN3CCCC(c4ccccc4)(c4ccccc4)C3=O)C[C@]21C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]12CN(C(=O)CN3CCCC(c4ccccc4)(c4ccccc4)C3=O)C[C@@H]1CCCN2

Procedure:
The product from Example 88A was dissolved in methylene chloride and reacted with trifluoroacetic acid at ambient temperature for 1 hour. The reaction mixture was concentrated to yield the trifluoroacetic salt of the title compound. m/z 418 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[C:27](O)(=[O:30])[CH2:28][OH:29]>>[OH:30][CH2:27][C:28]([N:1]1[CH2:2][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:4]1)=[O:29]
Reactant: O=C(O)CO
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(C(=O)CO)C3)ccc1OCC2

Procedure:
Following the procedure for 116, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with glycolic acid to give 150 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.87 (d, J=2.09 Hz, 1H); 7.28-7.21 (m, 1H); 7.24-7.19 (m, 1H); 6.87 (s, 1H); 5.68-5.59 (m, 1H); 4.60-4.48 (m, 4H); 4.20 (dd, J=9.89, 6.11 Hz, 1H); 4.16-4.07 (m, 1H); 4.05 (d, J=3.28 Hz, 2H); 4.03-3.96 (m, 1H); 3.18 (t, J=5.91 Hz, 2H); 1.58 (d, J=6.62 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=8.95 min, M+H+=409
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([N:11]([CH2:33][CH3:34])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:23]([CH3:24])=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=3)[NH:21][N:20]=2)=[O:18])[CH2:13]1)[CH3:10]>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]#[C:31][C:27]2[CH:26]=[C:25]([C:22]3[NH:21][N:20]=[C:19]([C:17]([N:14]4[CH2:15][CH2:16][CH:12]([N:11]([CH2:33][CH3:34])[CH2:9][CH3:10])[CH2:13]4)=[O:18])[C:23]=3[CH3:24])[CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Reactant: Clc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4cccc(Cl)c4)c3)c2C)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
A solution of 0.086 g (0.36 mmol) of 1-chloro-3-iodobenzene in 1.5 ml piperidine was degassed (argon) and treated with 17 mg (0.01 mmol) Pd(PPh3)4 and 3 mg (0.01 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min and then slowly (60 min) treated with 0.105 g (0.30 mmol) of (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone in 1.55 ml piperidine. After 30 min the bath was slowly (30 min) heated to 80° C. The reaction mixture was stirred at this temperature for 1 h and then partitioned between chilled water sat. KHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 97.5:2.5 to 95:5) yielded 0.090 g (65%) of the title compound as light yellow foam. MS: 461.1 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][O:16][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCO)c3ccccc32)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc32)c1
Yield: 62.8 %

Procedure:
A solution of 3-(2-Hydroxy-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester (0.41 g, 1.16 mmol), TsCl (0.23 g, 1.22 mmol), triethylamine (0.2 mL, 1.4 mmol) in dichloromethane (10 mL) was stirred at room temperature for 48 h. The solvent was removed under reduced pressure and the residue dissolved in EtOAc. The organic solution was washed with 10% KHSO4, dried over Na2SO4, and purified by silica gel chromatography (hexanes/EtOAc, 1/2) to give 0.37 g of 1-(3-methoxycarbonyl-phenyl)-3-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-indole-2-carboxylic acid methyl ester as a yellow oil (63% yield): 1H NMR (CDCl3, 300 MHz) δ 2.37 (s, 3H), 3.52 (t, J=7.24 Hz, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 4.34 (t, J=7.06, 2H), 7.00 (d, J=8.24 Hz, 1H), 7.17–7.31(m, 4H), 7.44 (d, J=8.02 Hz, 1H), 7.56–7.67(m, 4H), 7.93 (t, J=1.72 Hz, 1H); 8.13 (dt, J=7.82, 1.34 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>CCCCCCC>[CH2:7]([N:9]([CH2:10][CH3:11])[C:2](=[O:3])[O:4][CH2:5][Cl:6])[CH3:8]
Reactant: CCNCC
Reactant: O=C(Cl)OCCl
Solvent: CCCCCCC
Product: CCN(CC)C(=O)OCCl
Yield: 911.2 %

Procedure:
To a stirred solution of chloromethyl chloroformate (7.09 g, 5.5 mmol) in heptane (100 mL) at −20° C. add a solution of diethylamine (10.4 g, 14.7 mmol) in heptane (50 mL), dropwise. Maintain the internal temperature between −15° C. to −5° C. and after 1 h quench the reaction with water. Separate the layers and wash the organic phase with 10% aqueous HCl, water and NaHCO3 solution. Dry the organic layer (MgSO4), filter and concentrate under reduced pressure to obtain 8.3 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([CH3:29])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:27]#[N:28])[C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:13]=2)=[O:8].[OH-].[Na+].Cl>CO>[C:27]([C:11]1[C:12]2[C:17](=[CH:16][C:15]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:14][CH:13]=2)[C:18]([OH:19])=[C:9]([C:7]([NH:6][CH2:5][C:4]([CH3:30])([CH3:29])[C:3]([OH:31])=[O:2])=[O:8])[N:10]=1)#[N:28]
Reactant: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid methyl ester (38 mg, 0.091 mmol), 2 M NaOH (2 mL) and MeOH (2 mL) was stirred at r.t. for 3 h. 1 M HCl was added until pH was ˜2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound. MS: (−) m/z 404.11 (M−1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)CCOC([NH:26][C@@H:27]1[CH2:29][C@H:28]1[S:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)=O>O1CCCC1.C(#N)C>[NH2:26][C@@H:27]1[CH2:29][C@H:28]1[S:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H]1Sc1nc2ccccc2cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: N[C@@H]1C[C@H]1Sc1nc2ccccc2cc1-c1ccccc1
Reaction time: 5 h

Procedure:
A 1 M-solution of tetra-n-butylammonium fluoride in tetrahydrofuran (12 ml.) was added to a solution of 2-{trans-2-[2-(trimethylsilyl)ethoxycarbonylamino]-cyclopropylthio}-3-phenylquinoline (3.5 g.) in dry acetonitrile (35 ml.), and the mixture was stirred at 50° under argon for 5 hr. The mixture was cooled, the solvent was evaporated, and the residual oil was partitioned between ethyl acetate (70 ml.) and water (35 ml.). The mixture was separated and the organic phase was washed with water (2×30 ml.) and dried (Na2SO4). The solvent was evaporated and the residual brown oil (2.7 g.) was chromatographed on basic alumina (180 gm., Brockmann, Grade III) eluted with 30% v/v chloroform in petroleum ether to give 2-(trans-2-aminocyclopropylthio)-3-phenylquinoline as a pale yellow oil, which gave a hydrochloride of m.p. 140°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([F:26])[CH:12]=2)[CH2:6][S:5](=[O:28])(=[O:27])[CH2:4]1.[C:29]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([F:26])[CH:12]=2)[CH2:6][S:5](=[O:27])(=[O:28])[CH2:4]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c2)[C@@H]1O
Reactant: CC(C)(C)c1cccc(C=O)c1
Agent: Cl
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c3)[C@@H]2O)c1

Procedure:
The title compound was prepared in analogous manner as described for example 1h) from (3R,4S,5S)-3-Amino-5-[4-nitro-3-fluoro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol hydrochloride salt (1.26 g, 2.78 mmol) and 3-tert-butyl benz-aldehyde (0.361 g, 2.26 mmol); ESIMS [M+H]+=563, UPLC RtD=1.576 min, 1H NMR (600 MHz, DMSO-d6): δ 7.35 (s, 1H), 7.27-7.21 (m, 2H), 7.15 (m, 2H), 7.10 (d, 1H), 5.32 (d, 1H), 5.01 (q, 2H), 3.81 (m, 1H), 3.63 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.10 (m, 1H), 3.05-2.98 (m, 2H), 2.80 (m, 2H), 2.63 (m, 1H), 2.41 (s, 1H), 2.14 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][CH:34]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 576.9 (M+H)+.