Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](CC)(CC)[C:4]1[NH:12][C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[C:5]=1[CH2:13][CH2:14][OH:15])C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1.O>[NH:12]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[C:5]([CH2:13][CH2:14][OH:15])=[CH:4]1
Reactant: CC[Si](CC)(CC)c1[nH]c2cnccc2c1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c[nH]c2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
2-(2-(triethylsilyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanol (1.99 g, 7.24 mmole) was dissolved in THF (17 ml) and TBAF (7.96 ml, 7.96 mmole; 1 M solution in THF) was added at 0° C. The mixture was stirred for 1 hour at 0° C. and then heated to RT. Further TBAF (7.96 ml, 7.96 mmole, 1 M solution in THF) and H2O (5 drops) were added. After 2 days at RT 20 ml of H2O were added and the aqueous phase was extracted with DCM (3×60 ml). The organic phases were combined and washed with saturated NaCl solution (2×20 ml) and dried over MgSO4. After filtering off the drying agent the solvents were removed on a rotary evaporator and the residue was purified by column chromatography (DCM/MeOH=4:1). 2-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethanol (0.60 g, 51%) was formed as a colourless oil, which solidified over time.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C>>[CH3:14][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(CC(=O)O)c1cccc(Br)c1
Product: COC(=O)CC(N)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 3-amino-3-(3-bromo-phenyl)-propionic acid (1.0 g, 4.1 mmol) in methanol-toluene (100 mL; 1:1 solution) at room temperature is added trimethylsilyl diazomethane (2.0 M solution in hexanes, 20 mL, 40 mmol). After 30 min, excess trimethylsilyl diazomethane is quenched by addition of glacial acetic acid (5 mL). Concentration in vacuo affords of 3-amino-3-(3-bromo-phenyl)-propionic acid methyl ester (1.0 g, 95%) as a colorless liquid which solidifies upon standing.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:40])[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH2:25][CH2:26][CH2:27][N:28]2[N:32]=[N:31][CH:30]=[N:29]2)[CH:20]=[C:19]([Cl:41])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:41][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[CH2:25][CH2:26][CH2:27][N:28]1[N:32]=[N:31][CH:30]=[N:29]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2ccccc2F)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCn1ncnn1)c1ccccc1F
Yield: 87.6 %

Procedure:
A solution of {2-[3-chloro-5-(2-fluorophenyl-(3-tetrazol-2-yl-propyl)-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.048 g) in trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography, eluting with dichloromethane:methanol:ammonia (95:5:0.5 then 90:10:1 v/v/v), to give the title compound as an off-white foam (0.035 g).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[C:18](B2OC(C)(C)C(C)(C)C2)=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]=[CH:22]2.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.C(=O)(O)[O-].[Na+]>C(COC)OC.O.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>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:18]3[C:17]([F:16])=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[N:25]4)=[CH:20][CH:19]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2F)OC1(C)C
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Temperature: 75 °C

Procedure:
A stirred solution of 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (40 mg, 0.1 mmol), 8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)quinoline (52 mg, 0.15 mmol) and cesium carbonate (50 mg, 0.15 mmol) in dimethoxyethane (DME) (1.67 mL) and H2O (0.33 mL) was degassed for 10 minutes using N2. Tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) was added, and the reaction was heated to 75° C. and maintained at this temperature for 16 hours. After cooling, the reaction mixture was poured into saturated sodium bicarbonate (NaHCO3) solution (50 ml) and extracted with EtOAc (3×50ml). The combined organics were washed with brine (2×50ml), dried over magnesium sulfate (MgSO4), filtered and concentrated. The material was purified by chromatography on silica gel [eluting with 100% DCM→0.4% MeOH in DCM] resulting in the title compound as a white solid; 1H NMR (CDCl3, 400MHz) δ 2.06-1.99 (m, 1H), 2.10-2.20 (m, 1H), 2.42-2.52 (m, 2H), 2.62-2.71 (m, 2H), 4.14-4.21 (m, 1H), 7.45-7.56 (m, 3H), 7.74 (d, J=8.6 Hz, 1H), 7.79 (dd, J=6.3 Hz, 6.3 Hz, 1H), 7.87 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.21 (d, J=6.8 Hz, 2H), 8.27 (d, J=7.6 Hz, 1H); MS (ES+): m/z 411.00 (100) [MH+], HPLC: tR=3.53 min (MicromassZQ, polar—5 min).
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([OH:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]>C(Cl)Cl>[CH3:8][S:9]([O:33][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Et3N (1.50 mL, 10.8 mmol) and methanesulfonyl chloride (402 μL, 5.20 mmol) was added to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (1.15 g, 4.0 mmol) in CH2Cl2 (40 mL) held at 0° C. under nitrogen. The mixture was stirred at 0° C. for one hour, and poured into ice-water (100 g) and the water phase extracted with Et2O (50 mL). The combined organic extracts were added 0.5 M H2SO4 (35 mL), the organic phase washed with NaHCO3 (sat. aq.) (25 mL), before dried (Mg2SO4, gram). Filtration and concentration in vacuo afforded 1.24 gram of crude oil. Purification on Armen, SVP D26 column packed with 30 gram of 15-40 μm Merck silica, flow 20 mL/min, UV 210 nm and collecting 15 mL fraction, was performed using gradient elution: (starting heptane:EtOAc (100:0) and increasing during 10 min. to 10% EtOAc, then increasing 5 min. to 20% EtOAc (hold 10 min.), then increasing in 5 min. to 40% EtOAc (hold 0 min.). Fractions 6-14 afforded 1.16 g (79% yield) of the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Cl>C(O)C.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1
Reactant: Clc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1cccc(OCc2c[nH]cn2)c1Cl
Yield: 86.5 %

Procedure:
To a stirred suspension of 4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (150 mg) at r.t. in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture was heated to reflux for 6 hours, then concentrated to leave an off-white solid. This was taken up in saturated aqueous Na2CO3 and extracted with CH2Cl2/MeOH 4:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 4:1) to give 4-(2,3-dichloro-phenoxymethyl)-1H-imidazole (65 mg) as white solid. MS (ISP): 243.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 12.3 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-1H-indole-3-carboxylate (40 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aqueous NaOH (2.0 mL, 2.0 mL). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (10 mg, 11% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]([I:19])=[CH:4][N:3]=1.[CH3:20]I>C(Cl)(Cl)Cl>[I:19][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([O:1][CH3:20])=[N:3][CH:4]=1
Reactant: CI
Reactant: O=C(Nc1cc(I)cnc1O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ncc(I)cc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of benzyl (2-hydroxy-5-iodopyridin-3-yl)carbamate (16 g, 43 mmol) in CHCl3 (250 mL) was added Ag2CO3 (16.1 g, 58.4 g) and methyl iodide (27.0 mL, 434 mmol) in the dark, and the mixture stirred at RT for overnight. The solid was removed by filtration and the solvent was concentrated and purified by combi-flash (ISCO, 40g silica, UV254, 5:1 pet ether/ethyl acetate) to afford benzyl (5-iodo-2-methoxypyridin-3-yl)carbamate (8.85 g, 53% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.61 (br, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.35-7.42 (m, 5H), 7.12 (s, 1H), 5.21 (s, 2H), 3.95 (s, 3H); MS (ES) m/z 385 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:19][N:20]([CH3:32])[C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:28](=[O:27])[C:23]3[C:24](=[CH:30][CH:31]=[C:21]([N:20]([CH3:19])[CH3:32])[CH:22]=3)[C:25]2=[O:26])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(N(C)C)cc3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-dimethylaminoisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (572 mg, 2.09 mmol) and 4-dimethylaminophthalic anhydride (400 mg, 2.09 mmol) in acetic acid (20 mL). The product was obtained as a yellow solid (200 mg, 21% yield): mp, 161.5-163.50° C.; 1H NMR (DMSO-d6) δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.79 (s, 3H, CH3), 3.09 (s, 6H, CH3), 3.78-3.85 (m, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.51 (dd, J=9.7, 14.6 Hz, 1H, NCHH), 5.85 (dd, J=5.1, 9.6 Hz, AH, NCH), 6.75-6.84 (m, 2H, Ar), 7.03 (d, J=2.3 Hz, 1H, Ar), 7.10-7.16 (m, 2H, Ar), 7.61 (d, J=8.5 Hz, 1H, Ar), 13C NMR (DMSO-d6) δ 14.65, 40.40, 41.43, 48.83, 55.42, 55.89, 64.38, 105.80, 111.29, 112.43, 114.86, 116.90, 120.38, 125.11, 130.14, 134.27, 148.46, 149.38, 154.44, 168.14, 168.67; Anal Calcd for C22H26NO6S+0.2 H2O: C, 58.70; H, 5.91; N, 6.22. Found: C, 58.70; H, 5.93; N, 5.84.
Reaction SMILES: [O:1]=[S:2]1(=[O:44])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:24](=[O:42])[CH2:25][CH:26]([N:31]3C(=O)C4C(=CC=CC=4)C3=O)[C:27]([F:30])([F:29])[F:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:43])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.CN>C(O)C>[NH2:31][CH:26]([C:27]([F:28])([F:29])[F:30])[CH2:25][C:24]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:43])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:44])(=[O:1])[CH2:3][CH2:4]2)[CH:22]=1)=[O:42]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CC(N3C(=O)c4ccccc4C3=O)C(F)(F)F)c2c1
Agent: CN
Solvent: CCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CC(N)C(F)(F)F)c2c1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
To a solution of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanamide (25 mg, 0.04 mmol) in ethanol (3 mL) was added a solution of methylamine (30% in ethanol, 0.3 mL). The resulting mixture was heated at 90° C. for 2 hours. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with 50% ethyl acetate in hexanes) to afford 15 mg of the title compound as light solid (yield was 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[CH2:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:18]([C:16]1[N:17]=[C:12]([C:10](=[N:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH3:11])[CH:13]=[CH:14][CH:15]=1)[CH3:19])[CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Reactant: CCCCc1ccccc1N
Solvent: Cc1ccccc1
Product: CCCCc1ccccc1N=C(C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 (2.3 g, 0.0088 mol), 1.68 g (0.0244 mol) of 2-n-Butyl-phenylamine 12, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under the flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 5 ml of ethanol. The yield of (1-{6-[1-(2-n-butyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-(2,6-dimethyl-phenyl)-amine 11 was 2.60 g (76%) as a yellow solid. 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 166.8 (C═N), 166.1 (C═N).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](S(Cl)(=O)=O)[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.ClN1C(=[O:23])CCC1=O.C1(=O)C2C(=CC=CC=2)C=CN1>CC#N>[Cl:16][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:23])[NH:3][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=c1[nH]ccc2ccccc12
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
1,4-Dichloro-7-isoquinolinesulphonyl chloride ##STR107## A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in MeCN (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si]([N:37]=[C:38]=[O:39])(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:38]([NH2:37])=[O:39])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:23])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 2-{4-[l-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamine obtained by Example 53 (300 mg) and triethylamine (0.57 ml) in dichloromethane (10 ml) was added dropwise trimethylsilyl isocyanate (0.555 ml) at room temperature.
Reaction SMILES: F[B-](F)(F)F.[H+].N([O-])=O.[Na+].O1CCOCC1.N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C@@H:25]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:26]([N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][C:32]([O:40][CH3:41])=[C:33]([O:38][CH3:39])[CH:34]=2)[CH2:29]1)=[O:27]>[Cu-]=O.O>[C:19]1([NH:24][C@@H:25]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:26]([N:28]2[CH2:37][CH2:36][C:35]3[C:30](=[CH:31][C:32]([O:40][CH3:41])=[C:33]([O:38][CH3:39])[CH:34]=3)[CH2:29]2)=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1N)C(C)(C)C)CC2
Agent: O=[Cu-]
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1)C(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Tetrafluoroboric acid (1.5 ml) and an aqueous sodium nitrite solution (20 mg/0.2 ml, 0.29 mmol) were added, at 0° C., to a dioxane (2 ml) solution of (2S)-2-[(2aminophenyl)amino]-1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-3,3dimethylbutan-1-one (100 mg, 0.25 mmol) obtained in Example 25, and the mixture was stirred at that temperature for 30 minutes. Copper (I) oxide (75 mg, 0.52 mmol) was added to the reaction solution, and the mixture was stirred for 30 minutes. Dioxane (2 ml) and water (10 ml) were added to the mixture, and the mixture was concentrated under reduced pressure. The residue was extracted twice with chloroform (each 5 ml), and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography using hexane and ethyl acetate (2:1) as an eluent to obtain the captioned compound (68.0 mg, 70%) as a green oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([OH:31])(=[O:30])[CH2:26][CH2:27][C:28]#[CH:29]>C(NCC)C.[Cu](I)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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:29]#[C:28][CH2:27][CH2:26][C:25]([OH:31])=[O:30])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(O)CCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a mixture of the title compound of Example 5 (0.457 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added 4-pentynoic acid (0.098 g). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed. The residue is recrysallized from acetone/hexanes to yield 0.057 g of the desired product as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:11][CH3:12].C(N(CC)CC)C>C(#N)C>[CH2:11]([S:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:12]
Reactant: Fc1ccc(S)cc1F
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCSc1ccc(F)c(F)c1
Temperature: 80 °C

Procedure:
To thick-walled reaction pressure tube was added 3,4-difluorobenzenethiol (1500 mg, 10.26 mmol), iodoethane (1.095 mL, 13.34 mmol), acetonitrile (20 mL), and triethylamine (1.860 mL, 13.34 mmol). The vessel was capped and heated at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated. Methylene chloride was added and the mixture was washed with water three times. The organic layer was concentrated to provide crude 4-(ethylthio)-1,2-difluorobenzene which was used without further purification. This material was combined with 2-propanol (20 mL) and water (10 mL). To the mixture was added OXONE® (8388 mg, 13.7 mmol). After stirring at room temperature overnight, the reaction mixture was evaporated in vacuo and the residue was extracted with ethyl acetate. The ethyl acetate was washed with water three times followed by saturated aqueous sodium bicarbonate and then brine. The organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexane) to give Intermediate 8 (2 g, 99% yield) as white solid. 1H NMR (CDCl3, 500 MHz) δ 7.67-7.82 (m, 2H), 7.38 (dd, J=16.22, 9.07 Hz, 1H), 3.13 (q, J=7.70 Hz, 2H), 1.25-1.32 (m, 3H); MS (ESI) 207.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Product: O=C(O)CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
While cooling externally with a mixture of ice and common salt, 21.3 g (0.1 mol) of 4-(4-chlorophenyl)-4-oxobutanoic acid were added batchwise to 100 ml of fuming nitric acid in such a way that the temperature of the mixture did not exceed 0° C. The mixture was stirred for another 1 hour at an internal temperature of between −5 and 0° C., then stirred into 1 l of ice water, after ½ hour the precipitate was collected on a filter, thoroughly washed with water until free from acid, and the crystalline product was dried in a circulating air dryer. 23.4 g (91% of theoretical) of pale yellow crystals were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:18](OC(C)(C)C)(=[O:26])[C:19](OC(C)(C)C)=[O:20].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:19](=[O:20])[C:18]([OH:26])=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CCNc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 84 h
Yield: 47.8 %

Procedure:
To a solution of the title compound of Example C (5.41 g, 22.6 mmol) in dry THF (100 ml) was added di-tert-butyl oxalate (4.57 g, 22.6 mmol), followed by potassium tert-butoxide (5.07 g, 45.2 mmol) and the resulting dark yellow solution was stirred for 84 h at room temperature. The reaction mixture was then acidified with 1N HCl to pH=3, followed by the addition of H2O (35 ml) and the mixture was then extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and dried to give a solid which was chromatographed on silica gel eluting with 1/1/98 MeOH/HOAc/CH2Cl2 to give the title compound (3.166 g, 48%). Anal calcd for C15H16NO4F: C, 61.43; H, 5.50; N, 4.78. Found: C, 61.16; H, 5.50; N, 4.77.