Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][O:9]1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][C:20]1[N:12]2[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)OCc1nncn1-2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)OCc1nnc(Br)n1-2
Yield: 36.4 %

Procedure:
A suspension of Compound 9 prepared in Example 4-(1) (1.2 g), N-bromosuccinimide (0.675 g), and α,α'-azobis-isobutyronitrile (10 mg) in carbon tetrachloride (70 ml) is refluxed under heating for 1 hour. The insoluble materials are removed by filtration and the solvent is evaporated. The residue is treated on column chromatography (silica gel/ethyl acetate) to give the title compound (0.54 g), which is recrystallized from ethyl acetate. Yield 36.4%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][S:10]SC>CCCCCC.O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[S:10][CH3:9]
Reactant: CSSC
Reactant: Fc1cccc(Cl)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1c(F)cccc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 126.7 %

Procedure:
n-Butylithium (2.5M in hexane, 129 ml) was added to a solution of 3-fluorochlorobenzene (35 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3 hours and dimethyl disulphide (60.65 g) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was evaporated to dryness and the residue was suspended in ether and washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-chloro-6-fluorothioanisole (60 g) as a crude yellow oil containing some dimethyl disulphide, NMR (CDCl3) 2.45(s,3H), 6.95(t,1H), 7.1-7.3(m,2H).
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[CH:17]=[CH:16][C:15]([I:1])=[CH:14][C:5]=1[CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: ClI
Reactant: CCOC(=O)CNCc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CNCc1cc(I)ccc1N
Yield: 73.5 %

Procedure:
Iodine monochloride (3.24 g) was added to a stirred solution of ethyl N-(2-aminobenzyl)glycinate (4.16 g) (see U.S. Pat. No. 3,983,120) and sodium acetate (1.804 g) in acetic acid (100 cm3) at room temperature. After 1 hour volatile material was removed in vacuo and the residue was partitioned between chloroform (200 -cm3) and saturated aqueous sodium carbonate solution (50 cm3). The aqueous phase was further extracted with chloroform (2×50 cm3) and the combined organic extracts were washed with 10% aqueous sodium thiosulphate solution (50 cm3). The dried (MgSO4) organic extracts were evaporated in vacuo and the oily residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting witb chloroform. Combination and evaporation of the appropriate fractions gave a solid (4.9 g), a small portion of which was recrystallised from hexane-ethyl acetate to afford the title compound, m.p. 58°-61°.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].[Cl-].[Na+]>CN(C)C=O>[Cl:11][C:4]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:2]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: NCC(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2NCC(F)(F)F)c(F)c1
Yield: 84.1 %

Procedure:
A solution of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine (16 mg, 0.05 mmol) and 2,2,2-trifluoroethylamine (200 mg, 2.0 mmol) in 1 mL of N,N-dimethylformamide is stirred at room temperature for 16 h. A saturated sodium chloride solution is added, and the product is extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 7-chloro-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-5-amine as a white solid (16 mg, mp 155-157° C.). MS: m/z 381.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:26][C@H:25]2[CH3:39])=[O:23])=[C:6]([CH:19]=1)[CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C>[NH2:8][CH2:7][C:6]1[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][C:22]([N:24]1[CH2:29][C@H:28]([CH3:30])[N:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:26][C@H:25]1[CH3:39])=[O:23]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Reaction time: 17 h

Procedure:
To 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-isoindole-1,3-dione (0.87 g, 1.59 mmol) in ethanol (20 mL) was added 35% hydrazine (3 mL, 33.1 mmol). After 17 hours, the reaction was filtered and concentrated to a tan solid. This solid was triturated with methylene chloride and the title compound was obtained after filtration, drying over magnesium sulfate and concentrating in vacuo (0.62 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCCCCCCCO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCCCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 9-aminononanol. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.11-8.09 (dd, J=1.2 Hz, 1 H), 7.92 (s, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.71-7.67 (m, 2 H), 7.61-7.57 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H), 3.74 (s, 2 H), 3.50-3.46 (t, 2 H), 2.92-2.89 (t, 2 H), 2.46 (s, 3 H), 1.73-1.63 (m, 4 H), 1.50-1.38 (m, 10 H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:9]=2[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>FC(F)(F)C(O)=O>[C:24]1([C:8]2[C:9]3[C:14]([NH:15][CH2:16][CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[N:13][CH:12]=[N:11][C:10]=3[NH:6][C:7]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2c(-c3ccccc3)c(-c3ccccc3)c3c(NCCN4CCOCC4)ncnc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2[nH]c3ncnc(NCCN4CCOCC4)c3c2-c2ccccc2)cc1
Reaction time: 18 h

Procedure:
A solution of [7-(2,4-Dimethoxybenzyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(2-morpholin-4-ylethyl)-amine (54 mg, 0.1 mmol) in 2 mL of trifluoroacetic acid was heated to reflux. After 18 hours, the solution was concentrated to dryness and purified by preparative HPLC (C8 column, water, acetonitrile, 0.1% TFA) to give the title compound. Mass Spectrum (ESI) m/e=400 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:33]>CO>[CH2:31]([O:30][CH2:29][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:33])[C:11]=2[N:12]=1)[CH3:32]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(-c2ccccc2)no1
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCc1cc(-c2ccccc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (2.22 g, 4.97 mmol) in a solution of 7 M ammonia in methanol (25 mL) was heated at 150° C. for 17 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting solid was triturated with 1 M aqueous sodium hydroxide and isolated by filtration. The crude product was purified by flash chromatography (silica gel, gradient elution from 10% to 20% CMA in chloroform). The appropriate fractions were combined and concentrated to yield a solid that was triturated with hot diethyl ether and 9:1 dichloromethane/methanol (10 mL). The final material was dried at 80° C. under vacuum to yield 2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (954 mg) as a white powder, mp 171.0-172.0° C.
Reaction SMILES: [CH2:1]=O.[NH2:3][O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1>CO>[Si:12]([O:11][CH2:10][C@H:9]1[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6][C@@H:5]1[O:4][N:3]=[CH2:1])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14]
Reactant: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: C=O
Solvent: CO
Product: C=NO[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 6 h
Yield: 95 %

Procedure:
A solution of HCHO (20% aqueous, 1 ml) was added dropwise to a stirred solution of 3'-O-amino-5'-O-(t-butyldimethylsilyl)thymidine (3, 7.42 g, 20 mmol) in dry MeOH (400 ml) at room temperature. After 6 h, another portion of HCHO (20% aqueous, 1.5 ml) was added and stirring continued for 16 h. The resulting solution was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give compound 10 (7.25 g, 95%) as clear foam. 1H NMR (CDCl3) δ 0.1 [s, 3, (CH3)2 ], 0.9 [s, 9, (CH3)3 ], 1.9 (s, 3, CH3), 2.25-2.72 (m, 2, 2' CH2), 3.85-4.15 (2m, 3, 5' CH2, 4' H), 4.85 (m, 1, 3'H), 6.25 (dd, 1, 1'H), 6.5 and 6.95 (2d, 2, N=CH2), 7.43 (s, 1, (6H), 9.2 (br s, 1 NH).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH:8]=[CH:7]2)(=O)[CH3:2].[C:27](#[N:31])[CH2:28][C:29]#[N:30]>N1C=CC=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1]([CH3:2])=[C:28]([C:27]#[N:31])[C:29]#[N:30])[CH:5]=3)[CH:10]=2)[CH2:19][CH2:18]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Reactant: N#CCC#N
Solvent: c1ccncc1
Product: CC(=C(C#N)C#N)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Reaction time: 5.5 h
Yield: 77 %

Procedure:
tert-Butyl 4-(6-acetyl-2-naphthyl)-1-piperazinecarboxylate (177 mg, 0.5 mmol), prepared as described in Example 1(d), was heated with 40 mg (0.6 mmol) of malononitrile in 4 mL pyridine at 105-110° C. After 5.5 hours, an additional 24 mg of malononitrile was added, and heating was continued for a total of 12 hours and 40 minutes. The mixture was cooled and evaporated in vacuo. Polar components of the mixture were removed by column chromatography (70-230 mesh silica, φ20×120 mm, chloroform), and the product, tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthy]-1-piperazinecarboxylate, was finally purified by radial chromatography (silica, 2 mm, chloroform). 155 mg (77%) of tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl]-1-piperazinecarboxylate were obtained, which, after recrystallization from dichloromethane-petroleum ether mixture, melted at 169-171° C. Anal. Calculated for C24H26N4O2: C, 71.62; H, 6.51; N, 13.92. Found: C, 71.62; H, 6.66; N, 13.87. 1H NMR: δ1.50 (s, 9H, —C(CH3)3), 2.72 (s, 3H, CH3), 3.34 and 3.64 (t, J=5.1 Hz, 8H, piperazine), 7.09 (d, 1H, 5-H), 7.33 (dd, 1H 7-H), 7.58 (dd, 1H, 3-H), 7.74(d, 1H, 4-H), 7.81 (d, 1H, 8-H), 8.02 (d, 1H, 1-H); J5,7=2 Hz, J7,8=9.1 Hz, J1,3=2 Hz, J3,4=9.1 Hz.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C1COCC1>CO.[OH-].[Na+].[NH4+].[Cl-]>[O:16]([CH2:15][CH2:14][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=[CH:8]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc2c1ccn2CCOc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c1ccn2CCOc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2-Phenoxy-ethyl)-1H-indole-4-carboxylic acid methyl ester (185 mg, 0.626 mmol) is suspended in a mixture of MeOH (3 ml) and 2 M NaOH (2 ml). The suspension is stirred at room temperature for 2 hours, THF (1 ml) is added and the reaction is heated at 60° C. for 1 hour. The reaction is allowed to cool to room temperature and diluted with sat. NH4Cl solution (10 ml), extracted with EtOAc (10 ml×3), dried over MgSO4, and concentrated in vacuo to give the title compound; [M+H]+ 282
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(O)(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH3:19])[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: Cc1ccc([C@H](C)NC(=O)C2COCCN2c2nc(Cl)ncc2Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1ccc([C@H](C)N2C(=O)C3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
To an oven dried vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N-((S)-1-p-tolylethyl)morpholine-3-carboxamide (PREPARATION x32, 588 mg, 1.337 mmol), potassium phosphate tribasic (284 mg, 1.337 mmol), Xantphos (58.0 mg, 0.100 mmol) and palladium(II) acetate (15.01 mg, 0.067 mmol) in dioxane (15 mL) and tert-butanol (3 mL). The reaction mixture was degassed for 5 minutes with N2. The vial was then sealed and heated to 105° C. and the contents were stirred for 18 hours to give a brown suspension. The reaction mixture was subsequently diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×5 mL and brine (3×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetatehexane gradient to give two diastereomers whose absolute configuration was not assigned (Diastereomer 1, higher Rf, 97 mg; Diastereomer 2, lower Rf, 91 mg; 39% overall). Diastereomer 1: 1H NMR (400 MHz, DMSO-d6) δ 1.69 (d, J=7.33 Hz, 3 H), 2.29 (s, 3 H), 2.89-3.04 (m, 1 H), 3.46-3.67 (m, 2 H), 3.89-4.01 (m, 1 H), 4.13-4.27 (m, 2 H), 4.50-4.63 (m, 1 H), 6.16-6.30 (m, 1 H), 7.13-7.29 (m, 4 H), 7.29-7.38 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O2, 359.12; found 359.3. Diastereomer 2: 1H NMR (400 MHz, DMSO-d6) δ 1.75 (d, J=7.07 Hz, 3 H), 2.28 (s, 3 H), 2.90-3.04 (m, 1 H), 3.51-3.62 (m, 1 H), 3.64-3.75 (m, 1 H), 3.89-3.98 (m, 1 H), 4.16-4.26 (m, 2 H), 4.43-4.51 (m, 1 H), 6.06-6.17 (m, 1 H), 7.18 (d, J=2.53 Hz, 4H), 7.47 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O, 359.12; found 359.3.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].C[N:25](C=O)C.C1(P(ON)(C2C=CC=CC=2)=O)C=CC=CC=1>CCOC(C)=O>[NH2:25][N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: O=c1[nH]nc(-c2ccccc2)c2ccccc12
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Product: Nn1nc(-c2ccccc2)c2ccccc2c1=O
Reaction time: 0.75 h
Yield: 95 %

Procedure:
A mixture of 4-phenylphthalazin-1(2H)-one (Aldrich) (500 mg, 2.25 mmol) and KOtBu (3.37 mL, 3.37 mmol) was stirred for 45 minutes, diluted with DMF for solubility, and Example 17A (787 mg, 3.37 mmol) was added and stirred for 3 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give 509 mg (95%) of the title compound. MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]1[C:15]([O:17]C)=[O:16].[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)ccc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 1-methyl-5-benzoylpyrrole-2-carboxylate (0.78 g.) was heated on a steam bath for 1 hour with 40 ml. of 1 N sodium hydroxide and 20 ml. of methanol. The reaction mixture was cooled to room temperature, extracted with ether, made acid with conc. hydrochloric acid and 1-methyl-5-benzoylpyrrole-2-carboxylic acid recovered by filtration (0.47 g., m.p. 178°-181° C.). Recrystallization from acetone/hexane afforded product for analysis (0.34 g., m.p. 178°-180° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.IC1C=CC=CC=1O.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:42]1[CH2:45][CH:44]([NH:46][C:47](=[O:64])[CH2:48][NH:49][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([C:60]([F:63])([F:62])[F:61])[CH:58]=3)[N:53]=[CH:52][N:51]=2)[CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH:11]([N:42]2[CH2:43][CH:44]([NH:46][C:47](=[O:64])[CH2:48][NH:49][C:50]3[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:60]([F:61])([F:63])[F:62])[CH:58]=4)[N:53]=[CH:52][N:51]=3)[CH2:45]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC(c2ccccc2O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Oc1ccccc1I
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccccc3O)CC2)C1

Procedure:
Reaction of 4-(2-hydroxyphenyl)cyclohexanone (prepared by the reaction of 2-iodophenol with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=O>C(O)C>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(N)=S)cc1
Solvent: CCO
Product: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 91.7 %

Procedure:
To a solution of the compound (209 mg, 1.0 mmol) obtained in Example 178a in ethanol (4 mL) was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.0 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with diluted aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (346 mg, 92%) as a colorless oil.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH:17]1([S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:2]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:21]=3[F:20])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:18]1
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1ccc(F)cc1F
Product: CCOC(=O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 150 °C

Procedure:
Ethyl 2-bromo-2-(4-cyclopropylsulfonylphenyl)acetate (0.8 g, 2.30 mmol) [obtained as described in WO2009/047798 A2; Example A1] and 2,4-difluoroaniline (3.0 mL) mixed together and heated at 150° C. in a seal tube for 12 hrs. Reaction mixture was cooled to rt and purified by column chromatography using 20% ethyl acetate in hexane as eluent to provide ethyl 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetate (0.65 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(N)nc1
Yield: 97 %

Procedure:
A solution of 6-aminonicotinic acid (3.0 g, 19 mmol) in HCl/MeOH (2M, 100 mL) was heated at reflux overnight. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with aqueous Na2CO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness to give 6-aminonicotinic acid methyl ester as a white solid (2.8 g, 97%), which was directly used in the next step without further purification. 1H NMR (300 MHz, d-DMSO) δ 8.48 (d, J=1.5 Hz, 1 H), 7.79 (dd, J=1.8, 6.6 Hz, 1H), 6.81 (brs, 2H), 6.42 (d, J=6.6 Hz, 1H), 3.73 (s, 3H).