Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(C(=O)Cl)cc1

Procedure:
First, 1.2 g (6.1 mmol) of 4-pentyl benzoic acid was mixed with 1.1 g (9.1 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 2 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 4-pentylbenzoyl chloride.
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.C1C=CN=CC=1.[FH:30]>[Hg]=O>[F:30][C@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: F
Agent: O=[Hg]
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](F)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Yield: 50 %

Procedure:
6β-Bromo-1,2β-methylenandrost-4-ene-3,17-dione (0.72 g, 1.9 mmol) is added to a vigorously stirred suspension of yellow mercury (II) oxide (0.83 g, 3.8 mmol) in pyridinium poly (hydrogen fluoride) (7 ml) at room temperature. After 3 hours the mixture is poured onto crushed ice and extracted with dichloromethane. The combined extracts are washed with water, dried and evaporated in vacuo. The residue is chromatographed twice on silica gel using benzene/ethyl ether as eluant to yield pure 6β-fluoro-1,2β-methylenandrost-4-ene-3,17-dione (0.300 g, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH2:41].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.C(OCC)(=O)C.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][C:36]([NH:41][NH:40][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)NNC(=O)OC(C)(C)C)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.77 g), tert-butyl hydrazinecarboxylate (0.23 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g), 1-hydroxybenzotriazole (0.24 g) and N,N-dimethylformaldehyde (8 mL) was stirred at room temperature for 12 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.69 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[S:23][C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=1.[N-:24]=[N+:25]=[N-:26].[Na+].O>CS(C)=O>[S:23]1[C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=[C:10]1[C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:26][NH:25][N:24]=1
Reactant: Clc1ccccc1C#Cc1cc2c(s1)-c1cnccc1OCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccccc1-c1n[nH]nc1-c1cc2c(s1)-c1cnccc1OCC2
Temperature: 90 °C
Yield: 18.4 %

Procedure:
A mixture of 68 mg (0.2 mmol) of 2-((2-chlorophenyl)ethynyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine and 52 mg (0.8 mmol) of sodium azide in 4 ml of dimethylsulfoxide was heated at 90° C. for 36 hours. Water (20 ml) was added to the mixture and extracted 6 times with 10 ml of ethyl acetate. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuum and the crude product was recrystallized from ethyl acetate to give 324 (14 mg, 18%). 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.24 (d, J=5.5, 1H), 7.73-7.46 (m, 4H), 6.98 (d, J=5.5, 1H), 6.77 (s, 1H), 4.31 (t, J=4.7, 2H), 3.08 (t, J=4.7, 2H). MS: (ESI+) 381.1
Reaction SMILES: [NH2:1][C:2]1[C:7]([SH:8])=[N:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11](OC(=O)C)(=O)[CH3:12]>C1(C)C(C)=CC=CC=1>[Cl:10][C:4]1[N:3]=[C:2]2[N:1]=[C:11]([CH3:12])[S:8][C:7]2=[N:6][C:5]=1[Cl:9]
Reactant: Nc1nc(Cl)c(Cl)nc1S
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1nc2nc(Cl)c(Cl)nc2s1
Temperature: 110 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
A mixture of 9.8 g. (0.05 mol.) of 2-amino-5,6-dichloro-3-mercaptopyrazine and 5.1 g. (0.05 mol.) of acetic anhydride in 100 ml. of xylene was heated at 110° C. for 1 hour. The reaction mixture was cooled, another 5.1 g. of acetic anhydride was added and heating at 110° C. was continued for 15 hours. The reaction mixture was concentrated under reduced pressure to give a dark oil, which solidified under isopropanol-hexane while cooling in ice. The dark solid was purified by sublimation to give 7 g. (64% yield) of white solid, m.p. 58°-60° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]([CH3:46])[N:43]=[CH:44][CH:45]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]([CH3:46])[N:43]=[CH:44][CH:45]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: Cn1nccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K7) (150 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (114 mg).
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:34]([C:35](=O)[C:36]#[CH:37])=[C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][N:24]3[N:23]=2)=[CH:18][CH:17]=1>C(O)C.O>[CH:2]1([NH:7][C:8]2[N:10]=[C:35]([C:34]3[C:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)=[N:23][N:24]4[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=34)[CH:36]=[CH:37][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5 mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M in ethanol, 14 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. To this mixture was added 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0° C. for 30 minutes, followed by room temperature for 15 hours. The reaction mixture was diluted with water (400 mL). The solid precipitate was collected on a filter to provide N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (4.48 g, 98%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1 H), 8.51 (d, 1 H), 8.11 (d, 1 H), 7.64 (dd, 2 H), 7.44 (dd, 1 H), 7.17 (t, 2 H), 6.33 (d, 1 H), 5.17 (d, 1 H), 4.34 (m, 1 H), 2.15-2.06 (m, 2 H), 1.84-1.52 (m, 6 H); 19F NMR (CDCl3): δ −62.70, −112.25 MS m/z 442 (M+1); mp 155-156° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:34][CH:35]=3)=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C1COCC1.[Pt](=O)=O>[O:39]1[CH2:40][CH2:41][N:36]([C:33]2[N:34]=[CH:35][C:30]([C:27]3[CH:26]=[CH:25][C:24]([N:11]4[CH:12]([C:15]5[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=5)[CH2:13][CH2:14][CH:10]4[C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Charged a 100-mL round bottom flask with the product of Example 108A (174.7 mg, 0.317 mmol), partially dissolved in THF (12.50 mL) and absolute EtOH (2.50 mL), evacuated on house vacuum and filled flask with nitrogen, then added platinum (IV) oxide (14.38 mg, 0.063 mmol), evacuated flask on house vacuum and filled with hydrogen from a balloon, repeated evacuation/filling cycle 3 times, and stirred heterogeneous reaction mixture vigorously under hydrogen (1 atm). After 2 hr, charged reaction with additional platinum (IV) oxide (14.38 mg, 0.063 mmol) and continued to vigorously stir under hydrogen at 25° C. After 5 hr, added additional platinum (IV) oxide (14.38 mg, 0.063 mmol). The reaction mixture was then vacuum filtered through a bed of Celite 545 in a Büchner funnel, the filter pad was washed with CHCl3 (100 mL) and hot CHCl3 (2×50 mL), and the filtrate concentrated by rotary evaporation to give the title compound as a yellow solid (101 mg, 65%) as a mixture of stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.71-1.87 (m, 2H), 2.24-2.31 (m, 1H), 3.37-3.45 (m, 4H), 3.64-3.74 (m, 4H), 4.57 (t, J=4.99 Hz, 2H), 4.95 (s, 4H), 6.42-6.53 (m, 3H), 6.57 (d, J=8.35 Hz, 4H), 6.76-6.89 (m, 2H), 7.15 (d, J=8.35 Hz, 4H), 7.26 (d, J=8.78 Hz, 2H), 7.68 (dd, J=8.84, 2.44 Hz, 1H), 8.29 (d, J=2.39 Hz, 1H); MS (ESI+) m/z 492 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])[CH:6]=[CH:5]2.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:26](B(O)O)=[C:27]2[CH2:32][CH2:31][CH2:30][N:28]2[N:29]=1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:16][N:15]([CH3:17])[CH2:14][C:13]([NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:26]3[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[N:29][N:28]4[CH2:30][CH2:31][CH2:32][C:27]=34)[CH:3]=2)[N:8]=1)=[O:18]
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: CN(C)CC(=O)Nc1ccc2cc(Br)cnc2n1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1ccc2cc(-c3c(-c4ccccn4)nn4c3CCC4)cnc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.5 %

Procedure:
Add N-(6-bromo-[1,8]naphthyridin-2-yl)-2-dimethylamino-acetamide (148 mg, 0.48 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 100 mg, 0.44 mmol), potassium fluoride (84 mg, 1.45 mmol), and THF (1.5 mL) to a flask under nitrogen. Purge the system with nitrogen for 10 min and add tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.044 mmol) and tri-tert-butylphosphonium tetrafluoroborate (Strem; 25 mg, 0.088 mmol). Purge the system with nitrogen for 2 min then stir for 16 h at room temperature. Add additional tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.054 mmol) and tri-tert-butylphosphonium tetrafluoroborate (40 mg, 0.138 mmol) and heat the reaction to 65° C. for 9 h. Filter the reaction through Celite®, rinse with chloroform/methanol, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Collect the pure fractions from the HPLC, concentrate in vacuo, take up the residue in methanol, and treat with MP-carbonate beads. Filter, concentrate in vacuo, and triturate with hexanes to provide the title compound (10 mg, 5%) as a tan solid. MS ESI+ m/e 414 (M+1). 1H NMR (CDCl3) δ 10.21 (m, 1H), 8.93 (m, 1H), 8.48 (m, 2H), 8.09 (m, 2H), 7.68 (m, 2H), 7.20 (m, 1H), 4.27 (m, 2H), 3.17 (m, 4H), 2.72 (m, 2H), 2.41 (s, 6H). HPLC: 95.1%, Rt=11.21 min. TLC (SiO2): Rf0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane)
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH3:20])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19].C(N(C(C)C)C(C)C)C.F[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH3:3][C:4]1([CH3:20])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]2[CH2:18][CH2:17][N:16]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:15][CH2:14]2)[C:5]1=[O:19]
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2ncccc21
Reactant: Fc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N(C2CCN(c3ccccn3)CC2)c2ncccc21
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
A mixture of 3,3-dimethyl-1-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one dihydrochloride (intermediate 57, 0.1167 g, 0.367 mmol), N-ethyl-N-isopropylpropan-2-amine (0.192 ml, 1.100 mmol), and 2-fluoropyridine (0.189 ml, 2.200 mmol) was stirred at 150° C. for 90 minutes. The mixture was filtered and was purified by reverse phase HPLC (10-55% in 30 min, acetonitrile in water with 0.1% trifluoroacetic acid). The collected fractions were neutralized with solid sodium carbonate and extracted with dichloromethane three times. The organic phase was dried over sodium sulfate and concentrated in vacuo to give 3,3-dimethyl-1-(1-(pyridin-2-yl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.055 g, 0.171 mmol, 46.5% yield). M+1: 323.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 6 H) 1.72-1.84 (m, 2 H) 2.71-2.85 (m, 2 H) 2.95 (td, J=12.86, 1.86 Hz, 2 H) 4.43-4.65 (m, 3 H) 6.60 (dd, J=6.65, 5.28 Hz, 1 H) 6.71 (d, J=8.61 Hz, 1 H) 6.92 (dd, J=7.24, 5.28 Hz, 1 H) 7.41 (dd, J=7.24, 1.37 Hz, 1 H) 7.47 (ddd, J=8.71, 7.14, 1.96 Hz, 1 H) 8.12 (dd, J=5.18, 1.47 Hz, 1 H) 8.19 (dd, J=4.99, 1.08 Hz, 1 H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-]>CN(C=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>[Cl:13][C:10]1[N:9]=[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)[C:7]([CH:26]=[CH2:27])=[CH:12][CH:11]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (2.50 g, 6.3 mmol), tributyl(vinyl)stannane (2.41 g, 7.6 mmol) and anhydrous LiCl (805 mg, 19.0 mmol) in DMF (50 mL), Pd(PPh3)2Cl2 (222 mg, 0.3 mmol) was added under N2 protection. The reaction mixture was stirred at 60° C. for 1 h. Then it was concentrated in vacuo, the residue was purified by column chromatography (PE:EA=400:1-100:1) to give the product of 2-(6-chloro-3-vinylpyridin-2-yl)-4-fluoro-1H-indole (1.20 g, yield: 69%). 1H-NMR (CDCl3, 400 MHz) δ 9.63 (br s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.28˜7.11 (m, 4H), 7.04 (s, 1H), 6.84˜6.72 (m, 1H), 5.77 (d, J=17.2 Hz, 1H), 5.60 (d, J=11.2 Hz, 1H). MS (M+H)+: 273.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[NH2:7][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10](F)[CH:9]=1.O>C1COCC1>[NH2:7][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:9]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Reactant: OCC(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Potassium tert.-butylate (0.97 g, 8.7 mmol) was added to 2,2,2-trifluoroethanol (0.63 mL, 8.8 mmol) in 20 mL THF at ambient temperature and stirred for 10 min. Then the mixture was cooled to 5° C. and ethyl 4-amino-2-fluoro-5-nitro-benzoate (1.80 g, 7.9 mmol) in 20 mL THF was added and stirred for 1 h at 5° C. Then the mixture was poured into water, extracted with ethyl acetate, the combined organic layers dried over MgSO4 and evaporated to dryness.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[NH2:12]
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: NN
Solvent: O
Product: Cc1cnc(C)c(NN)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 3-chloro-2,5-dimethylpyrazine (26.0 g, 0.182 mol) placed in a round bottom flask was added hydrazine hydrate (75 mL). The reaction mixture was refluxed for 3 h, cooled to ambient temperature, and then kept in a refrigerator for 24 h. The precipitate was collected and washed with hexanes and diethyl ether to afford the title compound as dark colored solid. The compound was used in the next step without further purification. LC/MS 138.9 (M+1); 1H-NMR (500 MHz, CDCl3): δ 2.33 (s, 3H), 2.41 (s, 3H), 4.10 (br S, 2H), 5.75 (br s, 1H), 7.70 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](CC#N)[C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].O.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[N+:1]([C:4]1[CH:9]=[C:8]([CH2:27][C:26]([OH:29])=[O:28])[C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1

Procedure:
210.3 g of 3-nitro-6-(phenylthio)-phenylacetonitrile, 210 ml of water, 210 ml of concentrated sulphuric acid and 210 ml of acetic acid are heated to reflux for 20 hours. The mixture is cooled and extracted with ether. The organic phase is washed successively with water and aqueous sodium carbonate solution. The aqueous phase is made acid with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, evaporated under reduced pressure and the residue recrystallised from benzene. There is obtained 3-nitro-6-(phenylthio)-phenylacetic acid of melting point 138°-140° C.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42](=O)[C:36]=2[CH:35]=1.C=O>O1CCCC1.CCCCCC.CS(C)=O>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3/[C:42](=[CH:7]/[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:36]=2[CH:35]=1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2COc2ccc(Br)cc21
Agent: Br
Agent: C=O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CN(C)CC/C=C1/c2ccccc2COc2ccc(Br)cc21
Reaction time: 0.17 h

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (39.4 g., 0.08 mole) was suspended in 450 mL of dry tetrahydrofuran and 100 mL of a solution of n-butyl lithium in hexane (1.6M) was added dropwise at 0° C. under a nitrogen atmosphere during a 30 minute period. After an additional 10 minutes, 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (16.8 g., 0.06 mole) in 150 mL dry tetrahydrofuran was added slowly to the deep red solution and the reaction mixture was then refluxed for 18 hours. The reaction mixture was poured onto ice-water, and the mixture was extracted with diethyl ether. The ether layer was concentrated under reduced pressure and the residue was suspended in water and then acidified with 6N hydrochloric acid. The acidic aqueous layer was washed with hexanes and then was concentrated to give a gummy residue. The residue was crystallized from ethyl acetate/methanol to provide 5.3 g. of pure Z-isomer as its hydrochloride salt, m.p. 201°-204° C. The mother liquor was chromatographed on a silica gel column (Waters Associates-Prep. 500) with ethyl acetate/methanol (8:2) to give an additional 2.55 g. of pure Z-isomer as the hydrochloride salt and 2.79 g. of E-isomer as its hydrochloride salt, m.p. 230°-233° C. pmr (Z-isomer) (DMSO/d6) δ: 7.25-7.44 (m, 6H, aromatic), 6.81 (degenerate d, J=9.1 Hz, 1H, H4), 5.72 (t, J=7.1 Hz, 1H, CH=), 5.22 (s, 2H, CH2O), 3.18 (m, 2H, NCH2), 2.70 (m, 2H, CH2), 2.66 (s, 6H, NMe2). pmr (E-isomer) (DMSO/d6) δ: 7.23-7.50 (m, 6H, aromatic), 6.70 (d, J=8.6 Hz, 1H, H4), 6.10 (t, J=7.2 Hz, 1H, CH=) 5.15 (br, s, 2H, CH2O), 3.07 (m, 2H, NCH2), 2.65 (s, 6H, NMe2), 2.50 (m overlap with DMSO, 2H, CH2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.6 g 4-(4-Nitro-phenyl)-morpholin-3-one in 350 mL ethyl acetate and 17 mL ethanol, 13.2 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 2 h. Then, after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 2.07 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:40])([F:39])[C:13]([CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([OH:33])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:34][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:12]([F:11])([F:40])[F:39])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.