Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C1(C[C:10]2[C:15]([CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:14][CH:13]=[C:12]([NH2:22])[C:11]=2[NH2:23])CCCCC1.[F:24][C:25]([F:31])([F:30])[C:26](=N)OC.F[C:33](F)(F)[C:34](O)=O.N>CO>[CH:34]1([CH2:33][N:23]2[C:11]3[CH:10]=[C:15]([CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)[CH:14]=[CH:13][C:12]=3[N:22]=[C:26]2[C:25]([F:31])([F:30])[F:24])[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccc(Cn2ccnc2)c(CC2CCCCC2)c1N
Reactant: COC(=N)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: N#N
Solvent: CO
Product: FC(F)(F)c1nc2ccc(Cn3ccnc3)cc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.4 %

Procedure:
A mixture of 2.75 parts of N2 -(cyclohexylmethyl)-4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 1.85 parts of methyl 2,2,2-trifluoroethanimidate, 40 parts of methanol and 2.3 parts of trifluoroacetic acid was stirred for 7 hours at room temperature. The reaction mixture was made alkaline with methanol, saturated with ammonia. The solvent was evaporated in vacuo and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was dissolved in 11 parts of 2,2'-oxybispropane. The crystallized product was filtered off and dried, yielding 1.9 parts (52.4%) of 1-(cyclohexylmethyl)-6-(1H-imidazol-1-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole; mp. 165.4° C. (compound 202).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:30]=[CH:29][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26](O)=[O:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2].[NH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:30]=[CH:29][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26](=[O:27])[NH:35][C:36]5[CH:41]=[C:40]([C:42]([F:44])([F:43])[F:45])[CH:39]=[CH:38][N:37]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC(=O)O)CC4)cc3)oc12
Reactant: Nc1cc(C(F)(F)F)ccn1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC(=O)Nc5cc(C(F)(F)F)ccn5)CC4)cc3)oc12

Procedure:
The title compound was prepared from [trans-4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)cyclohexyl]acetic acid and 2-amino-4-(trifluoromethyl)pyridine as described in EXAMPLE 1. Mass spectrum (ESI) 604.1 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.50 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.35 (d, J=8.0 Hz, 2H); 8.02 (d, J=8.5 Hz, 2H), 8.02 (d, J=1.5 Hz, 1H); 7.65 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 3.50 (septet, J=7.0 Hz, 1H), 3.26 (d, J=7.0 Hz, 2H), 2.35 (d, J=6.5 Hz, 2H), 185-1.70 (m, 5H), 1.65 (m, 1H), 1.47 (d, J=7.0 Hz, 6H), 1.08-1.18 (m, 4H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:45][C:44]([CH3:46])=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:36][CH2:35][C:34]([C:41]3[S:45][C:44]([CH3:46])=[N:43][CH:42]=3)([OH:33])[CH2:39][CH2:38]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(C2(O)CCC(N[C@@H]3CC[C@@](C(=O)N4CCc5ccc(C(F)(F)F)cc5C4)(C(C)C)C3)CC2)s1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (30.0 mg, 0.0846 mmol) from Step C-2 of Example 1 and 4-hydroxy-4-(2-methyl-1,3-thiazol-5-yl)cyclohexanone (25.1 mg, 0.119 mmol) in dichloromethane (8 mL) was added triethylamine (0.0236 mL, 0.169 mmol) followed by sodium triacetoxyborohydride (42 mg, 0.20 mmol) at room temperature. After being stirred overnight, the mixture was quenched by addition of saturated NaHCO3. The resulting solution was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give two isomers (15 and 12 mg). LC-MS for both isomers: calculated for C29H38F3N3O2S (M+H)+550; found 550.2.
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14](=[O:40])[C@@H:15]([CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([F:38])=[C:33]([CH3:39])[CH:32]=1)[CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:19])C1C=CC=CC=1.[C-]#N.[K+].Cl.C1C[O:48]CC1.CO>>[F:38][C:34]1[C:35]([CH3:37])=[CH:36][C:31]([CH2:30][C@@H:15]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:19])[C:14]([NH:9][OH:48])=[O:40])=[CH:32][C:33]=1[CH3:39]
Reactant: C1CCOC1
Reactant: Cc1cc(C[C@@H](CCN(C)CCCc2ccc(F)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(C[C@@H](CCN(C)CCCc2ccc(F)cc2)C(=O)NO)cc(C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of (R)-4-benzyl-3-((S)-2-(4-fluoro-3,5-dimethyl-benzyl)-4-{[3-(4-fluoro-phenyl)-propyl]-methyl-amino}-butyryl)-oxazolidin-2-one (0.033 g, 0.0601 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), was added KCN (0.001 g, 0.006 mmol). After stirring at room temperature overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The product was isolated by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.016 g, 66% yield). LC-MS: tR=5.5 min, m/z 405 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>C1C=CC=CC=1>[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[C:15]3[CH3:20])=[O:8])[CH2:28][CH2:27]1
Reactant: OCCN1CCNCC1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CCN(CCO)CC2)c2nccc(C)c2c1
Yield: 72.4 %

Procedure:
A mixture of 7 g (0.019 mol) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 4.4 g (0.038 mol) of hydroxyethylpiperazine in 100 ml of benzene was heated under reflux for 48 hours, allowed to cool, mixed well with 50 ml of water and filtered to collect the crude product. Recrystallization from toluene with hexane afforded 5.7 g (72%) of crystalline material, mp 88°-90°.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:10]3[OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].C(OCC)(=O)C>[Pd].C(O)C>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:10]3[OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCC(=O)c1c(O)c2cc(C3CCCCC3)cnc2n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(C3CCCCC3)cnc21

Procedure:
Methyl 4-(6-cyclohexyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-4-oxobutanoate. The title compound is prepared by hydrogenation with palladium black in the presence of hydrogen gas in a suitable solvent such as ethyl acetate or ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:41]([C:43]1[N:44]=[C:45]([C:56]([O-])=[O:57])[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=1)#[N:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:56]([C:45]3[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=[C:43]([C:41]#[N:42])[N:44]=3)=[O:57])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2ncccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
A solution of 80.0 mg (0.395 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 277 mg (0.593 mmol) of PyBroP, 133 mg (0.435 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 207 μL (1.19 mmol) of DIEA. The mixture was stirred at RT for 17 h, diluted with CH2Cl2 (20 mL) and washed with water (1×10 mL). The aqueous layer was extracted with CH2Cl2 (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 10-g Isolute SPE column with 25% EtOAc-hexane afforded 95 mg (53%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.92 (br s, 1H), 8.72 (dd, 1H, J=8.0, 1.6 Hz), 8.37 (dd, 1H, J=4.4, 1.6 Hz), 7.77 (s, 1H), 7.23-7.18 (m, 1H), 6.00-5.94 (m, 1H), 5.93 (s, 2H), 3.70-3.63 (m, 2H), 2.51-2.43 (m, 2H), 2.18-2.11 (m, 2H), 1.61 (t, 2H, J=6.4 Hz), 1.12 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([F:21])[C:15]([C:18]([OH:20])=O)=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=1[OH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[OH:32][C:26]1[CH:27]=[C:28]([OH:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:18]([C:15]1[N:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])=[CH:13][C:14]=1[F:21])=[O:20]
Reactant: Nc1ccc(O)cc1O
Reactant: C[C@@H](COc1cnc(C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A mixture of 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-3-fluoropyridine-2-carboxylic acid (5.00 g), 4-aminobenzene-1,3-diol hydrochloride (2.57 g), HATU (6.05 g), N,N-diisopropylethylamine (5.56 mL), and DMF (50 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (2.51 g) as a mixture with impurities. Triethylamine (6.64 mL) was added to a solution of hexachloroethane (3.53 g) and triphenylphosphine (4.69 g) in acetonitrile (25 mL) at room temperature. The mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (2.51 g, a mixture with impurities) and acetonitrile (25 mL) was added, and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.770 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1.Cl([O-])=[O:15].[Na+].S(=O)(=O)(O)N.CCOC(C)=O>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([C:9]([OH:15])=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(C=O)cc1[N+](=O)[O-]
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1cnc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-methoxy-4-nitropicolinaldehyde (4 g, 0.02 mol) in acetone and water (1:1, 100 mL) was added sodium chlorite (5.9 g, 0.065 mol, spectrochem, india) and sulfamic acid (6.3 g, 0.065 mol, Rankem, India) and the reaction mixture was stirred for 1 h at rt. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion, the reaction mixture was concentrated to get a white precipitate which was filtered and dried to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.6 (brs, 1H) 8.90 (s, 1H), 8.41 (s, 1H), 4.15 (s, 3H). MS (ESI, positive ion) m/z: 197.8 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>CN(C=O)C>[CH2:3]([O:10][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[C:23]([F:24])([F:25])[F:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
60% NaH dispersion (1.4 g, 33.5 mmol) in mineral oil was washed with hexanes and then suspended in DMF (10 ml). To this NaH suspension in DMF, added benzyl alcohol (2.8 ml, 26.3 mmol) with water bath to keep the temperature below 30° C. The reaction mixture was stirred until the evolution of the hydrogen gas ceased. To a solution of 2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9 mmol) in DMF (20 ml) was added the benzyl alkoxide solution slowly at 0° C. Upon the completion of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 200 ml ice water, stirred until the yellow solid was formed. Filtered and the solid was washed with water and then trituated with pentane. 5.9 g yellow solid was collected (yield: 83%). ESI-MS m/z 298 (M+H)+
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.CO>C(O)C.ClCCl.[Pd]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reaction time: 8 h

Procedure:
A mixture of 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (400 mg, 1.67 mmol) and 10% Pd/C (400 mg) in ethanol (15 mL) was stirred under Hxxx2 overnight. The reaction mixture was filtered and the filtrate concentrated and purified by column chromatography. Elution with 5% methanol (2M/NH3) in dichloromethane gave the less polar isomer (297.7 mg, 73.5%) and with 10% methanol (2M/NH3) in dichloromethane gave the more polar isomer (73 mg, 18.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])[CH:2]=1.S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:18])=[O:11])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Product: O=C(Cl)c1cccc(-c2cccnc2)c1

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-3-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g crude 3-(pyridin-3-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 mg, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added 3-(pyridin-3-yl)benzoyl chloride (1.5 g, 7 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH:20]([CH3:22])[CH3:21])=[O:4].Cl.[CH3:24][O:25][NH2:26].[CH:27]([Mg]Cl)(C)C>O1CCCC1>[CH3:24][O:25][N:26]([CH3:27])[C:3]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH:20]([CH3:22])[CH3:21])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Reactant: CC(C)[Mg]Cl
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Temperature: -30 °C
Yield: 21.8 %

Procedure:
4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid methyl ester (14 g, 40.1 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (200 mL) and then cooled to −30° C. while stirring under nitrogen. N-methyl, N-methoxy amine hydrochloride (0.881 g, 9.04 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (8.73 mL, 2M soln. in THF, 17.46 mmol) is slowly added to the cooled suspension over 1 h. TLC will show complete consumption of starting material, then 30% solution of ammonium chloride is added with stirring. The reaction is diluted with diethyl ether and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid methoxy-methyl-amide (0.705 g, 1.97 mmol) is obtained in pure form after flash column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:23][OH:24].CN([CH:28]=[O:29])C>>[F:1][C:2]1[CH:3]=[C:4]2[C:28](=[O:29])[N:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[CH2:16][CH2:15]3)[C:23](=[O:24])[C:5]2=[CH:9][CH:10]=1
Reactant: CO
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C

Procedure:
To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophtahalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to 80° C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55° C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186°-188° C.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[N:25]=1.[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][OH:70])=[O:66])[CH:52]=[CH:53][C:54]=1B1OC(C)(C)C(C)(C)O1>CO.Cl>[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][OH:70])=[O:66])[CH:52]=[CH:53][C:54]=1[C:24]1[N:25]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:29]=1
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Agent: Cl
Solvent: CO
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NCCO)cc2F)n1
Temperature: 90 °C

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 13). Material was purified by prep HPLC (high pH) followed by purification by prep HPLC (low pH). Due to partial byproduct formation by reaction with formic acid the resulting material was taken up in MeOH (0.5 mL) along with 2 drops of 2M HCl and heated in the microwave for 20 minutes at 90° C. Reaction mixture was purified using a TsOH cartridge (100 mg) to afford a white solid, (12 mg, 8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#Cc1ccc(F)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(F)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 78% yield following oxidation. 1HNMR (CDCl3) δ 4.60 (2H, s), 6.65 (1H, d, JH,H=11.83), 7.20-7.65 (8H aromatic+1H ethylenic).