Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH2:12][OH:13])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH2:4][CH2:3]1.[H-].[Na+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17]>O1CCCC1>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:13][CH2:12][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH:8]2[CH2:9][O:10][CH2:11]2)[CH2:6][CH2:7]1)#[N:17]
Reactant: OCC1(F)CCN(C2COC2)CC1
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(S(N)(=O)=O)ccc1OCC1(F)CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 517B (0.185 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.090 g). After 30 minutes, 3-cyano-4-fluorobenzenesulfonamide (0.178 g) was added in one portion. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with 1N aqueous HCl (4 mL), diluted with dichloromethane (30 mL) and saturated aqueous NaHCO3 (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid material was triturated with dichloromethane and filtered to give the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].ClN([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32](OC)[CH:33]=2)[N:28]=[CH:27][N:26]=1)C1C=CC=CC=1F.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[N:26]=[CH:25][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)(=[O:5])=[O:4]
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ncc2ccccc2n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)-7-hydroxy-6methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. The reaction mixture was stirred for 1 hour at 0° C., allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxyquinazoline (270 mg, 60%) as a beige solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:12]1[CH:30]=[CH:29][C:15]([CH:16]=[CH:17][C:18]([NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[C:22]=2[OH:28])=[O:19])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:31][O:32][C:33](=[O:38])[CH:34]=[CH:35][CH2:36]Br.O>CC(C)=O>[CH3:31][O:32][C:33](=[O:38])[CH2:34][CH:35]1[O:28][C:22]2[C:21]([NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:30][CH:29]=3)=[CH:27][CH:26]=[CH:25][C:23]=2[O:24][CH2:36]1
Reactant: COC(=O)C=CCBr
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc(O)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1

Procedure:
Potassium carbonate (509 mg) was added to a solution of 3- (p-pentylcinnamoyl) aminopyrocatechol (300 rag; synthesized by the same procedure as reference example 1) and 4-bromo-2-butenoic acid methyl ester in acetone (10 ml), and the mixture was refluxed for 10 min. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was purified by column chromatography on silica gel (hexane: ethyl acetate=5:1) to give the title compound (341 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([Li])CCC.[C:27](=[O:29])=[O:28].Cl>C1COCC1.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[C:4]([CH3:21])=[CH:3][C:2]([C:27]([OH:29])=[O:28])=[CH:7][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C=O
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a solution of tert-butyl 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylate (400 mg) in THF (8 ml) was cooled to −78° C., and 1.63 M n-butyl lithium (0.9 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Crushed dry ice was put into another flask, and THF (30 ml) was poured thereinto. The mixture to which n-BuLi had been added dropwise immediately before was added thereto, followed by stirring as it was for 1 hour. To the reaction mixture was added water and 1 M hydrochloric acid, and the pH of the aqueous layer was adjusted to around 5.0. The aqueous layer was extracted with EtOAc, the organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazine-1-yl]-5-methylnicotinic acid (169 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N:10]1([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Reactant: Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
4-hydroxybenzylbromide (15.6 g, 84.3 mmol, prepared following Wissner A. et al., J. Med. Chem. 1992, 35, 1650) was added to a mixture of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (10.00 g, 54.30 mmol) and K2CO3 (8.20 g, 59.70 mmol) in dry THF (150 ml) at room temperature. The mixture was then stirred at room temperature for 2 h and after poured into water and extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (16.00 g as solid). Crystallization from ethyl acetate with ethanol yielded the expected product (6.50 g, 41%, mp: 180° C.)
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[C:2]([CH3:4])=[O:3].[Br:12]Br.C(=O)=O>O>[Br:12][CH2:4][C:2](=[O:3])[C:1]([O:6][CH2:7][C:8]([Cl:9])([Cl:10])[Cl:11])=[O:5]
Reactant: BrBr
Reactant: CC(=O)C(=O)OCC(Cl)(Cl)Cl
Agent: O=C=O
Solvent: O
Product: O=C(CBr)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 354.9 %

Procedure:
Trichloroethyl pyruvate (3.7 g, 1.7 mmole) is heated to 65° and 1.1 ml (17 mmole) of bromine is added dropwise over 1 hour. A stream of carbon dioxide is passed through the reaction mixture during the addition to remove the HBr formed in the reaction. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried over MgSO4, evaporated and distilled in vacuum to give 1.8 g of trichloroethyl bromopyruvate, bp 74°-77° (0.01 mm).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1>C1COCC1.CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Sodium borohydride (4.5 g, 115. mmol) was added to a solution of methyl 5-methylpicolinate (6.0 g, 39.5 mmol) in THF (60 mL) and methanol (6 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic layer was concentrated under vacuo to afford (5-methylpyridin-2-yl)methanol (3.5 g, 72.9%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.5 (s, 1H), 7.7 (d, 1H), 7.15 (d, 1H), 5.0 (s, 3H), 3.4 (s, 3H). MS: [M+H]+: m/z=124.0.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([NH:30][C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:27][C:28]=3[F:29])=[CH:11]2)(=O)=O)C=CC=CC=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:19]1([C:18]2[C:13]3[C:12]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([NH:30][C:31]5[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:27][C:28]=4[F:29])=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(Nc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(Cc3c[nH]c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To [5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (76, 0.170 g, 0.320 mmol) in 10.0 mL of tetrahydrofuran, tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-4023, 100.4 mg). MS (ESI) [M+H+]+=390.8.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(CC)CC.[BH4-].[Na+]>CO>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH2:18][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Reactant: NCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCNCc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 50 °C
Yield: 43.9 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde(23 mg, 0.05 mmol) in 3 mL MeOH, β-alanine (8.7mg, 0.1 mmol) and catalytic amount Et3N are added. The suspension is heated to 50° C. for 0.5 hours, followed by the addition of 2 mg of NaBH4. After Pre-LC-MS, 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-6-ylmethyl]-amino}-propionic acid is obtained as a white solid. MS m/z 456[M+1]+. 1H NMR (MeOD-d4): δ 8.22 (d, 1H), 7.93 (m, 2H), 7.86 (d, 1H), 7.81 (s, 1H), 7.40 (m, 1H), 7.34 (d, 1H), 7.28 (m, 3H), 7.24 (m, 2H), 4.26 (s, 2H), 3.15 (t, 2H), 2.52 (t, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:31])=[O:30])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=1)=[CH:12]2)=[O:6])[CH3:3].Cl[C:43]([O:45][CH3:46])=[O:44].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:30])=[O:31])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[N:25][C:43]([O:45][CH3:46])=[O:44])=[CH:27][CH:28]=1)=[CH:12]2)=[O:6])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CN(c1ccc2c(c1)cc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(c1ccc2c(c1)cc(Cc1ccc(C(N)=NC(=O)OC)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-indol-2-yl)-methyl]-benzamidine-hydrochloride, methyl chloroformate and potassium carbonate in tetrahydrofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[N:31]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[N:31]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)n1

Procedure:
Example 66 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.38–7.34 (m, 2H), 7.01–6.97 (m, 2H), 6.88 (d, 1H, J=7.2 Hz), 6.53 (br s, 1H), 3.27 (dd, 2H, J=6.0, 12.4 Hz), 2.94 (d, 2H, J=14.0 Hz), 2.54–2.48 (m, 4H), 2.32 (t, 2H, J=6.4 Hz), 1.99–1.60 (m, 14H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 495.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH2:30]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1)[CH3:31]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CCc1ccc(CCN)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCc1ccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Ethyl-phenyl)-ethylamine. MS (ESI): 461.4 (MH+).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[CH3:26])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH:10]C(=O)C2C=CC=CC=2)=[N:4]1.N12CCCN=C1CCCCC2>CO>[F:27][CH:2]([F:1])[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[CH3:26])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH2:10])=[N:4]1
Reactant: Cc1c(F)cccc1C1(C(F)F)N=C(NC(=O)c2ccccc2)OC2CC21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: Cc1c(F)cccc1C1(C(F)F)N=C(N)OC2CC21
Temperature: 40 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
N-(5-(difluoromethyl)-5-(3-fluoro-2-methylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide (1.0 g, 2.67 mmol) was dissolved in methanol (50 mL) under nitrogen and 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.798 ml, 5.34 mmol) was added. The reaction was heated to 40° C. After 18 hours, the reaction mixture was concentrated to dryness under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was isolated and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-60% ethyl acetate in hexanes afforded the title compound 5-(difluoromethyl)-5-(3-fluoro-2-methylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.470 g, 1.739 mmol, 65.1% yield). LC/MS (ESI+) m/z=270.9 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1)[CH:5]=[N:6][NH:7][C:8]([NH2:10])=[O:9].[S]Cl>C(OCC)(=O)C.C(O)(=O)C>[CH:23]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[O:14][C:13]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]2[NH:10][C:8](=[O:9])[NH:7][N:6]=2)=[CH:11][C:12]=1[CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(Oc2c(C)cc(C=NNC(N)=O)cc2C)cc1C(C)C
Agent: [S]Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(C)cc(-c3n[nH]c(=O)[nH]3)cc2C)cc1C(C)C
Yield: 24.2 %

Procedure:
A solution of the title compound of Step A (20 mg, 0.055 mmol) and sulfur monochloride (26.7 μl, 0.33 mmol) in ethyl acetate/acetic acid (2.4 ml/0.6 ml) was heated to reflux for about eight hours. The mixture was concentrated and the residue was purified by preparative TLC (5% methanol in dichloromethane) to afford the title compound (4.7 mg) as a white solid. MS (APCl+) Calc: 353.2, found: 354.2 (M+1).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:28]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1
Reactant: N#Cc1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3-chloro-4-(3,4-dichlorobenzyl)benzonitrile (0.93 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (300 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.64 g of desired compound (melting point: 179.0°-185.0° C.).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:8]([CH3:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([C@@H:8]([CH3:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)[C@@H](O)[C@@H](C)CC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)[C@@H](OC1CCCCO1)[C@@H](C)CC
Yield: 40.3 %

Procedure:
In a 200 ml flask were charged 10 g of ethyl (2S,3S)-2-hydroxy-3-methylvalerate, 10.5 g of 3,4-dihydro-2H-pyran, 0.24 g of p-toluenesulfonic acid, and 100 ml of diethyl ether, and the mixture was allowed to react at room temperature overnight. The reaction mixture was neutralized with a sodium hydrogencarbonate aqueous solution, and diethyl ether was removed by distillation to obtain 6.15 g (49.7%) of a crude product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[C:17]([Si:14]([CH3:16])([CH3:15])[O:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-aminocyclohexanol (5.0 g, 43.4 mmol) (TCl US) in dichloromethane (100 mL) was added imidazole (14.78 g, 0.22 mol) (Aldrich) and tert-butyldimethylsilyl chloride (19.63 g, 0.13 mol) (Avocardo Research Chemicals). The reaction mixture was stirred at room temperature for 1 day and then was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with 1N sodium hydroxide solution, water and brine, dried over magnesium sulfate, filtered and concentrated to give trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine. (Yield 7.62 g, 76.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>>[ClH:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:15]=1
Reactant: O=Cc1c(Cl)n(-c2ccc(F)cc2)c2ccccc12
Reactant: C1CNCCN1
Agent: Cl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(F)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-Chloro-1-(4-fluorophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-fluorophenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (40% yield) as a cream solid. ESI/MS 324 (M+H); RT 2.44 min; NMR 10.15 (1H, s); 8.13 (1H, d, J=9 Hz); 7.71 (2H, m); 7.54 (2H, m); 7.23 (2H, m); 6.95 (1H, d, J=9 Hz); 3.33 (4H, br s); 2.95 (4H, br s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][C@H:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1[C@@H]2CC[C@H]1CC(OS(C)(=O)=O)C2
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Tropine (14.2- g, 100 mmol) was dissolved in CH2Cl2 (210 ml) and triethylamine (23 ml, 160 mmol) was added. Methanesulfonyl chloride (9.3 ml, 120 mmol) was added rapidly dropwise which caused the methylene chloride solution to reflux gently. The mixture was stirred one hour further; then extracted with cold 0.5 molar sodium hydroxide, water, and brine, dried by filtration through phase separating paper and concentrated to yield 13.8 g (65%) of title product as a yellow solid; NMR 4.88 (t, J=5 Hz, 1H), 3.10-3.05 (m, 2H), 2.94 (s, 3H), 2.22 (s, 3H), 2.20-2.10 (m, 2H), 2.02-1.88 (m, 6H).