Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([CH3:8])N=[C:4]([N:9]2[C@@H:16]3[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].S1C=CC=[C:33]1C1C=CC=CC=1C(O)=O>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:22]([C:23]([N:14]2[CH2:13][CH2:12][C@@H:11]3[C@@H:16]([N:9]([C:4]4[CH:33]=[C:6]([CH3:8])[CH:7]=[CH:2][N:3]=4)[CH2:10]3)[CH2:15]2)=[O:24])[CH:26]=1
Reactant: Cc1cc(C)nc(N2CC3CCNC[C@@H]32)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1ccccc1-c1cccs1
Product: Cc1ccnc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)c1

Procedure:
The title compound was prepared in a manner analogous to Example 1 substituting Intermediate 41 for (1R,RS)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-thiophene-2-yl-benzoic acid. MS (ESI) mass calcd. for O21H21FN6O, 392.4; m/z found, 393.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Cl[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:15]1[C:10]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[N:11][CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: Nc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(N)c1
Yield: 44.7 %

Procedure:
Mix 2-aminopyridin-4-ol (3.3 g, 30 mmol), 2-chloro-3-methyl-5-nitropyridine (5.17 g, 30 mmol) in anhydrous DMF (50 mL), add K2CO3 (8.28 g, 60 mmol). Stir the reaction at 90° C. overnight. Concentrate under reduced pressure to give crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (3.3 g, 45%). MS: (M+1): 247.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:8][C:7]2=O.[BH3-]C#[N:26].[Na+]>CO>[NH2:26][CH:7]1[C:6]2[C:22](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cccc(Br)c12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1cccc(Br)c12
Yield: 133.1 %

Procedure:
To a stirred solution of tert-butyl 7-bromo-3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (196 mg, 0.52 mmol) in MeOH (20 mL) were added NH4OAc (795 mg, 10.3 mmol) and NaCNBH3 (324 mg, 5.2 mmol). The mixture was heated at reflux for 1 d. The mixture was concentrated under reduced pressure, diluted with EtOAc (90 mL), washed with 1M aq NaOH (25 mL) and dried over Na2SO4. Removal of the solvent gave crude (±)-tert-butyl 3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (264 mg) which was used without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].O1CCCC1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:34]([O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (14.4 mg) in a mixture of anhydrous tetrahydrofuran (1 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (60% oil dispersion, 4.7 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and benzylbromide (13.3 mg) was added. After stirred for 2 hours at ambient temperature, the reaction was quenched with water (2 ml) and extracted with diethyl ether (1 ml) three times. The combined organic layers were washed with water, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether/n-hexane=1/1) to give 4-[3-(2-benzyloxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (4.8 mg).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:5][C:4](CC#N)([CH3:6])[CH2:3]1.[OH-:11].[Na+].[CH2:13]([OH:15])[CH3:14]>O>[F:1][C:2]1([F:10])[CH2:5][C:4]([CH2:14][C:13]([OH:11])=[O:15])([CH3:6])[CH2:3]1
Reactant: [OH-]
Reactant: CC1(CC#N)CC(F)(F)C1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CC1(CC(=O)O)CC(F)(F)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a solution of Intermediate 229C (100 mg, 0.689 mmol) in ethanol (1 mL) and H2O (1 mL) was added a 10% aq. solution of NaOH (2 mL, 0.689 mmol) and the reaction mixture was stirred at 90° C. for 12 h. The reaction mixture was concentrated and the pH of the residue was adjusted to 4 with an aqueous solution of 1.5 N HCl, and the compound was extracted with EtOAc (3×10 mL). The combined organic layer was dried on Na2SO4, filtered and the filtrate evaporated under reduced pressure to afford Intermediate 229D as a yellow sticky liquid (80 mg, 71%). The crude intermediate was taken as such for further reaction without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.14 (brs, 1H), 2.11-2.39 (m, 6H), 1.15 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](O)CN(Cc2ccccc2)C1
Yield: 87.7 %

Procedure:
To a solution of (S)-benzyl-5-methyl-piperidin-3-one (1.1 g, 5 mmol) in dry tetrahydrofuran (15 ml) at −78° C. was added K-selectride (10.8 ml, 11 mmol, 1 M solution in tetrahydrofuran). After 2 h at −78° C. a few drops of water were cautiously added, the reaction allowed to reach room temperature, the tetrahydrofuran removed by evaporation and the residue the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 1:4) afforded the titled product as a crystalline solid (0.9 g, 43%). MS (ISP)-204.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.N[CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[Cl:8][CH:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:19])=[C:11]([CH3:20])[N:10]1[CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C)N(CCCCO)C(Cl)C([N+](=O)[O-])=C1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, triethylamine (14.19 mL, 101.8 mmol, 1.5 eq) was added in a single portion to a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (15.0 g, 67.86 mmol, 1.0 eq) and N,N-dimethylformamide (DMF) (200 mL). The reaction mixture was stirred for 10 minutes, 4-amino-1-butanol (8.76 mL, 95 mmol, 1.4 eq) in DMF (20 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to provide crude product as an oil. The oil was partitioned between ethyl acetate (300 mL) and water (50 mL). The aqueous layer was back-extracted with ethyl acetate (2×50 mL). The combined organic phases were separated, washed with water (3×30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an orange solid. This material was recrystallized from ethyl acetate/hexanes to provide 12.2 g of 4-(2-chloro-5,6-dimethyl-3-nitropyridin-1-yl)butan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>C1C=CC=CC=1>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH3:34])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 68 h
Yield: 83 %

Procedure:
A mixture of 1.5 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.22 g of sodium hydride (62.2% oil dispersion) and 45 ml of benzene is refluxed for one hour. After cooling, 0.53 g of dimethyl sulfate is added to the mixture, and the mixture is stirred at room temperature for 68 hours. The mixture is further stirred at 50° C. for 3 hours. The reaction mixture is washed with an aqueous 10% sodium hydroxide solution and water, successively. The washed solution is dried and evaporated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethanol (9:1)), converted into its hydrochloride and then recrystallized from a mixture of ethanol and ether. 0.7 g of (+)-cis-2-(4-methoxyphenyl)-3-methoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]N1C(=O)CCC1=O>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH2:10][CH:9]1[Cl:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1Cl
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 1.25 g (4 mmol) of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 75c) in 10 ml of isopropanol are added 0.72 g (4.2 mmol) of N-chlorosuccinimide. The solution is stirred for 6 h at 50° C. After this time, the solution is evaporated to dryness and the residue is dissolved in 100 ml of EtOAc. The solution is extracted with water, dried over MgSO4 and evaporated to dryness to provide the title compound: ES-MS: 342.2, 344.2 (M+H)+; analytical HPLC: tret=5.70 minutes (Grad 2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:4]=1[OH:11].N[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].C([N:22](CC)CC)C>C1COCC1>[NH2:22][S:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:4]=1[OH:11]
Reactant: Oc1c(Br)cc(Br)cc1CBr
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1S
Solvent: C1CCOC1
Product: NSc1ccccc1Cc1cc(Br)cc(Br)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(bromomethyl)-4,6-dibromophenol (1.48 g, 4.3 mmol) in THF (20 mL) was added dropwise to a solution of 2-Aminothiophenol (0.54 g, 4.3 mmol) and triethylamine (0.60 mL) in THF (20 mL) and stirred at room temperature for 12 hours. A solid had formed and was filtered out followed by removal of the solvent in vacuum. The crude product was dissolved in dichloromethane, washed with saturated NaCl solution and dried over MgSO4. The product was obtained as a yellow oil in a quantitative yield.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[N:15]=[CH:14]1>O.CO>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])[CH:17]=1
Reactant: COC(=O)CCCCCCCn1cnc(-c2ccccc2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCn1cnc(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Add sodium hydroxide (1.32 g, 33 mmol) in water (20 mL) to a suspension of 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid methyl ester (2.60 g, 8 mmol) in methanol (50 mL) at 0° C. under nitrogen and warm the mixture to room temperature and stir for 8 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate to provide 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid (1.70 g, 68%). APCI mass spectrum m/z 301 [C17H22N2O3—H]−.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].F[C:19](F)(F)[C:20]([O:22][C:23](=[O:28])[C:24](F)(F)F)=[O:21].[CH3:31]NC1C=CC(C(O)=O)=CC=1>C(OCC)C>[CH:23]([O:28][CH:17]([CH3:16])[CH3:9])([CH3:31])[CH3:24].[C:20]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:19].[CH3:1][N:2]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([F:6])([F:5])[F:7]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CNc1ccc(C(=O)O)cc1
Agent: CN(C(=O)C(F)(F)F)c1ccc(C(=O)O)cc1
Solvent: CCOCC
Product: CC(C)OC(C)C
Product: CCOC(C)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
4-(N-Methyltrifluoroacetamido)benzoic acid may be prepared in the following manner: a solution of trifluoroacetic anhydride (43.75 g) in anhydrous diethyl ether (50 cc) is added to a solution of 4-methylaminobenzoic acid (21 g) in anhydrous diethyl ether (200 cc) while the temperature is maintained in the vicinity of 0° C. The reaction mixture is then stirred for 20 hours at a temperature in the region of 20° C. and is thereafter concentrated to dryness under reduced pressure (2.7 kPa). On recrystallization of the residue obtained in a diisopropyl ether/ethyl acetate mixture (80:20 by volume), 4-(N-methyltrifluoroacetamido)benzoic acid (7.5 g), m.p. 175° C., is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28]O)[O:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[CH:13][N:12]=2)[CH:10]=[N:9][CH:8]=[N:7]1>>[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[O:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[CH:13][N:12]=2)[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: c1c[nH]nn1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-c2ccc(-n3cncn3)nc2)c(F)c1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(-n3cncn3)nc2)c(F)c1

Procedure:
The same procedure as in Example 24 was conducted, except for adding 1,2,3-triazole and using the compound 17 as a starting material, to obtain the title compound.
Reaction SMILES: [C@@H:1]1([OH:6])[CH2:4][CH2:3][C@@H:2]1[OH:5].[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Cl.[OH-].[Na+].[CH3:18]I>CS(C)=O>[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][O:5][C@@H:2]1[CH2:3][CH2:4][C@@H:1]1[O:6][CH3:18]
Reactant: CI
Reactant: Fc1ccccc1CCl
Reactant: O[C@@H]1CC[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CO[C@H]1CC[C@H]1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
396.0 g. (4.5 mol) of cis-1,2-cyclobutanediol and 650.3 g (4.5 mol) of 2-fluorobenzyl chloride were dissolved in 2.5 liters of dimethylsulphoxide, and 270 g (6.75 mol) of sodium hydroxide powder were added in portions at room temperature, whilst cooling with ice. The mixture was stirred at room temperature for 6 hours and 958.5 g (6.75 mol) of methyl iodide and, in portions, 270 g (6.75 mol) of sodium hydroxide powder were then added, whilst cooling. Thereafter, the reaction mixture was again stirred at room temperature for 6 hours and discharged onto 10 liters of ice-water. The mixture was extracted three times with 5 liters of petroleum ether each time and the combined organic phases were dried over sodium sulphate and concentrated by distilling off the solvent. 840 g (88.9% of theory) of cis-1-(2-fluorobenzyloxy)-2-methoxy-cyclobutane of refractive index nD21 =1.4948 were obtained.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][C:16]=1[F:27]>C(Cl)Cl>[Si:10]([O:25][CH:23]([CH3:24])[CH2:22][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:27])[CH:17]=1)[OH:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)CC(O)c1ccc(Cl)c(F)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(CC(O)c1ccc(Cl)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
Imidazole (96.0 mg, 1.42 mmol) and tert-butylchlorodimethylsilane (107 mg, 0.710 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)butane-1,3-diol (130 mg, 0.590 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (15 mL), washed with brine and water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford 3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butan-1-ol (130 mg, 66% yield) as oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:21][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.[ClH:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: N[C@@H]1CCCc2ccccc21
Product: Cl
Product: c1ccc2c(c1)CCC[C@H]2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and (R)-1,2,3,4-tetrahydro-l-naphthylamine by Procedure A (40 min at 170° C.). The product was filtered off and washed with acetonitrile to give the title compound as a HCl salt (white solid, mp 264-265° C.). MS(ES+) m/z 264 ([M+1]30, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:3]4[C:2]([Cl:1])=[CH:6][N:5]([CH2:7][CH3:8])[N:4]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCn1cc(Cl)c(C(=O)O)n1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n1
Temperature: 79 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
A dry flask was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid (0.179 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.227 g, 0.560 mmol, 54%).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:10]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:9]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:36][N:34]([CH3:35])[C:33]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[NH:14][C:15]([C:17]1[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[CH2:7][CH2:6][NH:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37]
Reactant: COC(=O)CNCCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(CCNCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a mixed solution of ({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]benzyl}methylamino)acetic acid methyl ester (120 mg) in THF (1 mL)-methanol (3 mL) was added 4N aqueous sodium hydroxide (0.2 mL) The mixture was stirred at 50° C. for 2 hours under heating, allowed to stand for cooling down to room temperature, and concentrated in vacuo. After addition of water to the residue, 1N hydrochloric acid was added portionwise to the aqueous solution under ice-cooling to adjust the pH to 6 to 7, followed by extraction with ethyl acetate four times. The extract was dried over anhydrous sodium sulfate and concentrated to give the title compound (110 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([NH:29][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone (Example 7) and ethyl-4-amino-1-piperidine carboxylate (Aldrich) using the procedure described in Step B. Example 6. HRMS, observed: 386.1762, calcd for M+: 386.1754.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].[Br:7][CH2:8][CH2:9][CH2:10]Cl>C(#N)C>[Br-:7].[S:1]1[C:2]2[S:6][CH2:8][CH2:9][CH2:10][N+:3]=2[CH2:4][CH2:5]1
Reactant: ClCCCBr
Reactant: S=C1NCCS1
Solvent: CC#N
Product: C1CSC2=[N+](C1)CCS2
Product: [Br-]

Procedure:
A mixture of 12 g. of thiazolidine-2-thione, and 16 g. of 1-bromo-3-chloro propane in 100 ml. of acetonitrile is refluxed for 12 hours, cooled and the product removed by filtration. Recrystallization from ethanol gives 2,3,5,6-tetrahydrothiazolo[2,3-b]-(1,3)-thiazinium bromide.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH3:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CI
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (2.0 g, 13.1 mmol) in DMF (10 mL) was added NaH (0.63 g, 15.7 mmol) at 0° C. under N2. After stirring for 30 min at 0° C., iodomethane (5.58 g, 39.3 mmol) was added and the mixture was stirred at room temperature for additional 1 hour. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound (1.9 mg, 8.9 mmol, 67.9% yield) as a white solid. MS: MS (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.71-7.68 (m, 1H), 7.31-7.27 (m, 3H), 3.79 (s, 3H).