Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:35][O:36][C:37](=[O:46])C1C=CC(CO)=CC=1>>[CH3:35][O:36][C:37](=[O:46])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:18]2[C:17]([C:7]3[N:6]([CH2:5][C:4]4[CH:32]=[CH:33][CH:34]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=4[N:8]=3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3cccc(Cl)c3)c2cc1F
Product: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 1-(3-chloro-benzyl)-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 11, intermediate) and 4-hydroxymethyl-benzoic acid methyl ester (CAS Reg. No. 6908-41-4). Colorless sticky solid (34%). MS (Turbo Spray): m/z=519.9 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A suspension of 3 g (14.74 mmol) of 2-chloro-3,5-dinitropyridine in dioxane is admixed with 3.46 g (17.69 mmol) of tert-butyl 4-aminobutanoate hydrochloride and then with 4.21 ml (22.11 mmol) of triethylamine. The reaction mixture is stirred at 60° C. for 3 hours.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:9])[CH2:7][CH2:6][C@@H:5]([NH2:8])[CH2:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([Cl:34])=[CH:27][C:26]=1[F:35])(=O)=O>C1COCC1.O>[Cl:34][C:28]1[CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:25]([NH:8][C@@H:5]2[CH2:6][CH2:7][S:3](=[O:9])(=[O:2])[CH2:4]2)=[C:26]([F:35])[CH:27]=1
Reactant: N[C@@H]1CCS(=O)(=O)C1
Reactant: O=[N+]([O-])c1cc(Cl)cc(F)c1OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)cc(F)c1N[C@@H]1CCS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.6 %

Procedure:
To a solution of (R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine hydrochloride (9.0 g, 52.43 mmol) in 400 mL of THF was added DIPEA (27.0 g, 210 mmol), followed by addition of a solution of 4-chloro-2-fluoro-6-nitrophenyl trifluoromethanesulfonate (20.36 g, 62.92 mmol). After being stirred at RT for 48 hours, the resulting mixture was diluted with water, and then extracted with EtOAc. The organic layer was washed by brine, and then dried over anhydrous Na2SO4, then filtered and concentrated. The residue was purified by flash chromatography to give 0.9 g of (4-chloro-2-fluoro-6-nitrophenyl)-((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH3:11])[NH:9][N:10]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH3:11])[C:7]=1[Cl:19])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(C)[nH]n1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]nc(C)c1Cl

Procedure:
Following protocol L, 3-methyl-2H-pyrazole-5-carboxylic acid ethyl ester was treated with NCS in DMF to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[NH3:14]>CO.C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][NH:14][C:5]2=[O:6]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Methyl 3-bromo-2-(bromomethyl)benzoate (1.28 g) was dissolved in a 11% solution of ammonia in methanol-THF mixed solution (3:2, 25 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was washed with saturated brine. Recrystallization from ethyl acetate-hexane gave the title compound (671 mg, 76%) as colorless needle crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]2=[CH2:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:35].[Na+].OO>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]2[CH2:25][OH:35])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C=C1N(C(=O)OC(C)(C)C)CCCC12CCN(Cc1ccccc1)C2
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1CO
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution of 5 mmol of tert-butyl 2-benzyl-6-methylene-2,7-diazaspiro[4.5]decane-7-carboxylate in 60 ml of tetrahydrofuran is admixed at 0° C. with 10.6 mmol of 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran). The reaction solution is stirred at 60° C. for 15 hours and then cooled to room temperature. The solution is admixed with 50 ml each of 3M sodium hydroxide solution and 30% hydrogen peroxide. The reaction mixture is stirred at room temperature for 2 hours. Subsequently the phases are separated and the aqueous phase is saturated with potassium carbonate and extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:4]([OH:6])[C:3]3[C:2](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:1]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccccc1N
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cc(-c2ccc(Cl)cc2)nc2ccccc12
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To a stirred mixture of 16.52 g (0.1 mol) of ethyl o-aminobenzoate, 15.46 g (0.1 mol) of p-choroacetophenone, and 250 ml of diphenyl ether was carefully added 18.67 g of aluminum chloride. This mixture was heated under reflux for 2 hr and then let cool to 60° C. The solids were collected and washed with 2×100 ml of toluene. These solids were triturated twice with a mixture of 500 ml of 6N hydrochloric acid and 50 ml of acetone. Each time the solids were collected they were washed with 100 ml of 6N hydrochloric acid, 3×100 ml of water, and 2×50 ml of acetone. There was obtained 22.34 g of the above-named product, mp 327-330.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2N=N1.NC1C=CC=CC=1>ClCCl>[C:42]1([NH:38][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:2][CH:3]=2)=[O:8])[CH:43]=[CH:44][CH:45]=[CH:46][CH:41]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)CCCCCCC(=O)c1ccc(-c2ccccc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a solution of carboxylic acid 50h (310 mg, 1 mmol) in dichloromethane (5 mL) stirred at room temperature under nitrogen was added triethylamine (135 μL, 1 mmol), followed by BOP (442 mg, 1 mmol), aniline (108 μL, 1 mmol) and triethylamine (405 μL, 3 mmol). The resulting reaction mixture was stirred for 12 hours at room temperature. The solvent was removed and the mixture was quenched with water (5 mL), extracted with ethyl acetate (3×10 mL), dried (MgSO4), concentrated. Purification by flash silica gel chromatography (5% methanol in dichloromethane) followed by crystallization from acetone afforded the corresponding amide 80 (20% yield). 1H NMR: (300 MHz, CDCl3) δ 8.00 (m, 4H), 7.40-7.60 (m, 10H), 3.00 (m, 2H), 2.60 (m, 2H), 1.60 (m, 4H), 1.20 (m, 4H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:26][C:27]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31](=[O:42])[N:32]2[CH2:39][CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[Br:26][C:27]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31](=[O:42])[N:32]2[CH2:39][CH2:40][N:23]1[CH2:24][CH2:25][CH:20]([N:12]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COc1cc(Br)c2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Br)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To 5 mL of dichloromethane solution containing 0.18 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.15 g of (5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and 29 μL of acetic acid were added and stirred at room temperature for 1 hour. To the reaction mixture, 0.16 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate] to give 0.17 g of tert-butyl (1-(2-(5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a light brown foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.O>[Si:21]([O:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(F)c(CO)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
1.6 g of 4-Fluoro-3-hydroxymethylbenzaldehyde was dissolved in 20 ml of dichloromethane, and 1.4 g of imidazole and 1.75 g of t-butyldimethylchlorosilane were added under ice-cooling, then the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (18% ethyl acetate-hexane), to give 2.6 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1OS(C(F)(F)F)(=O)=O)([O:3][CH3:4])=[O:2].Cl[P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.Cl[Ni]Cl.[Zn]>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[P:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:3][CH3:4])=[O:2]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: Cl[Ni]Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 108 °C

Procedure:
To a solution of 66.6 g (0.195 mol) of 1-carbomethoxy-2-(trifluoromethylsulfonyloxy)naphthalene in 450 ml DMF were added, under a nitrogen atmosphere, 3.65 g NiCl2 (dppe) (6.9 mmol) and 35 ml ClPPh2 (0.195 mol). The reaction mixture was cooled in an ice-water bath and 15 g zinc (20% excess) was added portionwise at 8°-15° C. The mixture was then heated to 108° C. for 2 hours, cooled to 50° C., filtered through silica and washed with three 20 ml portions of methanol. The filtrate was concentrated under vacuum to half of its original volume and allowed to crystallize at 0°-4° C. The product was collected and washed with methanol. Further concentration of the filtrate caused additional material to crystallize. The total yield of the title compound was 66.3 g (92%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH2:27][OH:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)([CH:27]=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step C (1.2 g, 2.4 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.03 g, 4.8 mmol) in portion at room temperature. After stirring for 0.5 h, the mixture was diluted with water (15 mL), extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/PE=1:8) to afford the title compound. LC/MS m/z=499.2[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:21].C1COCC1.CCO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:21]
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(N[C@H](C)c3ccc(Cl)cc3Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C[C@@H](Nc1cc(N2CCC(C(=O)O)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a stirred solution of (R)-ethyl 1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidine-4-carboxylate (3.1 g, 6.8 mmol) in 2:1 THF/EtOH (12 mL) was added a solution of sodium hydroxide (1.4 g, 34.1 mmol) dissolved in deionized water (4 mL). The reaction mixture was stirred at room temperature for 4 h, and the mixture was adjusted to pH-7 with aqueous 6 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% methanol in dichloromethane) to give (R)-1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidine-4-carboxylic acid (2.4 g, 5.6 mmol, 82%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:8]2[CH:9]=[C:10]([NH:13]N)[CH:11]=[CH:12][C:7]=2[S:6][CH:5]=1)[CH3:3].[CH2:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH3:16]>C(O)CO>[CH2:2]([C:4]1[C:8]2=[C:9]3[C:10](=[CH:11][CH:12]=[C:7]2[S:6][CH:5]=1)[NH:13][C:20]1[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][C:19]3=1)[CH3:3]
Reactant: CCc1csc2ccc(NN)cc12
Reactant: CCN1CCC(=O)CC1
Agent: Cl
Solvent: OCCO
Product: CCc1csc2ccc3[nH]c4c(c3c12)CN(CC)CC4

Procedure:
The compound is formed analogously to that described in Example 36, from 8.0 g of 3-ethyl-5-hydrazinobenzothiophene hydrochloride and 6.0 g of 1-ethyl-4-piperidone, by cyclisation under the influence of heat at 165°-170° C. in ethylene glycol for 3 hours.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])=[N:10][N:11]([CH:20]([CH3:22])[CH3:21])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])=[N:10][N:11]([CH:20]([CH3:22])[CH3:21])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)n1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2)c1-c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2)c1-c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-benzyl-3-(β-D-glucopyranosyloxy)-5-(4-hydroxyphenyl)-1-isopropyl-1H-pyrazole (0.02 g) and potassium carbonate (0.017 g) in N,N-dimethylformamide (20 mL) was added benzyl bromide at room temperature. The reaction mixture was stirred at 50° C. for 3 hours. After the reaction mixture was acidified by adding a hydrochloric acid aqueous solution (1 mol/L), the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:33])=[C:26]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[CH:27]=2)OC1>>[F:33][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[N:28]1[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-n3cccn3)c2)OC1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-n1cccn1
Yield: 39 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b)(1,2,4]triazine was coupled with 1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-pyrazole as described in Example 3, step f, final paragraph, to give 41 mg (39%) of the title compound: 1H NMR (360 MHz, DMSO-d6) δ 6.63 (1H, t, J 2.1 Hz), 7.74 (1H, dd, J 8.7, 11.2 Hz), 8.23 (1H, ddd, J 2.1, 4.2, 8.7 Hz), 8.31 (1H, t, J 2.8 Hz), 8.71 (1H, dd, J 2.5, 7.7 Hz), 9.00 (1H, s), 9.41 (1H, s); MS (ES+) m/z 349 [M+H]+.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[CH2:10]O.[NH:12]1C2=NC=CC=C2C(CN)=C1>>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:12]
Reactant: NCc1c[nH]c2ncccc12
Reactant: OCc1nc2cnccc2s1
Product: NCc1nc2cnccc2s1

Procedure:
Intermediate R was prepared from thiazolo[4,5-c]pyridin-2-ylmethanol (R-4) following similar procedures for synthesizing intermediate A from A-3, as described above. MS (m/z): 165 (M)+.
Reaction SMILES: [CH2:1]1[O:13][C:4]2[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][C:3]=2[O:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]1[O:13][C:4]2[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][O:12][S:15]([CH3:14])(=[O:17])=[O:16])[CH:7]=[CH:8][C:3]=2[O:2]1
Reactant: OCCCc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc2c(c1)OCO2

Procedure:
A solution of 1,2-methylenedioxy-4-[3-hydorxypropyl]benzene, (10.0 g), methanesulfonyl chloride (6.33 g, 4.28 ml) and triethylamine (5.6 g) in methylene chloride (100 ml) is stirred at 0° for 2 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is dissolved in acetonitrile (100 ml).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1)=[O:11].[OH-].[Li+]>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
ethyl 1-(1H-indole-2-carbonyl)piperidine-4-carboxylate (3.0 g, 9.99 mmol) and lithium hydroxide, H2O (4.19 g, 100 mmol)) were dissolved in THF (Ratio: 1, Volume: 20 ml) and Water (Ratio: 2, Volume: 40.0 ml) and allowed to stir overnight at room temperature. The reaction was diluted with water, and extracted with diethyl ether. The aqueous layer was acidified using 2N HCl to pH ˜2. A fine, white suspension resulted. The aqueous layer was extracted with ethyl acetate twice. The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford the product as a white solid. (Yield: 678 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 12.33, 11.53, 7.60, 7.41, 7.21-6.94, 6.76, 4.40-4.21, 3.17, 2.66-2.53, 1.97-1.82, 1.63-1.47
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2(C(OCC)=O)[CH2:11][C@@H:10]([C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9][C:8]2=[O:28])=[CH:4][CH:3]=1.Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:8](=[O:28])[O:9][C@H:10]([C@@H:12]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11]2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1(Cc2ccc(Br)cc2)C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CC(Cc2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of the product from Example 92A (22.4 g) in ethanol (120 mL) was treated with LiOH monohydrate (8.0 g, 190.7 mmol) solution in water (30 mL) and the mixture was stirred at 25° C. for 16 hours. The mixture was cooled to 0° C., adjusted to pH 5 by addition of 4N HCl and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (400 mL) was then heated at reflux for 18 hours, cooled and concentrated to give the title compound (18.4 g), which was used without further purification.