Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1.[Cl-].[CH3:20][O:21][CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:20][O:21][CH:22]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCC=O)cc1
Agent: [Cl-]
Product: COC=CCCCc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
By following the same procedure as described in Reference Example 1, tert-butyl 4-(4-oxobutyl)benzoate (993 mg) was treated with (methoxymethyl)triphenylphosphonium chloride to give the subject compound (918 mg) in the form of a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C#Cc2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-4-ethynylbenzene (2.76 g, 20.20 mmol) in THF (50 mL) at −78° C. was added 2.5 M butyllitium (8.81 ml, 22.03 mmol in hexane) and stirred for 1 h at −78° C. tert-Butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (Compound 1.2, 5 g, 18.36 mmol) was added. The mixture was stirred at −78° C. for 30 min, then warmed up to 0° C., stirred for another hour at the same temperature, and diluted with water. The organic layer was separated and the aqueous was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, and the drying agent was filtered off. The filtrate was concentrated. The residue was purified by silica gel column chromatography using gradient elution (5 to 30%, EtOAc/hexane). LC-MS m/z 292.06 [M−56+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([OH:14])[C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:10](=[O:15])[N:11]([O:14][CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C@H:12]1[CH3:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)CCl
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Solvent: CN(C)C=O
Product: C=CCOC(=O)CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Reaction time: 96 h

Procedure:
To a solution of 17.3 g of (3S-trans)-3-(t-butyloxycarbonylamino)-1-hydroxy-4-methyl-2-azetidinone and 12.9 g of chloroacetic acid, 2-propenyl ester in 350 ml of dry dimethylformamide. The mixture was allowed to stand for 4 days at room temperature and subsequently worked up as described in Example 90B. Yield 25.5 g of crude ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.[CH3:21][Mg]Br>O1CCCC1>[CH3:21][C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH:9]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCCNC1c1ccccc1

Procedure:
A solution of 1-t-butoxycarbonyl-2-phenyl-piperidin-3-one (0.57 g, Example 48a)in 5 ml anhydrous tetrahydrofuran at -78° C. was treated with methyl magnesium bromide (1.6 ml of 1.5M solution in toluene-THF). The reaction was partitioned between saturated ammonium chloride-diethyl ether, the organic phase dried and evaporated in vacuo. The residue was chromatographed using 20% ethyl acetate in hexane as eluant to give 1-t-butoxycarbonyl, 3-methyl-2-phenyl piperidin-3-ol as a crystalline solid, m.p.=95°-97° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13](OS(C3C=CC(C)=CC=3)(=O)=O)[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[F-:39].[K+]>C(#N)C.O>[F:39][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH2:13][C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:38])[CH2:11]1
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CC(=O)c2ccc3c(c2)C(F)CC(C)(C)O3)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-(2,2-dimethyl-chroman-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (21.6 mg, 0.04 mmol) in anhydrous ACN (0.5 mL) is added KF (4.72 mg, 0.08 mmol) and Kryptofix (30.6 mg, 0.08 mmol). After completion of addition the reaction mixture is heated to 90° C. After 15 minutes, the reaction mixture is cooled down to room temperature and diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using reverse phase to yield the desired compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[C:9]2[C:4]=1[C:5](=[O:39])[C:6]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32]C3CCCCO3)=[CH:25][CH:24]=1)=[CH:7][N:8]2[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:8]1[C:9]2[C:4](=[C:3]([F:2])[CH:12]=[CH:11][C:10]=2[O:13][CH2:14][CH2:15][CH3:16])[C:5](=[O:39])[C:6]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=2)=[CH:7]1)[CH3:22]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCCOC4CCCCO4)cc3)cn(CC(=O)OCC)c12
Agent: Cl
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCCO)cc3)cn(CC(=O)OCC)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
2N hydrochloric acid (6.3 ml) was added to an ethanol solution (20 ml) of ethyl (5-fluoro-4-oxo-8-propoxy-3-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-quinolin-1-yl)acetate (840 mg, 1.59 mmol) and stirred at 50° C. for 2 hours. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. Ethyl acetate and water were added to the residue, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, giving a pale yellow oily substance of ethyl{5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetate (627 mg, yield: 89%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[N+:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[C:34]2[CH:38]=O)([O-:28])=[O:27]>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:34]3[C:33]4[C:37](=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=[CH:31][CH:32]=4)[NH:36][CH:35]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c([N+](=O)[O-])cccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 518.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.077 g, 0.022 mmol) in methanol (2.0 mL) was added with 7-nitro-1H-indole-3-carboxaldehyde (0.038 g, 0.020 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.054 g, 50%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH2:33][CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[CH:29]([CH3:28])[CH2:33][CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CCC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (51 mg, 49%), MS (ISP) m/z=415.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and rac-2-methylbutanoic acid
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:9][CH:8]=1)(=O)=O.[CH:23]([N:26](CC)[CH:27](C)C)(C)C.CNC>O1CCCC1>[CH3:23][N:26]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=1)[CH3:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCCc1ccc(COS(C)(=O)=O)cc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.9 %

Procedure:
To a stirred suspension of 4-(2-(tert-butoxycarbonylamino)ethyl)benzyl methanesulfonate (0.33 g, 1.0 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) in tetrahydrofuran (50 mL) was added a 2M solution of dimethylamine in tetrahydrofuran (5.0 mL, 10 mmol). The resulting mixture was stirred in an oil bath set to 60° C. for 6 hours. The solution was cooled to ambient temperature and concentrated. The residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 99/1 to 98/2 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford tert-butyl 4-((dimethylamino)methyl)phenethylcarbamate as a colorless oil (0.15 g, 54% yield).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22])([O-])=O>C(O)C.O>[NH2:9][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[OH:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O
Temperature: 55 °C
Yield: 39.9 %

Procedure:
Sodium dithionite (97.0 g, 0.5 mole) was added in portions over a period of 6 hours to a solution of 2-nitro-4-trifluoromethylphenol (31 g, 0.15 mole) in a mixture of ethanol (120 ml) and water (90 ml), the solution being heated, with stirring, at a temperature of 55° C. during the addition. The mixture was filtered, the filtrate retained, and the collected solid was triturated with ethanol and refiltered. The solvent was removed from the combined filtrates by distillation under reduced pressure to give a yellow solid. The solid was dissolved in water, the aqueous solution extracted with diethyl ether (4×100 ml) and the combined ethereal phases were washed with brine. The ethereal phase was dried over anhydrous magnesium sulfate and the solvent evaporated to give a yellow solid which was recrystallised from petroleum ether (700 ml, bp 100°-120° C.) to give the title compound as a pale yellow solid (10.6 g).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[BrH:14].[NH2:10][CH2:11][CH2:12][S:13][CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][N:4]=1
Reactant: Cn1cnnc1CO
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cn1cnnc1CSCCN

Procedure:
Reaction of 3-hydroxymethyl-4-methyl-1,2,4-triazole with cysteamine hydrochloride and hydrobromic acid by the procedure of Example 1 gives 3[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175°-177°.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([CH3:6])[CH2:4][NH2:5].[C:8](N1C=CN=C1)([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:9]>CN(C=O)C>[F:2][C:3]([F:7])([CH3:6])[CH2:4][NH:5][C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:9]
Reactant: CC(F)(F)CN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(F)(F)CNC(=O)n1ccnc1

Procedure:
TEA (1.3 mL, 0.8 mmol) was added to a solution of 2,2-difluoropropylamine hydrochloride (82 mg, 0.62 mmol) and 1,1′-CARBONYLDIIMIDAZOLE (114 mg, 0.7 mmol) in DMF (3 mL) (clear colorless solution). The solution was used for the synthesis of compound 5 without further isolation of compound 9.
Reaction SMILES: Cl.O[CH2:3][C:4]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][N:5]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:3][C:4]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][N:5]=1
Reactant: OCc1cc(/C=C/c2ccccc2)[nH]n1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cc(/C=C/c2ccccc2)[nH]n1
Temperature: 50 °C
Yield: 82 %

Procedure:
90 mg of the hydrochloride was dissolved in 3 ml of chloroform, and 0.5 ml of thionyl chloride was added. The mixture was heated at 50° C. for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was washed with ethyl acetate and filtered to give 60 mg (yield 82%) of the captioned compound as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([C:16]1[C:17]2[NH:25][CH:24]=[N:23][C:18]=2[CH2:19][CH2:20][NH:21][CH:22]=1)=[O:15])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[NH:25][CH:24]=[N:23][C:18]=2[CH2:19][CH2:20][N:21]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:22]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1=CNCCc2nc[nH]c21
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2nc[nH]c21
Temperature: 25 °C

Procedure:
4-fluorobenzoyl chloride was added dropwise to a stirred solution of 3,6,7,8-tetrahydro-imidazo[4,5-d]azepine-4-carboxylic acid ethyl ester (Example 1, 60 mg, 0.29 mmol) and Et3N (0.2 mL) in dry CH2Cl2 at 0° C. under nitrogen. The resulting mixture was allowed to warm to ambient temperature overnight. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel eluting with hexane-EtOAc (80:20) to give the title compound as a yellow solid. 1H-NMR(CDCl3): δ 8.27-8.21 (3H, m), 7.16 (2H, t), 7.00 (1 H, s), 5.10 (1 H, br s), 4.35 (2H, q), 3.56 (2H, m), 3.14 (2H, t), 1.39 (3H, t); MS (ES): 330 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncc(-c2ccccc2)cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccccc3)cn2)CC1

Procedure:
A mixture of 2-chloro-5-phenyl-pyrimidine (1.2 g, 6.29 mmol, 1.0 equiv; commercially available from Acme Bioscience Inc., USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.52 g, 12.59 mmol, 2.0 equiv; commercially available) and triethylamine (1.75 mL, 1.27 g, 12.59 mmol, 2.0 equiv) in anhydrous acetonitrile (5 mL) was heated by microwave irradiation to 150° C. for 30 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.06 g (48%) of the title compound. MS (ISP): 355.5 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[S:19][C:9]2=[N:10][C:11]3[N:17]([CH3:18])[N:16]=[CH:15][C:12]=3[C:13](=[O:14])[N:8]2[CH2:7]1)=[O:5])C.[OH-].[Li+]>O1CCOCC1.O>[C:4]([CH:6]1[S:19][C:9]2=[N:10][C:11]3[N:17]([CH3:18])[N:16]=[CH:15][C:12]=3[C:13](=[O:14])[N:8]2[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cn2c(nc3c(cnn3C)c2=O)S1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2c(=O)n3c(nc21)SC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
In a mixture of 50 ml of dioxane and 14 ml of water was dissolved 1.30 g (6.24 mmol) of Compound 42 prepared in Example 33, and 0.52 g (12.5 mmol) of lithium hydroxide was added to the solution, followed by stirring at room temperature for 30 minutes. After evaporation of the solvent, the residue was dissolved in water, and then hydrochloric acid was added. The precipitated crystals were collected by filtration, and washed with water, followed by recrystallization from dimethylformamide/water to give 1.09 g (69%) of Compound 43.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:36])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.I[CH3:38].[H-].[Na+]>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:36][CH3:38])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
tert-Butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate (0.056 g, 0.114 mmol), iodomethane (0.00858 mL, 0.137 mmol) and sodium hydride (0.00915 g, 0.229 mmol) were added to DMF (1 mL) at ambient temperature and stirred for 2 hours. The reaction was concentrated and the residue was purified on Silica gel using methanol (containing 6% NH4OH) and DCM, to yield 39 mg of the desired product (67% pure). MS ESI (+) m/z 504 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3[C:13](=[O:23])[N:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:15](=[O:17])(=[O:16])[C:6]=3[C:5]=2[CH:4]=1.C[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C>[OH:23][C:13]1[C:7]2[N:8]([CH3:12])[C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[S:15](=[O:17])(=[O:16])[NH:14][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CN1C(=O)c2c(c3cc(OC)ccc3n2C)S1(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(O)c2c(c3cc(OC)ccc3n2C)S(=O)(=O)N1
Yield: 58.5 %

Procedure:
35.1 gm (0.104 mol) of methyl 3,4-dihydro-7-methoxy-4-methyl-3-oxo-2H-isothiazolo[4,5-b]indole-2-acetate 1,1-dioxide were reacted analogous to Example 18(e) with sodium methylate in toluene/tert. butanol to form 20.6 gm (59% of theory) of methyl 2,5-dihydro-4-hydroxy-8-methoxy-5-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide; M.p.: 225°-226° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Mg+]
Reactant: CC(C)(C=O)c1ccc(F)c(Br)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(3-bromo-4-fluorophenyl)-2-methylpropanal (27 g, 110 mmol) in anhyd THF (300 mL) at 0° C. was added MeMgBr (3M in ether, 73 mL, 220 mmol, 2 eq) dropwise over 2 h. After stirring 1 h, the reaction was allowed to warm to room temperature, quenched carefully with 1N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EA=10:1) to give 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-ol (19 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 1H), 7.32-7.28 (m, 1H), 7.07 (t, J=8.4 Hz, 1H), 3.84-3.79 (m, 1H), 1.31 (d, J=6.4 Hz, 6H), 1.04 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:36]=[CH:35][C:30](/[CH:31]=[CH:32]/[CH:33]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:33](/[CH:32]=[CH:31]/[C:30]2[CH:35]=[CH:36][C:27]([C:26]([F:25])([F:37])[F:38])=[CH:28][CH:29]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C/C=C/c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-(trifluoromethyl)cinnamaldehyde as described in Reference example 32 to obtain the desired compound as a major product (yield: 62%). Physical data and spectral data coincided with those of the compound described in Example 2.
Reaction SMILES: Cl.[CH2:2]=[C:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.O.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]1([S:19][CH2:2][CH:3]2[C:8](=[O:9])[CH:7]3[CH2:10][CH2:11][N:4]2[CH2:5][CH2:6]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: Sc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: O=C1C2CCN(CC2)C1CSc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone hydrochloride (1 g, 0.0057 mol) in water (10 ml) triethylamine (1.73 g, 0.0171 mol), tetra-n-butyl ammonium bromide (180 mg, 0.00057 mol) and thiophenol (0.63 g, 0.0057 mol) were added and the reaction mixture was allowed to stir at 80° C. for 18 h. The completion of reaction was monitored by tlc. The reaction mixture was quenched with ice-cold water (20 ml), extracted with dichloromethane (4×50 ml), organic layers were washed with brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified (550 mg) by column chromatography on silica gel using chloroform as eluent.