Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9](=[S:15])[NH:10][CH2:11][C:12](Cl)=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[Cl:21]C1C=CC=CC=1>>[CH2:1]([S:8][C:9]1[S:15][C:12]([CH2:13][Cl:21])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cl)CNC(=S)SCc1ccccc1
Reactant: Clc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 5.5 °C
Reaction time: 0.33 h

Procedure:
Under a slight stream of nitrogen, 35.8 g of (2-chloro-allyl)-dithiocarbamic acid benzyl ester and 31.8 g of sodium hydrogen carbonate are placed in 250 ml of chlorobenzene. The mixture is then cooled to 5-6° C. The apparatus is flushed thoroughly with nitrogen. Then 28.2 g of sulfuryl chloride are added in the course of 120 minutes in such a manner that the temperature can be maintained at 5-10° C. When the addition is complete, stirring is carried out for about 20 minutes. The reaction mixture is filtered off with suction, the filtration residue is washed with 20 ml of chlorobenzene, and the filtrate is thoroughly degassed in vacuo at 20-25° C. Then the solvent is removed by distillation at 30° C. under reduced pressure. 90 ml of hexane are added to the residue. Seeding is carried out, then the mixture is stirred at about 0° C. and about 0.8 g of hydrogen chloride gas is introduced until the solution will take up no more gas. The mixture is stirred for a further 15 minutes, the crude product is filtered off at 0-5° C., and the filtration residue is washed with 10 ml of hexane and dried in vacuo. In that manner 2-benzylsulfanyl-5-chloromethyl-thiazole is obtained in the form of the hydrochloride.
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1.CCN(C(C)C)C(C)C>C(O)C>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:4]1[CH2:3][CH2:2][N:9]([CH2:10][C@H:11]([OH:12])[C:13]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[O:17][CH2:16][C:15]=3[C:14]=2[CH3:23])[CH2:6][CH2:5]1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc4c(c3)C[C@@H](C)OC4=O)CC2)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (150 mg, 0.54 mmol) in ethanol (2 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 24)(110 mg, 0.54 mmol) and Hunig's base (95 uL, 0.54 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield (3R)-6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one as a diastereomeric mixture.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[CH:31]1[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[C:34]([NH2:40])=[CH:33][CH:32]=1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][NH:40][C:34]3[CH:33]=[CH:32][CH:31]=[CH:36][C:35]=3[C:37]([OH:39])=[O:38])[C:17]=2[CH:16]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1NCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Yield: 88 %

Procedure:
Reaction of the bromide (58) prepared as described in example 172 with o-anthranilic acid using the procedure described in example 179 gave the aniline (60) (88%), mp 261–263° C. 1H NMR δ [(CD3)2SO] 11.05 (s, 1H), 9.38 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.76 (m, 1H), 7.75 (s, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.55 (m, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7.12 (dd, J=8.7, 2.4 Hz, 1H), 6.59–6.50 (m, 2H), 4.57 (t, J=6.7 Hz, 2H), 3.22–3.10 (m, 2H), 2.15–2.05 (m, 2H). FABMS found M+: 541.1230, 539.1234. C30H22ClN3O5 requires 541.1218, 539.1248.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[S:17][CH:16]=[C:15]([C:18](O)=[O:19])[CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:15]1[CH:14]=[C:13]([Br:12])[S:17][CH:16]=1)=[O:19])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1csc(Br)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1csc(Br)c1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 5-bromothiophene-3-carboxylic acid. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were evaporated, the residues dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated. After drying under vacuum, the hydrochloride salt of the title compound was obtained as a colourless solid; MS (ES+) 315, 317 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C2C=CC(O)=CC=2OC1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[Br:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[C:40]([C:10]2([OH:17])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[O:18])[CH:41]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (90%) as an orange solid: MS (ES+) m/z 486.2 (M+1), 488.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])[CH3:2]>C(O)C.[C].[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc(N)cc2C1
Reaction time: 8 h

Procedure:
To 125 ml of suspension in ethanol of 136 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride was added 98 ml of triethylamine and 83 ml of ethyl acrylate, and the solution was heated and stirred overnight under reflux. The solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure to obtain 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline. The thus obtained 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 1,000 ml of ethanol, and a catalytic amount of 10% palladium-carbon was added to the solution. The solution was stirred overnight under hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 7-amino-2-(2-(ethoxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline, which was a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]([C:14]([F:17])=[CH:15][CH:16]=1)[C:11](O)=[O:12].C[N:21](C=O)C>C(Cl)Cl>[Br:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]([C:14]([F:17])=[CH:15][CH:16]=1)[C:11]([NH2:21])=[O:12]
Reactant: COc1c(Br)ccc(F)c1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(Br)ccc(F)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (15 mL) was added dropwise at 0° C. to a suspension of 3-bromo-6-fluoro-2-methoxybenzoic acid (15 g, 60 mmol) in 100 mL of DCM with 0.5 mL of DMF. The mixture was stirred at 25° C. for 2 hours and the clear solution was concentrated to dryness under reduced pressure. The residue dissolved in 60 mL of anhydrous acetonitrile was added to 600 mL of aqueous NH3.H2O at 0° C. and stirred for 2 hours, then filtered to give 3-bromo-6-fluoro-2-methoxybenzamide.
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13]CC)=[O:12])[N:8]=[C:7]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:6]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[N:9]([CH2:10][C:11]([OH:13])=[O:12])[N:8]=[C:7]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:6]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1nc(-c2cccnc2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2cccnc2)nn1CC(=O)O
Temperature: 85 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To a suspension of ethyl 2-[5-acetamido-4-(2-phenylethynyl)-3-(3-pyridyl)pyrazol-1-yl]acetate (410 mg, 1.1 mmol) in ethanol (10 mL) was added 25% NaOH aqueous solution (6.5 mL). The reaction mixture was stirred at 85° C. for 6 h. The reaction mixture was cooled down to room temperature and ethanol was evaporated in vacuo. The resulting aqueous suspension was filtered and the solid was washed with acetonitrile and dried, yielding 235 mg of 2-[5-amino-4-(2-phenylethynyl)-3-(3-pyridyl)pyrazol-1-yl]acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14]>C1COCC1>[C:13]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=1)(=[O:15])[CH3:14]
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NNC(C)=O)cc1
Reaction time: 1 h

Procedure:
To 40 mL of THF were added 1.8 g (10.8 mmol) of 4-methoxybenzoylhydrazine, 0.9 g (11.5 mmol) of acetyl chloride and 1.1 g of TEA. The reaction mixture was stirred for 1 hour, followed by evaporation off ca. ½ volume of THF. The product was precipitated into methanol, filtered and dried over night under vacuum. Yield was 2.14 g (95%). MS (EI, m/e) calcd for C10H12N2O3 208, found 208 M+, 6.7); mp 146-148° C.
Reaction SMILES: B.[C:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([NH:10][CH2:11]OC)=[O:9])#[N:3].[O:17]1[CH2:21]CC[CH2:18]1>>[NH2:3][CH2:2][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([NH:10][CH2:11][CH2:18][O:17][CH3:21])=[O:9]
Reactant: COCNC(=O)c1cccc(CC#N)c1
Reactant: C1CCOC1
Agent: B
Product: COCCNC(=O)c1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Borane (1N in tetrahydrofuran, 467 ml, 0.467 mol) was added dropwise to a solution of 3-(cyanomethyl)N-(methoxymethyl)benzamide (14.57 g, 0.067 mol) [see preparation 40] in tetrahydrofuran (30 ml) over 20 minutes. The reaction mixture was then stirred at room temperature for 18 hrs and then heated to reflux for 2 hrs, after which time the solvent was evaporated under reduced pressure and the residue acidified with hydrochloric acid (2N). The resultant mixture was heated to reflux for 10 minutes after which time it was basified with sodium hydroxide. The product was extracted with dichloromethane (3×30 ml), the combined organic layers were dried over MgSO4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5) changing to (92.5:7.5:0.25) changing to (90:10:1) to afford the title compound, 6.15 g, (44%).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(OCC2C=CC=CC=2)=O)[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:27]([OH:31])[C:28]([OH:30])=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.C([O-])=O.[NH4+]>CN(C=O)C.CO.[Pd]>[CH2:32]([C@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[C@@H:27]([OH:31])[C:28]([NH:1][C:2]1[NH:6][C:5]([CH3:7])=[CH:4][N:3]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cn(C(=O)OCc2ccccc2)c(N)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a 5.00 ml solution of benzyl 2-amino-4-methyl-1H-imidazole-1-carboxylate obtained in Reference Example 32 601 mg (2.60 mmol), (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid 590 mg (2.00 mmol) and HOBt.H2O 321 mg (2.10 mmol) in DMF was added WSC.HCl 422 mg (2.20 mmol) and the mixture was stirred at room temperature for 5 hours. After distillating DMF off, the mixture was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on sodium sulfate. Filtration and concentration gave a residue and the resulting residue was redissolved in methanol 30 mL. To this solution were added ammonium formate 2.52 g (40.00 mmol), 10% Pd/C (containing 50% water) and the mixture was heated under reflux for 2 hours. The mixture was filtered to remove 10% Pd/C and concentrated. The concentrated residue was suspended in ethyl acetate and washed with 5% sodium carbonate and an aqueous saturated sodium chloride solution. The organic layer was dried on sodium sulfate. After filtration and concentration of the mixture, the mixture was purified by a column chromatography on silica gel (eluted with a mixed solvent of chloroform and methanol) to give 558 mg (1.49 mmol) of the title compound (yield: 75%).
Reaction SMILES: [O-][C:2]#[N:3].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(=O)=O.O>CS(C)=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:9][C:2]#[N:3]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2F)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCc1ccccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 9.89 gm of sodium cyanate in 35 ml of dimethylsulfoxide (hereinafter abbreviated as DMSO) was added dropwise a solution of 31.2 gm of the compound prepared in (4) above in 70 ml of DMSO. The mixture was stirred for 12 hours at room temperature. After the addition of 500 ml of water, the mixture was extracted twice with 200 ml of ether. The extract was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 15.4 gm of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5](C1C=C(OC)C(OC)=C(OC)C=1)[CH2:6][C:7]2=[O:16].C1OC2C=CC(C=O)=CC=2O1.Cl>[OH-].[Na+].O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:16]
Reactant: COc1cc(C2CC(=O)c3cc(OC)c(OC)c(OC)c32)cc(OC)c1OC
Agent: Cl
Agent: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c(OC)c1OC)CCC2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 162.2 %

Procedure:
4,5,6-trimethoxy-3-(3,4,5-trimethoxyphenyl)-indan-1-one (formula 7, 250 mg) was taken in 2.5% methanolic sodium hydroxide (10 mL). To this stirred solution 3,4-methylenedioxybenzaldehyde (100 mg) was added and further stirred at room temperature at 30° C. for 1 hour. On completion, the reaction mixture was diluted with water, acidified with dil. HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated to get a residue. The residue was purified through silica gel column to get 2-benzo[1,3]dioxo-5-ylmethylene-4,5,6-trimethoxy-3-(3,4,5-trimethoxyphenyl)-indan-1-one (formula 8, 232 mg)
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([CH:28]=1)[NH2:27]>CN(C)C1C=CN=CC=1.O>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([NH:27][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=1
Reactant: Cc1ccc(N2CCCCC2)c(N)c1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCCCC2)c(NC(=O)c2ccncc2)c1
Reaction time: 19 h
Yield: 28.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (172 mg, 0.966 mmol, commercially available product), triethylamine (340 μl, 2.44 mmol), and a catalytic amount of 4-(dimethylamino) pyridine were sequentially added at room temperature to a dichloromethane (5 ml) solution of 5-methyl-2-(1-piperidinyl)aniline (155 mg, 0.815 mmol), obtained as described in Referential Example 16-2. The resulting mixture was stirred for 19 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 g, hexane/ethyl acetate=1/1). Thus, N-[5-methyl-2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0342) (69.5 mg, 28.8%) was yielded as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([OH:26])[CH2:25][NH:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:24]3[CH2:25][C:22]([CH3:21])([OH:26])[CH2:23]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(O)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2CC(C)(O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (150 mg, 0.51 mmol) in DCE (10 mL) was added 3-methyl-azetidin-3-ol (65 mg, 0.75 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (215 mg, 1.01 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (83 mg, 45%)._LCMS (Method H): RT=2.29 min, [M+H]+ 367.5
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])O)[CH2:10][CH2:9]1.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)[CH2:10][CH2:9]1
Reactant: OC(c1ccc(Cl)cc1Cl)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3Cl)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.2 ml (2.76 mmol) of trifluoroacetic acid was added to 500 mg (2.30 mmol) of the compound from Example 147A and 408 mg (2.30 mmol) of the compound from Example 8A in 32 ml of dichloromethane, and the mixture was stirred at RT for 30 min. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 342 mg (35% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[CH2:1]([S:5]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Nc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCCCS(=O)(=O)Nc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Oxidation of tert-butyl 3-(3-(butylsulfonamido)phenyl)-3-hydroxypropylcarbamate by PCC following the method used in Example 18 gave tert-butyl 3-(3-(butylsulfonamido)phenyl)-3-oxopropylcarbamate as white solid: Yield (0.18 g, 41%); 1H NMR (400 MHz, CD3OD) δ 8.01-8.04 (m, 1H), 7.82-7.84 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.49-7.52 (m, 1H), 5.86-5.64 (m, 1H), 3.71-3.75 (m, 2H), 3.43 (q, J=6.0 Hz, 2H), 3.21 (t, J=6.8 Hz, 2H), 1.82-1.90 (m, 2H), 1.48-1.58 (m, 2H), 1.41-1.44 (m, 18H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1.Cl.[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][S:5][C:6]4[S:10][C:9]5[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:8]=5[CH:7]=4)[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1CCCc2sc(SCCCCl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCc2sc(SCCCN3CCC(c4noc5cc(F)ccc45)CC3)cc21
Yield: 58.7 %

Procedure:
A mixture of 0.5 g of 2-((3-chloropropyl)thio)-4-oxo-4,5,6,7-tetrahydrobenzo(b)thiophene, 0.5 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 0.6 g of potassium carbonate and 0.4 g of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was mixed at 100° C. for 4 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 0.5 g of 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4-oxo-4,5,6,7-tetrahydrobenzo(b)-thiophene. The resulting compound was dissolved in 20 ml of ethanol, and 0.1 g of hydroxylamine hydrochloride and 0.12 g of sodium hydrogencarbonate were added thereto. After the mixture was refluxed for 3 hours, the solvent was distilled away in vacuo and water was added to the residue, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. To the residue was added isopropyl ether to give 0.5 g of an oxime compound as crystals. A mixture of 0.35 g of the oxime compound and 3.5 g of 115% polyphosphoric acid was stirred at 100° C. for 5 hours, poured into water and extracted with chloroform. The extract was washed with water, dried and concentrated. The residue was separated and purified by column chromatography on a silica gel and each of resulting crystals was recrystallized from isopropyl ether to give 0.06 g of 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, m.p. 119°-121° C. and 0.019 g of 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 125°-127° C.