Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:21][C:22]1[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH:24][N:23]=1.CS(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: COc1cc(CC(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)O)ccc1-c1ccnc(C)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetic acid 182-2 (590 mg, 1.9 mmol) and 2-methyl-4-(tributylstannyl)pyridine (730 mg, 1.9 mmol) in DMF (2.0 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33 mg, 0.04 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give 2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetic acid 182-3. MS m/z 258.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1c[n+]([O-])ccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a mixture of 0.20 g of 2-(3-methylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml of chloroform, 0.30 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred at room temperature for three hours, then diluted with ethyl acetate, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.17 g of 3-methyl-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 24”).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:1][C:2]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: COc1ccc(C(=O)O)c(S)c1
Solvent: c1ccncc1
Product: COc1ccc2c(=O)nc(-c3ccccn3)sc2c1
Yield: 46.8 %

Procedure:
A mixture of 2-mercapto-4-methoxybenzoic acid (1.4 g, 7.9 mmol), 2-cyanopyridine (0.89 g, 8.5 mmol) and pyridine (10 ml) was refluxed for 10 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.0 g, 47%) as crystals.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:34])([F:33])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]([O:30]CC)=O)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>O1CCCC1.CO>[F:3][C:4]([F:33])([F:34])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]([NH:2][CH3:1])=[O:30])=[O:25])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reaction time: 12 h

Procedure:
7.10 ml (14.15 mmol) of a solution of methylamine (2M) in tetrahydrofuran are added to a solution of 1.60 g (3.54 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{4′-[(trifluoro-methyl)oxy]-4-biphenylyl}-1-piperazinecarboxylate, prepared in step 1.3., in 14 ml of methanol. Stirring is continued at room temperature for 12 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. A solid is obtained, and is recrystallized from a mixture of ethyl acetate and diisopropyl ether. 0.86 g of pure product is thus obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[O:6][CH2:5][CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1([CH:7]([CH3:11])[C:8]([NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:10])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC(C(=O)O)C1(C)OCCO1
Reactant: NCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C(=O)NCCc1ccccc1)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-propionic acid of Example 1b (1.60 g, 10 mmol) in dry dichloromethane (15 mL) was cooled to 0° C. under an argon atmosphere. A solution of oxalyl dichloride (2.92 g, 2.0 mL, 23.0 mmol) in dichloromethane (5 mL) was added dropwise. After 5 min at 0° C., the mixture was allowed to warm to room temperature. After stirring for 2 h at room temperature, the excess oxalyl dichloride was removed under reduced pressure to produce a yellow oil which was dissolved in dichloromethane (7 mL). The solution was cooled in an ice bath and phenethylamine (1.12 g, 10.0 mmol) in pyridine (5 mL) was added drop-wise. After the addition was complete, the reaction was warmed to room temperature and allowed to stir overnight. The solution was diluted with dicholoromethane (100 mL) and poured into ice-cold hydrochloric acid (1N, 150 mL). The organic layer was separated and washed with water (100 mL), sodium bicarbonate solution (5%, 50 mL), water (100 mL), and brine (100 mL). After drying with sodium sulfate and concentration on a rotary evaporator, the product was purified by flash chromatography on silica gel, eluting with hexanes-ethyl acetate (3:2) to give 2-(2-methyl-[1,3]dioxolan-2-yl)-N-phenethyl-propionamide (1.81 g, 69%) as colorless crystals.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:18](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was charged with NaH (50 g, 1.25 mol, 60% in mineral oil) and tetrahydrofuran (2,500 ml) and cooled to 0° C. A solution of ethyl 2-(diethoxyphosphoryl)acetate (260 g, 1.16 mol) in tetrahydrofuran F (200 ml) was added dropwise. The resulting solution was allowed stir for 1 h at 0° C. Then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (215 g, 1.16 mol) in tetrahydrofuran (300 ml) was added dropwise. The resulting solution was allowed to stir for 0.5 hours at 0° C. The reaction mixture was quenched by the addition of 1,000 ml of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×2,000 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford tert-butyl-3-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate as colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.[CH:22]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:27]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:29])=[O:28])=[CH:14][CH:13]=2)[N:4]=1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: O=S(=O)(Cl)C1CCCC1
Product: O=S(=O)(NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C1CCCC1

Procedure:
The title compound was prepared from ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine and cyclopentanesulphonyl chloride using a similar procedure to that described for Example 88.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH:14]=[C:10]([CH3:9])[N:11]=[CH:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(Cl)ncn2)cn1
Yield: 36.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine (11.92 g, 80 mmol), 4-methyl-1H-imidazole (6.57 g, 80 mmol), and cesium carbonate (26.1 g, 80 mmol) was stirred in DMF (50 mL) at room temperature for 18 h. The reaction was diluted into 200 mL water and extracted three times with 200 mL EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 300 g silica gel cartridge with 25 to 75% ethyl acetate in hexane to yield a mixture of the two regioisomeric products. The pooled fractions were concentrated to about 200 mL volume and cooled to yield 4-chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine (5.70 g, 37% yield). The positive identification of the 4-methylimidazole regioisomer was accomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (1H, d, J=0.50 Hz), 8.36 (1H, d, J=1.26 Hz), 7.29-7.31 (1H, m), 7.25 (1H, d, J=1.01 Hz), 2.27 (3H, d, J=1.01 Hz). LCMS: RT=0.50 min, MH+=195.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(C(F)(F)F)cc3)c2)CC1
Yield: 98.4 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-(trifluoromethyl)benzoyl chloride (102 μl, 0.687 mmol), 88.0 mg (98%) of the title compound were recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:27]2[CH2:28][CH2:29][C@H:25]([F:24])[CH2:26]2)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CC[C@H](F)C2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following similar methods to those described in Preparation 352 starting from (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.88 mmol) and (S)-3-fluoro-pyrrolidine (165 mg, 1.32 mmol). MS: [M+H]+=392.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].C(Cl)(Cl)Cl>O>[CH2:6]([N:5]([CH2:4][CH:3]1[CH2:2][O:20]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCl)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Yield: 76 %

Procedure:
50.7 g (0.175 mol) of 1-chloro-3-dibenzylamino-2-propanol and 9.5 g (0.24 mol) of sodium hydroxide in 5 ml of water are stirred together for one hour at 95° c. After the addition of 50 ml of chloroform and 20 ml of water, the phases are separated and the organic phase is washed with 20 ml of water, dehydrated with sodium sulphate and concentrated by evaporation. Distillation of the resulting yellow oil under vacuum yields 33.7 g (76%) of the oxirane as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(Cl)cc2Cl)sc1C(=O)NCc1ccccc1
Yield: 21 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2,4-dichlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 21% yield; 1H NMR (CDCl3, 300 MHz) δ 7.74 (d, J=8.3 Hz, 1H), 7.45-7.24 (m, 7H), 5.99 (s, 1H), 4.57 (d, J=5.4 Hz, 2H), 2.35 (s, 3H); MS (ES+) m/z 420.0 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CN(C)C=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C(=O)O)Cc1ccccc1-3
Temperature: 50 °C
Yield: 96.9 %

Procedure:
Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (308 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (5 mL) and treated with LiOH (173 mg, 7.2 mmol). The mixture was heated at 50° C. for 4 hr, afterwhich the solvent was removed in vacuo. The residue was dissolved in H2O (5 mL) and the resultant mixture was acidified by the addition of a 10% aqueous HCL solution. A precipitate formed which was collected by filtration and air dried to afford the title compound as a bright yellow solid (290 mg, 97%). ESI-MS m/z [M+1]=415.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[NH:12][C:13]([CH2:16][CH2:17][C:18]3[N:19]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:20]=[C:21]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][CH3:26])[N:22]=3)=[N:14][N:15]=2)[CH:7]=[CH:8][C:9]=1[F:10].[CH3:35]I>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[N:12]=[C:13]([CH2:16][CH2:17][C:18]3[N:19]([S:29]([N:32]([CH3:33])[CH3:34])(=[O:30])=[O:31])[CH:20]=[C:21]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH3:26])[N:22]=3)[N:14]([CH3:35])[N:15]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCc2nnc(-c3ccc(F)c(F)c3)[nH]2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCc2nc(-c3ccc(F)c(F)c3)nn2C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (21 mg, 0.87 mmol) was added to a solution of 2-{2-[5-(3,4-difluorophenyl)-4H-1,2,4-triazol-3-yl]ethyl}-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (135 mg, 0.29 mmol) in DMF (4 mL) at 0° C., and the reaction was stirred at rt for 30 min. Methyliodide (0.09 mL, 1.4 mmol) was added and stirring continued for 1 hr. The reaction mixture was partitioned between water and diethyl ether. The organic phase was washed with water and brine, dried (sodium sulfate) and concentrated to give a residue. Chromatography of the residue over silica gel (eluting with 60-100% ethyl acetate/hexane) afforded 2-{2-[3-(3,4-difluorophenyl)-1-methyl-1H-1,2,4-triazol-5-yl]ethyl}-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide as an off-white solid.
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][CH:4]=2)[N:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(I)ccc1Oc1cc(Cl)ncn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
6-Iodo-2-methylpyridin-3-ol (2.00 g, 8.51 mmol) and 4,6-dichloropyrimidine (5.00 g, 33.6 mmol) were dissolved in DMA (40 mL) and sonicated and sparged with Ar for 10 min. K2CO3 (2.00 g, 14.5 mmol) was added and the reaction mixture was stirred at 110° C. for 16 h. The mixture was partitioned between water (260 mL) and EtOAc (100 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×25 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 4-chloro-6-((6-iodo-2-methylpyridin-3-yl)oxy)pyrimidine (2.8 g, 95%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z: 348.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13][S:12][C:9]2=[C:10]([Br:22])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (1.07 g, 3.56 mmol) in CCl4 was added N-bromosuccinimide (666 mg, 3.74 mmol) and benzoyl peroxide (43.1 mg, 0.18 mmol). The reaction mixture was refluxed with stirring for 4 h. After cooling to r. t. the mixture was filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title compound as white solid (1.08 g): MS (m/z) 378.9, 380.9 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:36])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[N:27]=[C:28]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)[S:29][CH:30]=3)[CH2:23][C:22](=[O:36])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2csc(-n3ccnc3)n2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K91) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (46 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.CO.O.[NH2:16][NH2:17]>O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[C:3]([NH:16][NH2:17])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(O)c(O)c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(O)c(O)c1

Procedure:
120 g of 3,4-dihydroxybenzoic acid methyl ester was subjected to reaction with 340 ml of methanol and 340 ml of hydrazine hydrate over 3 days at room temperature. Then 340 ml of water was added thereto and the solvent was evaporated in vacuum. Addition of water and evaporation were repeated twice. Subsequently the product was crystallized from 340 ml of water. m.p. 260° C. (decomposed).
Reaction SMILES: C([NH:4][C:5]1[C:18]([F:19])=[CH:17][C:8]([CH:9]([OH:16])[CH2:10][NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:7]([F:20])[CH:6]=1)(=O)C.[OH-].[Na+]>CCO>[NH2:4][C:5]1[C:18]([F:19])=[CH:17][C:8]([CH:9]([OH:16])[CH2:10][NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[C:7]([F:20])[CH:6]=1
Reactant: CC(=O)Nc1cc(F)c(C(O)CNC(C)(C)C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)NCC(O)c1cc(F)c(N)cc1F
Yield: 90 %

Procedure:
A stirred mixture consisting of 3.6 g of 4-acetamido-α-[(tert-butylamino)methyl]-2,5-difluorobenzyl alcohol, 36 mL of EtOH and 36 mL of 10% aqueous NaOH is heated at reflux under N2 for 4 h. The EtOH is evaporated in vacuo and the residue is extracted with 4×60 mL of CH2Cl2. The combined organic extracts are washed with 25 mL of H2O, dried with anhydrous Na2SO4 and evaporated in vacuo to furnish the title compound which is crystallized from CH3CN/hexane, 2.77 g (90% yield), m.p. 115°-116° C.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:32]>CO>[ClH:32].[ClH:32].[NH2:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (38 mg, 0.075 mmol, from Step A), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent gave 34 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD): δ 2.59–2.66 (m, 2H), 2.92 (m, 2H), 3.89–4.16–4.22 (m, 5H), 4.70–4.84 (m, 2H), 5.42 (m, 1H), 6.86 (m, 1H), 7.06 (m, 1H), 7.24 (m, 1H). ESI-MS 407(M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[C:5]([OH:16])[NH:4][N:3]=1.[C:17]1(=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[O:18]1>C(O)(=O)C>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[C:5]([OH:16])=[N:4][NH:3][C:2]=1[N:1]1[C:17](=[O:18])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:26]
Reactant: Nc1n[nH]c(O)c1Cc1cccc(Cl)c1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1[nH]nc(O)c1Cc1cccc(Cl)c1Cl
Yield: 47.8 %

Procedure:
A mixture of 3-amino-4-(2,3-dichlorobenzyl)-1H-pyrazol-5-ol (18 g, 70 mmol) and isobenzofuran-1,3-dione (20 g, 140 mmol) in acetic acid (100 mL), was stirred under reflux for 16 h. The reaction mixture was cooled and filtered to provide the titled compound (13 g, 50%); LC/MS: MS (ES+) m/e 388 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.66 (s, 2H), 7.20-7.31 (m, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.99-8.02 (m, 2H), 8.11 (s, 2H), 8.25-8.28 (m, 2H).