Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:36])[CH2:11][CH2:12][N:13]([CH:33]([CH3:35])[CH3:34])[C:14](=[O:32])[C:15]1[CH:20]=[C:19]([O:21][CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:18]=[C:17]([CH3:31])[CH:16]=1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:33]([N:13]([C:14](=[O:32])[C:15]1[CH:20]=[C:19]([O:21][CH2:22][CH2:23][NH:24][C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[CH:18]=[C:17]([CH3:31])[CH:16]=1)[CH2:12][CH2:11][C:10]([OH:36])=[O:9])([CH3:35])[CH3:34]
Reactant: COC(=O)CCN(C(=O)c1cc(C)cc(OCCNc2ccncc2)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Yield: 89.5 %

Procedure:
To a solution of 3-(isopropyl-{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-amino)-propionic acid methyl ester trifluoroacetate (0.031 g) in dioxan (1 ml) was added 2M aqueous sodium hydroxide (0.078 ml), and the resultant solution was stirred at room temperature for 3 h. 1M Aqueous hydrochloric acid (ca 0.5 ml) was added and the resultant solution was concentrated under reduced pressure. Th residue was subjected to preparative hplc and the title compound (0.027 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:21])[C:3]=1[C:4]#[N:5].Cl.CCO.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:21])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1c(F)cc(-c2ccn[nH]2)cc1Cl
Yield: 94.1 %

Procedure:
2-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (1.09 g, 3.55 mmol) was stirred with 10% HCl (g)/EtOH-solution (50 ml) at room temperature for 1 h. Reaction mixture was poured into water (50 ml) and made slightly alkaline with saturated NaHCO3 solution. Thus resulting precipitate was filtered, washed with water and dried in vacuum to obtain 0.74 g (94%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.06 (d, 1H), 7.94 (dd, 1H), 8.05 (m, 1H), 13.4 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:13][C:11]2[S:10][CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][C:3]([F:14])=[C:2]([CH3:1])[CH:7]=3)[N:12]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Product: Cc1cc(-c2csc(NS(=O)(=O)c3cccc(Cl)c3C)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (39.7 mg) with purity >90%. MS (pos) m/z 397.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[C:19]#[CH:18]
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(NC(=O)c2ccccc2C)c1
Yield: 87.4 %

Procedure:
A mixture of 22.7 g (0.1 mol) of 3'-hydroxy-2-methylbenzanilide, 11.9 g (0.1 mol) of propargylbromide, 10.6 g (0.1 mol) of sodium carbonate and 250 ml of acetone was prepared and the nixture was refluxed for 4 hours with stirring. After cooling, the reaction mixture was filtered and the acetone was removed by distillation. The residual material was dissolved in benzene, washed with water and dehydrated over anhydrous sodium sulfate. The benzene was removed and the product was recrystallized from aqueous ethanol to obtain a 23.2 g (87.7%) of fine white needles having a melting point of 93°-95° C. EXAMPLE 8
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:8].Cl.[OH-].[K+]>C(Cl)Cl>[CH2:7]([N:9]1[CH2:14][CH2:13][N:12]([C:2]([CH3:6])([CH3:5])[CH:3]=[O:4])[CH2:11][CH2:10]1)[CH3:8]
Reactant: CCN1CCNCC1
Reactant: CC(C)(Br)C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN1CCN(C(C)(C)C=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 2-bromo-2-methyl-propanal (2504 mg, 16.58 mmol), prepared as in Example 5, in 15 mL of DCM was added 1-ethylpiperazine (2.53 mL, 19.9 mmol) and TEA (2.31 mL, 16.58 mmol) and the solution stirred at rt for 24 hours. The mixture was worked up with 1N HCl (50 mL) and DCM (50 mL×2). The aqueous was basified with KOH to pH ˜11 and washed with DCM (50 mL×3). The organic layers were washed with saturated sodium chloride, dried (MgSO4), and then concentrated to obtain 2-(4-ethylpiperazin-1-yl)-2-methyl-propanal (90% yield) as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:19]([CH3:20])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C@H:2]1[C@@H:19]([CH3:20])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@H](C)[C@H](C)NC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1NC(=O)c2cc3ccc(C(=O)O)cc3n2[C@@H]1C
Temperature: 80 °C
Yield: 95.5 %

Procedure:
To a suspension of ethyl cis-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-α]indole-7-carboxylate (2.1 g, 7.3 mmol) in ethanol (60 mL) is added 1M NaOH solution (20 mL, 20 mmol). The reaction mixture is heated at 80° C. for 1 h and then cooled to room temperature. The reaction mixture is acidified using concentrated HCl and ethanol is removed under vacuum. The resulting solid is filtered, rinsed with water and dried to afford the title compound (1.8 g, 96%).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:9]([C:11]#[N:12])=[CH:10][C:5]2=[N:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:8]1[C:9]([C:11]#[N:12])=[CH:10][C:5]2[N:6]([C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: N#Cc1cc2nnc(Cl)n2cc1-c1ccc(Cl)cc1Cl
Reactant: C1COCCN1
Product: N#Cc1cc2nnc(N3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Reaction time: 5 h

Procedure:
A solution of the crude [3-chloro-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (50 mg, 0.148 mmol) in morpholine (1.2 mL) was heated at 110° C. and stirred for 5 h. The reaction mixture was concentrated in vacuum, the remaining residue was suspended in water (10 mL) and extracted with AcOEt (3×5 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to give the crude 6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile, which was used without further purification. MS: 374 [M+1+]; HPLC: AtRet=1.94.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12].[OH-].[Na+]>O>[CH2:10]([NH:13][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=1)[CH2:11][NH:12][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(N)nc(NCCNc2nc(N)nc(N)n2)n1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
29.1 g of 2,4-diamino-6-chloro-s-triazine was added to 300 ml of water to obtain a slurry. Then 6 g of ethylenediamine was added thereto, and the mixture was stirred for 15 minutes. Then, 16 g of a 25 wt% sodium hydroxide aqueous solution was added thereto, and the mixture was refluxed under heating for two hours. At that time, about 3 g of a 25 wt% sodium hydroxide aqueous solution was further gradually added over a period of two hours to maintain the reaction solution in a weakly alkaline state. After completion of the reaction, the reaction mixture was left to cool, whereupon the crystals were collected by filtration and washed with water to obtain 25.3 g of ethylenebismelamine. Then, 5.9 g of ethylenebismelamine and 17 g of formaline were mixed, and mixture was subjected to a heating reaction at 90° C. for 4 hours while maintaining the mixture at pH 9 to 10 with an aqueous sodium hydroxide solution. Then, the formed methylol product was taken out, and 30 ml of methanol was added thereto. The mixture was adjusted to pH 4 with hydrochloric acid. After the solution became uniform, it was heated for 5 minutes and neutralized. Then, methanol was distilled off to obtain 3.2 g of methoxymethylated ethylenebismelamine. The product was analyzed by IR and NMR and was found to be a mixture containing octamethoxymethylethylenebismelamine as the main component.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:27]=2)=[N:7][N:6]=1)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>CS(C)=O.O>[N:38]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:27]=2)=[N:7][N:6]=1)=[N+:39]=[N-:40]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N=[N+]=[N-])s3)ccc21
Temperature: 60 °C
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (300 mg, 0.554 mmol) in DMSO (3 mL) was added sodium azide (215.8 mg, 3.32 mmol). The reaction was heated at 55-65° C. for 4 h, then diluted with H2O and extracted with EtOAc (80 mL×3). The combined organic layers were washed with water (50 mL×4), dried, filtered and concentrated to give the crude material (240 mg). MS (ESI, pos. ion) m/z: 505 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of (4-phenoxy-phenyl)-methanol (408 mg, 2.04 mmol) in carbon tetrachloride (8.2 mL) was added triphenylphosphine (642 mg, 2.45 mmol) under nitrogen atmosphere at room temperature, and the reaction solution was stirred under reflux for 7 hours and 40 minutes. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (409 mg, 92%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH2:8])[CH2:3]1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)Cl>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH2:3]1
Reactant: NC1CCCC(N)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1CCCC(NS(=O)(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 1,3-diaminocyclohexane (1.14 g, 10 mmol, undetermined isomer mixture) in methylene chloride (50 mL) was cooled to 0° C. and phenylsulfonyl chloride (0.64 mL, 5 mmol) was added dropwise. The mixture was stirred at 0° C. for 4 h, then 1N sodium hydroxide solution (10 mL) was added and the mixture stirred an additional 5 min. The phases were separated, the organic phase was dried (K2CO3), filtered, and concentrated in vacuo. Toluene was added and the mixture re-concentrated to remove any remaining diamine, to give 0.77 g of a semi solid. 1H—NMR was consistent with the desired structure. MS (ion spray) 255 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:14]#[N:15])[CH2:10][C@H:9]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:18]=2)[C:14]2[N:33]=[N:34][NH:35][N:15]=2)[CH2:10][C@H:9]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H]1C[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of the crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butylester (52 mg, 0.11 mmol), sodium azide (72 mg, 1.11 mmol) ammonium chloride (60 mg, 1.11 mmol) in DMF (2 mL) is stirred at 90° C. for 12 hours. The reaction mixture is diluted with water after letting it cool to room temperature. The product is extracted twice with EtOAc. The combined organic layer is washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is passed through silica pad (eluent: n-hexane/EtOAc) to give crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[N:28][CH:29]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:33][N:31]([CH3:32])[C:30]([C:27]1[N:28]=[CH:29][C:24]([O:23][C:21]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:10](=[O:9])[NH:1][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)[CH:22]=2)=[CH:25][N:26]=1)=[O:34]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Product: CN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (152 mg, 1.56 mmol) and 4-(2-dimethylcarbamoyl-pyrimidin-5-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (164b) (58 mg, 0.16 mmol) to give a white solid (64 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1 H) 8.47 (s, 2 H) 7.20-7.34 (m, 1 H) 7.07 (d, J=1.52 Hz, 2 H) 6.76 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 3.14 (s, 3 H) 2.98 (s, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H24N6O4 m/z 437.00 (M+H+); Anal. Calcd. for C22H24N6O4.0.15 CHCl3: C, 58.55; H, 5.36; N, 18.50; Found: C, 58.59; H, 5.45; N, 18.61.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride from Example 746 (150 mg, 0.28 mmol) and DIPEA (192 μL, 1.12 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (22 μL, 0.28 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 765 (67 mg, 44%). LCMS (method I): RT 3.30 min, [M+H]+ 541.2. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.64 (1 H, m), 7.25-7.24 (2 H, m), 6.05 (1 H, s), 4.26 (4 H, brd s), 3.96 (3 H, s), 3.78 (4 H, t, J=4.60 Hz), 3.61 (2 H, s), 3.44-3.41 (1 H, m), 3.28-3.26 (2 H, m), 3.06-3.03 (1 H, m), 2.95 (3 H, s), 2.17-2.14 (1 H, m), 2.09-1.92 (2 H, m), 1.80-1.70 (1 H, m), 1.33 (3 H, t, J=7.43 Hz)
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N(CC)CC)C.[CH2:22]([OH:26])[CH:23]([CH3:25])[CH3:24]>>[OH:13][C:12]1[C:3]([CH2:2][O:26][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: CC(C)CO
Solvent: CCN(CC)CC
Product: CC(C)COCc1c(O)ccc2c1CCCC2=O
Temperature: 108 °C

Procedure:
To a solution of 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one, prepared as described Chem. Pharm. Bull. 25(11)2988-3002(1077), (0.211 g, 0.001 mol) and triethylamine (0.167 ml, 0.0012 mol, Mallinckrodt) contained in a 16×125 mm screw top glass tube, was added isobutyl alcohol (3 ml, Aldrich Chemical). The tube was capped with a teflon lined cap and placed on an orbital mixing heat block at reflux temperature (˜108° C.) for 16 hrs. The reaction mixture was concentrated in vacuo to a pink-red syrup. On addition of ethyl ether, a pinkish solid precipitated from the syrup. Washed mixture with 5% citric acid, brine, and dried organic phase over anhydrous sodium sulfate. Evaporated mixture in vacuo to yield a red-pink powder, 0.210 g, 85% crude yield. Low resolution mass spectroscopy (APCI) 249 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid (5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:18])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:19]([C@@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](Cl)=O)[CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20]>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[NH:7][C:6](=[O:18])[C:5]3=[C:2]([CH2:3][CH3:4])[N:1]=[C:29]([C@H:26]4[CH2:27][CH2:28][C@@H:23]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:24][CH2:25]4)[N:10]3[N:9]=2)=[CH:12][CH:13]=1
Reactant: CCC(N)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccc(Br)cc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 23A, 7.6 g (24.6 mmol) 6-(1-aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one (Example 29A), 4.98 g (24.55 mmol) cis-4-tert-butylcyclohexylcarbonyl chloride (Example 42A) and proportionate amounts of the other reagents are used.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[C:3](=[NH:7])[O:4]CC.[O:18]1CCC[CH2:19]1>C1(C)C=CC=CC=1>[F:17][C:14]([F:15])([F:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:2]1[O:1][C:19](=[O:18])[NH:4][C:3]1=[O:7]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2ccccc2C(F)(F)F)O1

Procedure:
By the procedure of Method A of Example 12, ethyl 1-hydroxy-1-(2-trifluoromethylphenyl)methanecarboximidate (10 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-trifluoromethylphenyl)oxazolidine-2,4-dione (5.3 g., 54%; m.p. 91°-93° C.; m/e 245)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:9]([N:22]1[CH2:25][CH:24]([O:26][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: Brc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Yield: 68.5 %

Procedure:
This compound was prepared by the method outlined for example 5 step 1. Thus 5-bromo-2-chloropyridine (31.31 g, 0.163 mol) and 1-benzhydryl-azetidin-3-ol (38.92 g, 0.163 mol) were reacted to afford title compound (44.14 g, 64%) as light brown solid.
Reaction SMILES: Cl.O.[OH:3][B:4]1[C:8]2[CH:9]=[C:10]([O:14][C:15]3[S:16][C:17]([N+:20]([O-])=O)=[N:18][N:19]=3)[CH:11]=[C:12]([CH3:13])[C:7]=2[CH:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:5]1>C(O)C.[Fe]>[NH2:20][C:17]1[S:16][C:15]([O:14][C:10]2[CH:11]=[C:12]([CH3:13])[C:7]3[CH:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:5][B:4]([OH:3])[C:8]=3[CH:9]=2)=[N:19][N:18]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Temperature: 85 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Concentrated aq. HCl (50 mL) and water (1000 mL) were added to a mixture of ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (70 g, 0.18 mol) and iron powder (51 g, 0.9 mol) in ethanol (3000 mL) at room temperature. The resulting mixture was stirred at 85° C. for 2 hrs, cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated and the residue dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to give compound ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (40 g, 63% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (1H, s), 7.32 (1H, m), 7.16 (1H, m), 7.15 (2H, s), 5.50 (1H, m), 4.03 (2H, m), 3.08 (1H, m), 2.32 (4H, m), 1.10 (3H, m).