Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:20]([C:21]2[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=2[F:31])[C:19]2[C:18](=[O:32])[CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][C:14]=2[NH:13][C:12]=1[CH3:40])=[O:10].CO.Cl.[H][H]>[Pd].O>[Cl:2][C:3]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:20]([C:21]2[C:22]([F:31])=[C:23]([F:30])[C:24]([F:29])=[C:25]([F:28])[C:26]=2[F:27])[C:19]2[C:18](=[O:32])[CH2:17][NH:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH3:40])=[O:10]
Reactant: CC1=C(C(=O)OCCOc2cccc(Cl)c2Cl)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CN(Cc3ccccc3)CC2=O)N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)OCCOc2cccc(Cl)c2Cl)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CNCC2=O)N1
Reaction time: 72 h

Procedure:
The hydrochloride from above (10 g), 500 ml of methanol, 25 ml of water, 5 ml of concentrated hydrochloric acid and 0.5 g of 10% palladium on carbon were shaken with hydrogen (45 psig initial pressure) for 4 hours. The catalyst was separated and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and shaken with dilute sodium hydroxide solution. The ethyl acetate solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in methanol and saturated with hydrogen chloride. The solution was evaporated to dryness. The residue crystallized on standing with ethyl acetate for 3 days. The solid was treated with boiling ethyl acetate and filtered to obtain the title compound as the hydrochloride, m.p. 228°-231° C. dec.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:11]([SH:14])[CH2:12][SH:13]>C(Cl)(Cl)Cl>[CH3:2][C:3]1[CH:4]=[C:5]([CH:6]2[S:14][CH2:11][CH2:12][S:13]2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C=O)c1
Reactant: SCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C2SCCS2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Anhydrous HCl was bubbled rapidly for about 5 minutes through a solution of 46.87 gm (0.39 moles) of 3-methylbenzaldehyde and 44.92 gm (0.477 moles) of 1,2-ethanedithiol in 300 ml of CHCl3. During the addition of HCl, there was a slight exotherm with a rise in temperature to about 60° C. After completion of the addition of HCl, the reaction was stirred for 1 hour at room temperature, washed twice with 100 ml portions of water, dried with MgSO4, and fractionated to give 54.55 gm (0.278 moles) of a clear, colorless liquid (71% yield) b.p. 108°-110° C. (0.2 mm/Hg). Elemental analysis for C10H12S2 :
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]=[C:13](OCC)[NH:12]3)[CH2:10][C:9]([CH3:21])([CH3:20])[O:8][C:5]2=[CH:6][CH:7]=1.[NH3:22].O>CCO>[NH2:22][C:13]1[NH:12][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]([CH3:20])([CH3:21])[CH2:10]2)[C:15](=[O:16])[N:14]=1
Reactant: CCOC1=NC(=O)C2(CC(C)(C)Oc3ccc(Br)cc32)N1
Reactant: N
Solvent: CCO
Solvent: O
Product: CC1(C)CC2(NC(N)=NC2=O)c2cc(Br)ccc2O1
Yield: 30 %

Procedure:
To a solution of 6-bromo-2′-ethoxy-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (500 mg, 1.42 mmol) in EtOH (30 mL) was added NH3.H2O (30 mL). The mixture was refluxed for 18 h. The solvent was removed in vacuo to give a residue, which was purified by preparative TLC to give 2′-amino-6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(3′H)-one (120 mg, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:18][C:12]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a solution of 3-nitrophenol (7.5 g, 53.9 mmol) and ethyl 2-bromo-2-methylpropanoate (12.62 g, 64.7 mmol) in DMF (25 ml) was added K2CO3 (14.90 g, 108 mmol). After stirring at rt for 16 hr, the reaction mixture was concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate (3×30 ml), the combined organic layer was washed with NaOH solution (10%, 75 mL), water (75 mL) and brine, dried over sodium sulphate and concentrated under vacuum to give the title product (6.7 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[C:6]([O:31][CH3:32])[CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:11]=2)=[C:6]([O:31][CH3:32])[CH:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1OC
Temperature: 60 °C
Yield: 78.9 %

Procedure:
A solution of sodium hydroxide 10N (0.2 mL; 2 mmol) was added to a mixture of methyl 2-(4-(4-chloro-2-methoxyphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.063 g; 0.148 mmol) in methanol (2 mL). The mixture was heated at 60° C. in a sealed tube for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate formed. The precipitate was collected by filtration and dried under reduced pressure over phosphorus pentoxide to afford 0.048 g (77%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][C:25]1=[O:30].C(N(CC)CC)C>O1CCCC1>[C:7]([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][C:25]1=[O:30])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1CCCNC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 45.3 %

Procedure:
Add triphenylmethyl chloride (35.11 g, 126.0 mmol) to a suspension of 3-amino-piperidin-2-one dihydrochloride (21.42 g, 114.5 mmol) in tetrahydrofuran (250 mL), follow by dropwise addition of triethylamine (55.9 mL, 400.8 mmol). Stir the reaction at room temperature under nitrogen overnight. Filter the mixture, wash with tetrahydrofuran, concentrate the filtrate to a yellow oil, and partition the material between 20% isopropanol/chloroform and water. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1.25% methanol/chloroform) which gives 18.50 g of the title compound as a white foam, 45% yield. 1H NMR: consistent with structure. MS (ion spray) 113 (M+−1).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[CH2:12][N:13]([C:16]1[N:21]=[N:20][C:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][CH2:2][CH2:3][CH2:4][CH3:5])=[C:11]([CH:29]=1)[CH2:12][N:13]([C:16]1[N:21]=[N:20][C:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: CCCCI
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCCCC)nn1

Procedure:
The title compound was prepared by reacting 1-iodobutane and butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate using a similar method to that of reference example 4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([SH:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]3[O:40][CH2:39]3)[C:33]([O:35]C)=[O:34])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]([OH:40])[CH2:39][S:11][C:9]3[S:10][C:6]4[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=4[N:8]=3)[C:33]([OH:35])=[O:34])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: CCOc1ccc2nc(S)sc2c1
Product: CCOc1ccc2nc(SCC(O)CC(NS(=O)(=O)c3ccc(-c4ccc(OC)cc4)cc3)C(=O)O)sc2c1

Procedure:
Example 25 is prepared from 6-ethoxy-2-mercaptobenzothiazole and 1d using the procedure described for compound 20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)[C@H](C)O.O>[CH:8](=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC=Cc1ccccc1
Reactant: Nc1ccccc1
Agent: CCOC(=O)[C@H](C)O
Solvent: O
Product: C(=Cc1ccccc1)C=Nc1ccccc1
Reaction time: 0.07 h

Procedure:
10 mmol aniline was dissolved in approximately 2.5 mL 80% ethyl L-lactate in water (v/v). Separately, 10 mmol of cinnamaldehyde was dissolved in approximately 2.5 mL 80% ethyl L-lactate in water (v/v). The two solutions were combined and the resulting reaction mixture was swirled until homogeneous and then allowed to sit undisturbed at room temperature for four minutes, when crystal formation was complete. Crystals were chilled, rinsed with cold brine and vacuum filtered, washed with cold water, and allowed to air dry. Some of the hydroxyl-containing imines had to be desiccated to completely remove water, especially when humidity was high. All melting points and spectroscopic data were acquired on the crude imines. However, these imines can be recrystallized from ethyl lactate or low molecular weight alcohols.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nccc(Nc2ccc3[nH]ncc3c2)n1
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-aminoindazole (1 mmol) dissolved in 5 ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulted oil was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine in a yield of 80%.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[C:15]([CH3:37])([CH3:36])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[C:15]([CH3:37])([CH3:36])[CH2:14]2
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)NS(=O)(=O)C3CC3)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a suspension of 60% sodium hydride (294 mg, 7.4 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (908 mg, 7.5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (300 mg, 0.75 mmol) and 1,1′-carbonyldiimidazole (244 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (113 mg, 30%) as a white solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 505.05, observed: 504.0.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[C:4]([OH:11])(=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]>O>[C:4]([O-:11])(=[O:10])[CH2:5][CH2:6][C:7]([O-:9])=[O:8].[Mg+2:2]
Reactant: O=C(O)CCC(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCC(=O)[O-]

Procedure:
Magnesium hydroxide (99 g) was added to a solution of 200 g succinic acid in 888 g water at room temperature and heated up to complete dissolution (by visual observation).
Reaction SMILES: [OH-:1].[Na+:2].[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:15]([OH:18])([OH:17])=[O:16])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1>O.CC(O)C.CO.C(O)C>[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:11]([O-:14])([OH:13])=[O:12])([P:15]([O-:17])([OH:18])=[O:16])[OH:10])[CH:4]=1.[OH2:1].[OH2:10].[OH2:10].[OH2:10].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (0.7 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38 ml) was added drop-wise to a suspension of Zoledronic acid form XII (4.98 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate disodium crystal form VII.
Reaction SMILES: [C:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2].S(Cl)([Cl:17])=O>>[C:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1ccc(C(=O)O)cn1
Product: CCOC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
The starting material is prepared as follows: The suspension of 10 g of 6-carbethoxynicotinic acid in 40 ml of thionyl chloride is refluxed for 2 hours and evaporated. The residue is suspended in toluene and the mixture again taken to dryness. Another such cycle is repeated to yield the pure 6-carbethoxynicotinoyl chloride. It is dissolved in 150 ml of acetone and the solution cooled in an ice bath to 10°. 4.2 g of sodium azide, dissolved in 20 ml of water, are added dropwise to the acetone solution, whereupon a solid separates after several minutes. The mixture is stirred for 2 hours in the ice bath, then 150 ml of ice water are added and the solid is collected and washed with ice water, to yield the 6-carbethoxynicotinoyl azide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)COc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)COc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-2-phenoxy-ethyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[S:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[S:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)sc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 71 mg (0.23 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzothiazol-2-one and 0.047 mL (0.27 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The reaction mixture was taken up in acetonitrile/water and purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[N:18]=2)=[O:16])[CH2:10]1)=O)(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[NH2:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[N:18]=2)=[O:16])[CH2:10]1
Reactant: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.20 g (6.14 mmol) of cis-3-t-butoxycarbonylamino-4-methyl-1-(1-methylindazol-3-ylcarbonyl)pyrrolidine in 22 ml of ethanol was added 11 ml of ethanol saturated with hydrogen chloride at room temperature, and then the mixture was stirred for 3 hours at room temperature. After completion of the reaction, solvent was distilled off and resultant residue was crystallized with addition of dioxane to give 1.81 g (quantitative) of aimed compound. m.p. 177°-180° C.
Reaction SMILES: OO.Cl[C:4]1C(C(SC2C=NC(Cl)=CC=2)C2C=CN=CC=2)=NC(Cl)=CC=1.C(OCC)(=O)C.[Si:32]([O:39][CH2:40][CH2:41][CH:42](C)[CH:43]([C:54]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:55]=1[F:61])[S:44]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CO.CCCCCC>[Si:32]([O:39][CH:40]([CH3:4])[CH2:41][CH2:42][CH:43]([C:54]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:55]=1[F:61])[S:44]([C:47]1[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=1)(=[O:46])=[O:45])([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34]
Reactant: Clc1ccc(SC(c2ccncc2)c2nc(Cl)ccc2Cl)cn1
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: OO
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
A 31% aqueous hydrogen peroxide solution (2 ml) and hexaammonium heptamolybdate tetrahydrate (30 mg) were added to a solution of 3,6-dichloro-2-[(6-chloropyridin-3-ylthio) (pyridin-4-yl)methyl]pyridine (82 mg, 0.24 mmol) in methanol (4 ml). The resulting mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture. After washing with a saturated aqueous solution of sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. A fraction obtained from the elution portion with hexane:ethyl acetate=3:2 was concentrated under reduced pressure, whereby the title compound A (41 mg, 0.098 mmol, 46%) was obtained. A fraction obtained from the elution portion with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, whereby the title compound B (isomer A) (low polarity) (8 mg, 0.020 mmol, 9%) and the title compound B (isomer B) (high polarity) (8 mg, 0.020 mmol, 9%) were obtained, respectively each as a white solid.
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH2:21][OH:22])=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[N:10]1[NH:9][N:8]=[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH2:21][OH:22])[CH:11]=1
Reactant: OCc1cc(Cl)ccc1Nc1cnnn1Cc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: OCc1cc(Cl)ccc1Nc1cn[nH]n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2-[(3-benzyltriazol-4-yl)amino]-5-chloro-phenyl]methanol 7a (300 mg, 0.95 mmol) in MeOH (5 mL) was treated with formic acid (1.00 mL, 26.51 mmol). The mixture was degassed by vacuum/nitrogen cycles before the addition of palladium on carbon (507.1 mg, 0.48 mmol). The mixture was stirred under an argon atmosphere at room temperature for 18 h and then filtered through celite and concentrated. The material was purified by FractionLynx to afford the title compound I-9 as a solid (90.0 mg, 40%). 1H NMR (500 MHz, DMSO) δ 14.20 (1H, s), 7.85-7.80 (1H, s), 7.60 (1H, s), 7.51 (1H, s), 7.31 (1H, d), 7.19 (1H, d), 4.55 (2H, s). MS m/z: 223.1 (M−H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][N:11](Cl)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:27]#[N:28])(C)C.O1CCOCC1>[I-].[Zn+2].[I-].O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][CH:10]1[C:27]#[N:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: ClN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Product: N#CC1NC[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the toluene solution was added zinc iodide (0.5 g) and trimethylsilyl cyanide (20 ml, 160 mmol). The mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Dioxan (5 ml) and water (5 ml) were added and stirring was continued for 11/2 hour at room temperature. Water (150 ml) was added, the organic phase isolated and washed with water (200 ml), dried with magnesium sulphate and evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: ethyl acetate) afforded (3R,4R)-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (13.5 g, yield: 82% overall) as an oil.