Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1>C(#N)C>[CH:1]1([CH:6]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC=CC1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 65 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
Method B. Into a four-neck 250 mL round bottom flask equipped with a stir bar, thermocouple, condenser and nitrogen inlet was charged (3S)-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 13.9 g, 31.5 mmol), acetonitrile (84 mL) and 3-cyclopentylacrylonitrile (8, a mixture of E and Z isomers, 3.82 g, 31.5 mmol, 1.0 equiv) at room temperature. The resulting mixture was then treated with cesium carbonate (Cs2CO3, 2.57 g, 7.88 mmol, 0.25 equiv) at room temperature. The reaction mixture was warmed to 65° C. and checked after 12 hours by chiral HPLC to determine the enantiomeric ratio of compound (R)-10 to compound (S)-10. When the ratio of compound (R)-10 to compound (S)-10 reached to one to one, the reaction mixture was then allowed to cool to room temperature gradually and stirred at room temperature for 24 to 48 h. The reaction mixture was monitored by HPLC to determine the level of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5). The reaction was considered complete when the level of compound 5 was found to be ≦2% by HPLC area %. The reaction mixture was then filtered through a Celite pad to remove insoluble solids present in the reaction solution. The filtrates were then concentrated under reduced pressure to remove about 40 mL of solvent. The concentrated solution was diluted with ethyl acetate (40 mL) and washed with 1 N aqueous HCl solution (40 mL). The two layers were separated, and the aqueous acid wash solution was back extracted with ethyl acetate (20 mL). The combined organic fractions were washed with 1 M aqueous sodium bicarbonate (NaHCO3) solution (45 mL) and 20% (w/w) brine solution (40 mL). The organic fraction was dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to afford the crude racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 13.6 g, 13.9 g theoretical, 97.8%) as an amber oil, which was found to be identical to the material made by Method A. This crude product was found to be pure enough (>96 area % by HPLC) and was directly used in the subsequent chiral separation without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:19][CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH2:29])=[C:24]([CH3:32])[CH:23]=1)[CH3:18]>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([NH:29][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])=[CH:23][C:24]=2[CH3:32])=[N:3][CH:4]=[N:5][C:6]=1[CH3:9]
Reactant: Cc1ncnc(Cl)c1Cl
Reactant: CCOCCc1ccc(OCCN)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1
Yield: 75.7 %

Procedure:
1.6 g of 4,5-dichloro-6-methylpyrimidine was dissolved in 50 ml of toluene. 1.0 g of triethylamine and 2.2 g of 2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethylamine were added to the solution, and the reaction mixture was heated under reflux for 5 hours, whilst stirring. At the end of this time, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The toluene was removed by distillation under reduced pressure, and the oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to isolate the product. The crystals thus obtained were recrystallized from hexane to afford 2.6 g of the title compound as colorless needles melting at 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[O:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:15]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(Cl)c1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3Cl)n2)cc1
Yield: 68.9 %

Procedure:
Using 2-[(E)-2-(2-chloro-4-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (243 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (304 mg) as colorless needle crystals.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([O:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCOC1CCC(C2CCC(O)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC1CCC(C2CCC(OS(C)(=O)=O)CC2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4′-propoxybicyclohexyl-4-ol (1 g) and triethylamine (0.81 ml) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (0.39 ml) at 0-5° C., and stirred for 3 hours. The reaction mixture was washed with water and brine, and dried, and evaporated under reduced pressure to give 4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.44 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH2:29][SH:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH2:29][S:30][C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:15][CH:14]=3)=[O:13])[CH:20]=[CH:19][C:18]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CS)ccc21
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Product: C=CCOC(=O)c1ccc(C(=O)SCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.34 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylmethanethiol, 3.4 g (81%) of the expected allyl ester, melting point 79°-80° C., are obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:21](=[O:22])[CH2:20][CH2:19][C:18]3=[O:23])[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:21](=[O:22])[CH2:20][CH2:19][C:18]3=[O:23])[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Product: Nc1cccnc1Nc1cccc(N2C(=O)CCC2=O)c1
Yield: 92.1 %

Procedure:
The solution of 3-nitro-2-(3-succinimidophenylamino)-pyridine (3.47 g) was hydrogenated with palladium on carbon (0.5 g) at 3 atm for 5 hours. The mixture was filtrated and evaporated to give 3-amino-2-(3-succinimidophenylamino)pyridine (2.89 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:11]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:15]=2[F:14])=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1nc(N)sc1C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc(NC(=O)c2cc(C(F)(F)F)ccc2F)sc1C(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.4 %

Procedure:
A mixture of commercially available methyl 2-amino-5-isopropylthiazole-4-carboxylate (1 g, 4.99 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.31 g, 5 mmol) in anhydrous CH2Cl2 (25 mL) was treated dropwise at 0° C. with triethylamine (0.84 mL, 6 mmol). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with hexanes-EtOAc (1:1) to afford 1.8 g of the title compound. MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([N+]([O-])=O)[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[N+:9]=1[O-:10].[OH:21][CH2:22][CH2:23][OH:24]>>[OH:21][CH2:22][CH2:23][O:24][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[N+:9]([O-:10])=[C:4]([CH3:3])[CH:5]=1
Reactant: OCCO
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-c2cc(OCCO)cc(C)[n+]2[O-])n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Sodium hydride (2.07 g, 51.8 mmoles) was added to 1,2-dihydroxyethane (100 ml). After 15 minutes 6,6'-dimethyl-4-nitro-2,2'-bipyridine-N-oxide (17) (6.35 g, 25.9 mmoles) was added and the mixture was stirred at 60° C. for 4 hours. Excess of 1,2-dihydroxyethane was removed by evaporation in high vacuum and the product was purified by flash chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([N+:23]([O-])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1

Procedure:
Dissolve 2(S)-(2-cyclohexylethyl)-5-(R)-(1-(R)-hydroxy-2-(S)-nitro-3-phenylpropyl)-morpholine-4-carboxylic acid tert-butyl ester (152 mg, 0.32 mmol) in methanol (5 mL), and place in a room temperature oil bath. Add dry nickel (II) chloride (62 mg, 0.48 mmol) followed by sodium borohydride (30 mg, 0.80 mmol). After 3 minutes add a second portion of sodium borohydride (30 mg, 0.80 mmol). Quench with water (1 mL) then 0.1 N sodium hydroxide (3 mL). Dilute with ethyl acetate and extract (3×30 mL). Wash the combined extracts with saturated aqueous sodium chloride, filter through a pad of Celite®, dry (sodium sulfate) and concentrate to give the desired compound as a white solid which is used without further purification (140 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]([C@@H:9]([NH:11]C(=O)OC(C)(C)C)[CH3:10])=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cc(F)ccc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of (S)-tert-butyl 1-(5-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)ethylcarbamate (661 mg, 1.9 mmol) in DCM (9 mL) was added TFA (4.5 mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM (20 mL) and a saturated solution of NaHCO3 (40 mL). The two phase system was stirred for 10 min, then the organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) affording (S)-1-(5-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine as a yellow oil (379 mg, 78%). LCMS: RT 1.77 min [M+H]+ 256.2
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][NH:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: Nc1nncs1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2nncs2)c(OC)c1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 2-amino-1,3,4-thiadiazole (3.05 g, 0.0302 mol) and 2,4-dimethoxy-benzaldehyde (4.55 g, 0.0274 mol) in dichloromethane (125 mL) was added chlorotriisopropoxytitanium (16 mL, 0.067 mol) portionwise over 5 minutes. After stirring for 1 hour, sodium triacetoxyborohydride (11.72 g, 0.05530 mol) was added portion wise and stirred for 24 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and adjusted to pH 9 with sodium hydroxide (6 N aqueous solution) and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with methanol:dichloromethane (gradient 0:1 to 1:9, by volume) to afford the title compound as a white solid, 590 mg, 45% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:20])[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[C:6]([O:10][C:11]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (135 μl, 1.74 mmol) was added to a cooled (ice bath, 0-4° C.), stirred solution of trans-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester (0.25 g, 1.16 mmol) and triethylamine (243 μl, 1.74 mmol) in dichloromethane (10 ml). Following the addition the reaction was stirred at this temperature for 30 minutes before being allowed to warm to ambient temperature. After stirring at ambient temperature for 2 hours, aqueous sodium hydrogen carbonate (10 ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (20 ml) and aqueous sodium hydrogen carbonate (20 ml) and after partitioning the organic phase was washed with water (20 ml), dried (magnesium sulphate) and evaporated to dryness under reduced pressure to yield methanesulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (340 mg, 100%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C([O-])(=O)C.[Na+].[Br:17]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.[Fe]>[Br:17][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1O
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45.9 %

Procedure:
Isovanillin (5 gm, 0.033 mol) was dissolved in glacial acetic acid (30 ml). Anhydrous sodium acetate (5.4 gm) was added to the above solution followed by powdered iron (0.15 gm). The system was flushed thoroughly with nitrogen. A solution of bromine (5.79 gm, 0.0362 mol) in glacial acetic acid (10 ml) was added to the above stirred suspension at room temperature over a period of 15 min. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was poured into aqueous 2% sodium bisulfite (200 ml) and stirred for 10 min. The precipitate was filtered washed with water (100 ml), and dried to obtain 3.5 gm of 2-bromoisovanillin as white powder mp: (200–202° C.).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.O.[OH-].[Na+]>O1CCCC1>[C:9]1([CH3:12])[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][OH:2])=[CH:11][CH:10]=1
Reactant: COC(=O)CCc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab) prepared by above Step 2 was dissolved in 100 ml of tetrahydrofuran under Ar atmosphere. Then 27 ml of lithium aluminium-hydride was added thereto with stirring for 2 hrs at 0° C. After 3 ml of distilled water, 3 ml of NaOH (1N) and 9 ml of distilled water were added to the reaction mixture sequentially, the mixture was stirred for 30 min and filtered using cellite in glass filter and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:2) as an eluant to give 971 mg of 3-p-tolyl-propane-1-ol (40ac) (yield: 93%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([SH:11])=[S:10])[CH2:4][CH2:3]1.[OH-:12].[Na+:13]>O>[OH2:12].[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([S-:11])=[S:10])[CH2:4][CH2:3]1.[Na+:13]
Reactant: [OH-]
Reactant: CN1CCCN(C(=S)S)CC1
Agent: [Na+]
Solvent: O
Product: CN1CCCN(C(=S)[S-])CC1
Yield: 54.3 %

Procedure:
57.0 g (0.3 moles) of 4-methyl-1-homopiperazinedithiocarboxylic acid (FLA-57) was dissolved in 300 ml of water with 12.0 g (0.3 moles) of NaOH. The solution was evaporated. The residue was recrystallized from ethanol-isopropyl ether, 37.5 g of sodium 4-methyl-1-homopiperazinedithiocarboxylate monohydrate was obtained. Mp 123°-125° C. elemental analysis. C calculated 36.60%, found 36.5%, H calculated 6.56%, found 6.54%, N calculated 12.16%, found 12.1%, S calculated 27.84%, found 27.8%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)=[CH:29][CH:28]=2)[CH2:16][C:17]([NH:19][O:20]C(OC)(C)C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].Cl.C([O-])(O)=O.[Na+]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)=[CH:31][CH:32]=2)[CH2:16][C:17]([NH:19][OH:20])=[O:18])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)OC)Cc2ccc(-n3ccnc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 0.39 g (0.74 mmol) of 2-[(4-but-3-enyloxy-benzenesulfonyl)-(4-imidazol-1-yl-benzyl)-amino]-N-(1-methoxy-1-methyl-ethoxy)-acetamide (stage 80.4), 2.46 ml of 6 N aqueous hydrochloride is added at r.t. After being stirred for 15 min, the reaction mixture is neutralized with sat. NaHCO3 and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 2-[(4-but-3-enyloxy-benzenesulfonyl)-(4-imidazol-1-yl-benzyl)-amino]-N-hydroxy-acetamide as a colorless powder. To a solution of 0.17 g (0.37 mmol) of the above prepared hydroxy acetamide in 3 ml of dioxane, 0.447 ml of 1 N aqueous hydrochloride is added and stirred for 10 min. The reaction mixture is concentrated under reduced pressure and dried in vacuo to give ther title compound. 1H-NMR (400 MHz, DMSO-d6): 2.40–2.50 (m, 2H), 3.61 (s, 2H), 4.07 (t, 2H, J=6.52 Hz), 4.37 (s, 2H), 5.00–5.15 (m, 2H), 5.75–5.90 (m, 1H), 7.04 (d, 2H, J=8.56 Hz), 7.48 (d, 2H, J=8.56 Hz), 7.65–7.75 (m, 5H), 7.81 (s, 1H), 8.19 (s, 1H), 9.57 (s, 1H), 10.54 (brs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:32][O:31][C:27]1[CH:26]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][N:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:28]=1[O:29][CH3:30]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1nccc(Nc2cc(-c3ccccc3)on2)n1
Product: COc1cc(Nc2nccc(Nc3cc(-c4ccccc4)on3)n2)cc(OC)c1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(5-phenylisoxazol-3-yl)-4-pyrimidineamine and 3,4,5-trimethoxyaniline. MS (MH+)=420.4, Calc'd for C22H21N5O4— 419.44.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.ClCCl.O>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCN)C[C@H]1OC
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCNc2ncccn2)C[C@H]1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A mixture of 4.6 parts of cis-4-amino-N-[1-(4-aminobutyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.4 parts of 2-chloropyrimidine and a few drops of N,N-dimethylacetamide was stirred overnight at 80° C. The reaction mixture was taken up in a mixture of dichloromethane, water and hydrochloric acid. The separated aqueous layer was treated with sodium carbonate and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (96:3:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.34 parts (24.1%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-(2-pyrimidinylamino)butyl]-4-piperidinyl]benzamide; mp. 114.8° C. (compound 29).