Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1C(=O)c1ccccc1
Yield: 86 %

Procedure:
2-Benzoylbenzoic acid was reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 2.6 g (86%) of the product were obtained.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C(Cl)CCl.CCOC(C)=O>C(Cl)Cl>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:1](=[O:4])[CH3:2])=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2ncco2)cc1-c1ccc(N)cc1
Reactant: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(-c2cc(-c3ncco3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into an 8 ml sealed tube, was placed acetic acid (48 mg, 0.80 mmol). This was followed by the addition of a solution of 2′-Methyl-5′-oxazol-2-yl-biphenyl-4-ylamine (100 mg, 0.40 mmol) in CH2Cl2 (2 g) with stirring for 10 mins in a bath of H2O/ice. This was followed by the addition of a solution of EDC (90 mg, 0.47 mmol) in CH2Cl2 (2 g). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:1). The resulting mixture washed 3 times with 10 ml of HCl(10%), 3 times with 10 ml of sat.NaHCO3 and 3 times with 10 ml of H2O. The organic layer was dried over Na2SO4. Removal of the solvents under reduced pressure afforded the title compound, N-(2′-Methyl-5′-oxazol-2-yl-biphenyl-4-yl)-acetamide, as a yellow solid (82 mg, 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([OH:33])=O)=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=1.[CH3:36][NH:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.ON1C2C=CC=CC=2N=N1.[ClH:55].CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:55][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([N:37]([CH3:36])[CH2:38][C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:33])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=1
Reactant: CNCc1cccnc1
Reactant: Cl
Reactant: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)Cc3cccnc3)n2Cc2ccccc21
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a stirred solution of the 10-[(2′,6-dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine carboxylic acid of Step C (0.250 g, 0.49 mmol) in N,N-dimethylformamide (2 mL) was added 3-(methylaminomethyl) pyridine (0,073 g, 0.59 mmol), 1-hydroxybenzotriazole (0.074 g, 0.54 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.093 g, 0.54 mmol), and N,N-diisopropylethyl amine (0.096 g, 0.74 mmol). After stirring overnight, the reaction mixture was taken up in chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and evaporated to dryness. Trituration of the residue with ethyl acetate provided the title compound (0.225 g) as a white solid, m.p. 196–198° C., found to be 93.88% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: 45/55 acetonitrile/water containing 0.1% phosphoric acid].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]([C:6](=[O:9])[CH2:7][CH2:8]1)[CH2:4][CH2:3][C:2]2=[O:11].[C:12]1([CH3:22])C(S(O)(=O)=O)=CC=CC=1.[OH2:23]>C(O)CO>[CH2:12]1[O:23][C:2]2([CH2:3][CH2:4][CH:5]3[CH2:10][CH:1]2[CH2:8][CH2:7][C:6]3=[O:9])[O:11][CH2:22]1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: O=C1CCC2CC1CCC2=O
Reactant: O
Solvent: OCCO
Product: O=C1CCC2CC1CCC21OCCO1
Reaction time: 2 h

Procedure:
5 g of bicyclo[3.3.1]nonane-2,6-dione were suspended in 27 mL of dry ethylene glycol and 283 mg of p toluene sulfonic acid were added. After 2 h all starting material was converted. 80 mL of water were added and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and sat. sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to give 0.5 g of the desired product along with 6.75 g of the diketal. The diketal was dissolved in 135 mL of acetone and 13.5 mL of 2M HCl were added. The mixture was allowed to stir at room temperature for 1 h. The mixture was neutralized by addition of 2 N NaOH, the acetone was removed in vacuo and the remaining aqueous layer was extracted with ethyl acetate and dichloromethane. The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by chromatography to give another 4.38 g of the desired product. Rt=0.84 min (Method C). Detected mass: 197.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=1)C.O.[NH2:15][NH2:16]>C(O)C>[CH3:12][N:7]1[C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]1
Reactant: NN
Reactant: CCOC(=O)Cc1cc(C)nn1C
Solvent: CCO
Solvent: O
Product: Cc1cc(CC(=O)NN)n(C)n1
Yield: 78 %

Procedure:
As described for example 112a, (2,5-dimethyl-2H-pyrazol-3-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) at reflux for 16 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 78%). MS: m/e=169.3 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C1CCN2C(=NCCC2)CC1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[CH:2][C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(Br)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of methyl 2-bromo-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (15.0 g), 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (6.2 g) and toluene (200 ml) was stirred for 2 hours at 70° C. The reaction mixture was poured into ethyl acetate (200 ml), which was washed with 2N HCl and a saturated aqueous saline solution, followed by drying (MgSO4). The solvent was distilled off under reduced pressure to leave methyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate (10.8 g, 88%). Recrystallization from ethyl acetate-hexane colorless needles, m.p.114-115° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[NH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][N:25]([CH:33]3[CH2:35][CH2:34]3)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)[C:17]([Cl:36])=[CH:16]1.O>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[NH:12][CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH:33]3[CH2:34][CH2:35]3)[CH:22]=2)[C:17]([Cl:36])=[CH:16]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(Cl)cn(CCN)c2c1)C1CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)NCCn1cc(Cl)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine (80 μL) and methyl chloroformate (38 μL) were added to a solution of tert-butyl {[1-(2-aminoethyl)-3-chloro-1H-indol-6-yl]methyl}cyclopropylcarbamate (120 mg) in chloroform (4.0 ml) under ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform/methanol=100/1 to 20/1) to give methyl[2-(6-{[(tert-butoxycarbonyl)(cyclopropyl)amino]methyl}-3-chloro-1H-indol-1-yl)ethyl]carbamate (106 mg) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.CN(C=O)C.Br[CH2:36][CH3:37].O.[OH-].[Cs+]>>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:36][CH3:37])[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CCBr
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.10 mmol; prepared as in Example 39, Step H) in dry DMF (519 μL, 0.10 mmol) was added bromoethane (11 mg, 0.10 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves. The reaction mixture was stirred for one hour, filtered through an Acrodisk, rinsed with DCM and MeOH, and concentrated under a nitrogen stream to a residue. Preparative thin layer chromatography eluting with 10% MeOH, 0.5% NH4OH in CHCl3 provided the final product (10 mg). MS (ES+APCI) m/z=414 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.[CH3:50][CH:51]([CH3:67])[CH2:52][CH:53]([NH2:66])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[N:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([NH:66][CH:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[N:60]2[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]2)[CH2:52][CH:51]([CH3:67])[CH3:50])=[O:18])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CC(C)CC(N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3 g (11.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mmols) of triphenylphosphine, 3.3 ml (23. 8 mmols) of triethylamine and 1.15 ml (11.9 mmols) of carbon tetrachloride were added successively to a solution of 2.9 g (11.9 mmols) of 3-methyl-1-(2-piperidino-phenyl)-1-butylamine in 29 ml of acetonitrile. The mixture was then stirred for 15 hours at room temperature, the solvent was removed in vacuo, and the residue was taken up in a mixture of ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone=10/1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:20][CH3:21])[C:11]1[CH:19]=[CH:18][C:14](C(O)=O)=[CH:13][CH:12]=1.ClC([O:25][CH2:26]C)=O.[NH2:28][NH2:29]>ClCCl>[CH3:21][O:20][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:18][C:19]=1[C:26]([NH:28][NH2:29])=[O:25])[O:9][CH3:8]
Reactant: COC(OC)c1ccc(C(=O)O)cc1
Reactant: NN
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1ccccc1C(=O)NN
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Triethylamine (11.8 mL, 84.6 mmol) was added to a solution of 4-(dimethoxymethyl)benzoic acid (11.0 g, 56.4 mmol, prepared as described in Tetrahedron 1998, 54,15679-15690) in dichloromethane (120 mL) at room temperature. The reaction mixture was cooled to −40° C., ethyl chloroformate (6.7 mL, 70.0 mmol) was added dropwise, and stirring continued at −40° C. for 30 min. Hydrazine (8.85 mL, 282 mmol) was added and the reaction mixture was warmed to room temperature and stirred for an additional 1 h. The reaction mixture was diluted with dichloromethane, washed with water, dried with Na2SO4, and concentrated in vacuo to give 9.06 g (77%) of the title compound, which was used in the next step without further purification. MS 211 (M+H)+.
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]([Cl:16])([Cl:15])[F:14])=[CH:4]1.[F:17][C:18]([F:27])([F:26])[CH2:19][CH2:20][CH:21]([C:24]#[N:25])[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:15][C:13]([Cl:16])([F:14])[S:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:21]([CH2:20][CH2:19][C:18]([F:17])([F:26])[F:27])([C:22]#[N:23])[C:24]#[N:25])[CH:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(Cl)(Cl)Sc1cn(CCl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
0.61 g of 1-(chloromethyl)-3-{[dichlorofluoromethyl]thio}-1H-indole and 0.35 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.28g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of [(3-{[dichlorofluoromethyl]thio}-1H-indole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (44), hereinafter) shown by below formula.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:39](=[O:41])[CH3:40])[C@@:29]2([CH3:42])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:43][Si:44](OS(C(F)(F)F)(=O)=O)([CH3:46])[CH3:45].N1C(C)=CC=CC=1C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:44]([CH3:46])([CH3:45])[CH3:43])[C@@H:30]([O:38][C:39](=[O:41])[CH3:40])[C@@:29]2([CH3:42])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)O[C@@H]1[C@H](O[Si](C)(C)C)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)-12-acetoxyspirostan-11-ol was silylated with trimethylsilyltriflate and 2,6-lutidine in methylene chloride according to the procedure described in Tetrahedron Letters, 1981, 22, 3455.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=O)=O.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>CN(C)P(N(C)C)(N(C)C)=O.O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1
Yield: 63.4 %

Procedure:
A solution of 10.0 g of 6-(2-naphthyloxy)-1-hexanol O-methanesulfonate and 9.7 g of ethyl 4-aminobenzoate in 50 ml of hexamethylphosphoramide is heated at 110° C. for 16 hours. The solution is cooled, diluted with water, filtered and the solid washed with ethanol and water to give 7.7 g of product. Recrystallization from ethanol and once from acetone-hexane gives crystals, mp 109°-110° C.
Reaction SMILES: Cl.[NH:2]1[CH2:9][CH2:8][CH2:7][CH:3]1[C:4]([NH2:6])=[O:5].CCN(CC)CC.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC#N.C(Cl)Cl>[C:4]([CH:3]1[CH2:7][CH2:8][CH2:9][N:2]1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1)(=[O:5])[NH2:6]
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC(=O)C1CCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1CCCN1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A solution of dl-prolinamide hydrochloride (2.5 g, 21.8 mmol) in CH3CN (35 mL) was treated with Et3N (7.45 mL) and 4-chlorobenzyl chloride (3.88 g, 24.1 mmol). The reaction mixture was stirred at 70° C. for 4 h and then at 25° C. for 16 h. The resulting mixture was diluted with CH2Cl2 (20 mL) and was washed with water (3×30 mL). The organic phase was dried (MgSO4) and concentrated. Chromatography (SiO2, 1% CH3OH—CH2Cl2) afforded 2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine (5.21 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]=[C:12]([NH:15][NH2:16])[CH2:13][N:14]=1.[CH:22]1([C:28](Cl)=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]2[C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:16][N:15]=[C:12]2[CH2:13][N:14]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(nnc1C1CCCCC1)CN=C2c1ccccc1Cl
Reaction time: 3 h
Yield: 58.2 %

Procedure:
5-(2-Chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno[2,3-e] [1,4]diazepine (20 g) was suspended in chloroform (200 ml) at room temperature. Cyclohexanecarboxylic acid chloride (10.1 g) was added, and the mixture was stirred for 3 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated to give an oil. The oil was dissolved in a mixed solvent of toluene (200 ml) and acetic acid (5.4 ml), and the mixture was refluxed for 3 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate), and isopropyl ether was added to give 15 g of 4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([OH:13])[CH3:12]>>[ClH:2].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:13][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Hydrogen chloride gas was passed through a solution of 4-chloro-benzonitrile (1.0 g, 7.3 mmol) in anhydrous ethanol (100 mL) cooled to 0° C. After 3 h, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 4-chloro-benzimidate hydrochloride (1.12 g, 83%). It was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(Br)cc2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(-c3cnn(C)c3)cc2)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
A mixture containing 0.145 g (0.28 mmol) of 9-(4-bromo-benzoylamino)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 10), 0.082 g (0.40 mmol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester, 0.35 mL (0.71 mmol) of sodium carbonate (solution 2M), 0.065 g (0.06 mmol) of tetrakis(tri-phenylphosphine)palladium in 5.60 mL of toluene/EtOH (10/1) under argon atmosphere was stirred at 90° C. for 15 hours. The reaction mixture was cooled, aqueous saturated solution of sodium carbonate was added and the resulting solution extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 to 97/3/0.3 to afford 0.088 g (76%) of the pure product as a white powder.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=O.C#[N:8].[C:9](=[O:12])([O-])[O-:10].[NH4+].[NH4+]>>[NH2:8][C@H:5]([C:9]([OH:10])=[O:12])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: C#N
Reactant: CSCCC=O
Agent: [NH4+]
Product: CSCC[C@H](N)C(=O)O

Procedure:
As a process for producing methionine, a process in which a raw material, 3-methylthiopropanal is reacted with hydrogen cyanide in the presence of a base (a cyanohydrination step); subsequently, the resulting product is reacted with ammonium carbonate (a hydantoination step); and then the resulting product is hydrolyzed to give methionine is widely known (see JP-A-2002-114758, JP-A-2002-105048, JP-A-2003-104958, JP-A-2003-104959, JP-A-2003-104960, JP-A-10-182593, JP-A-2003-119557, JP-A-11-217370 and JP-A-2007-314507).