Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:26][CH:25]=3)[CH2:22][CH2:21][N:20]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:19]2)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:71](OC(=O)C)(=[O:73])[CH3:72]>O1CCCC1>[C:71]([NH:1][CH2:4][CH2:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:26][CH:25]=3)[CH2:22][CH2:21][N:20]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:19]2)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])(=[O:73])[CH3:72]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCN=[N+]=[N-])cc1
Reactant: CC(=O)OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.13 g of tert-butyl 3-{2-[5-(2-azidoethyl)-6-chloro-2-methylpyrimidin-4-yloxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 25 ml of tetrahydrofuran is admixed at room temperature successively with 3.1 ml of water, 0.54 g of triphenylphosphine and 0.74 ml of acetic anhydride. The reaction mixture is stirred at room temperature over 16 hours and subsequently concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (3:1 EtOAc-heptane); Rt=5.49.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:27]CCCl>ClC(OC(Cl)C)=O>[ClH:27].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:26])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])[CH2:12][CH2:13]1
Reactant: O=C(Cc1ccccc1C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Reactant: ClCCCl
Agent: CC(Cl)OC(=O)Cl
Product: Cl
Product: O=C(Cc1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
After dissolving 1.30 g of 1-(1-benzylpiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone in 10 ml of 1,2-dichloroethane, 0.58 ml of 1-chloroethyl chloroformate was added while stirring at room temperature and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, 10 ml of methanol was added to the residue and heating to reflux was continued for 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate/n-hexane was added to the residue and the precipitate was filtered out to obtain the title compound (916 mg, 83% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:14])[O-:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:15]([O-:17])=O.[Na+].[C]=O>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]([C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:14])[O:13][C:4]([CH3:10])([CH3:5])[CH3:3])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)=[O:17]
Reactant: COc1ncc(Br)cc1CNC(=O)[O-]
Reactant: O=C[O-]
Agent: [C]=O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc(C=O)cc1CNC(=O)OC(C)(C)C
Yield: 77.6 %

Procedure:
1.009 g of N-[(5-bromo-2-methoxy-3-pyridyl)methyl]carbamate, 45 mg of dichlorobistriphenylphosphine palladium, 325 mg of sodium formate and 17 mg of triphenylphosphine were dissolved in 3 ml anhydrous N,N-dimethylformamide, followed by stirring at 110° C. for 2.5 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 401 mg of tertiary butyl N-[(5-formyl-2-methoxy-3-pyridyl)methyl]carbamate was obtained from fractions eluted with hexane-ethyl acetate (3.5:1).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1cccc(C(=O)c2ccccc2)c1OCc1ccccc1
Reactant: COc1c(Br)cccc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2)cccc1C(O)(c1ccccc1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Reaction time: 0.33 h
Yield: 42.9 %

Procedure:
A solution of 3-bromo-2-methoxybiphenyl (1.18 g, 4.5 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred under nitrogen at −78° C. and 2.5 M n-butyllithium in hexanes (1.8 mL, 4.5 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued on the cold bath for 20 min and a solution of 14 (1.55 g, 4.5 mmol) in dry tetrahydrofuran (8 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued on the cold bath for 30 min then the reaction mixture was allowed to reach room temperature and stirred for 2 hr. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (180 mL). The organic extract was washed with water (2×80 mL), dried over sodium sulfate and stripped. The crude product was purified by chromatography on silica (85 g) with 0.2% ethyl acetate in heptane (6 L). Pure 15 (1.02 g, 43%) was isolated.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=O)[N:4]=1>P(Cl)(Cl)(Cl)=O>[F:16][C:2]([F:1])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]#[N:14])[N:4]=1
Reactant: NC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nc(C(F)(F)F)n2c1CNCC2
Yield: 107.6 %

Procedure:
3-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (100 mg, 0.43 mmol) was dissolved in 5 mL of phosphorus oxychloride. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 10 mL of saturated sodium carbonate solution and extracted with ethyl acetate (25 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile 25a (100 mg) as a brown solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[N:5]=[CH:4]1)[CH3:2].[OH2:12]>>[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([OH:10])(=[O:12])=[O:9])[N:5]=[CH:4]1)[CH3:2]
Reactant: O
Reactant: CCn1cnc(S(=O)(=O)Cl)c1
Product: CCn1cnc(S(=O)(=O)O)c1

Procedure:
5.6 g (29 mmol) of 1-ethyl-4-imidazolesulfonyl chloride from Example C-2 are suspended in 70 ml of water at room temperature until a clear solution is formed. After evaporating in vacuo, the residue is recrystallized from ethanol/water in order to give the title compound of melting point 278° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1.O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) in DMSO (5.0 mL) was added potassium carbonate (276 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, before addition of ethyl 4-(bromomethyl)benzoate (235 mg, 0.97 mmol). The resulting mixture was heated to 70° C. with stirring for 3 hours before cooling back to room temperature. Water (50 mL) and EtOAc (50 mL) were added and the layers partitioned. The aqueous fractions were washed with EtOAc (2×50 mL) and the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (350 mg, 100%).
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.I[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23]>CCOCC>[F:26][C:21]([F:27])([C:22]([F:25])([F:24])[F:23])[C:20]([F:29])([F:28])[S:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=1
Reactant: Nc1ccc(S)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(SC(F)(F)C(F)(F)C(F)(F)F)cc1
Yield: 63.2 %

Procedure:
To an acetonitrile solution (20 ml) of 4-aminothiophenol (1.25 g, 9.98 mmol) and triethylamine (1.11 g, 11.0 mmol) was added 1-iodoheptafluoro-n-propane (5.91 g, 19.9 mmol), and the resultant mixture was stirred at room temperature for 3 hours. The mixture was diluted with ether, and washed with a 1N sodium hydroxide aqueous solution. Then, the product was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.85 g (yield 63%) of the title compound.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:19]C(=O)OC(C)(C)C)[C:9]([N:11]([CH2:13][C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:10])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:6][CH:5]=1)[C:9]([N:11]([CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:10]
Reactant: CN(Cc1ccco1)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccco1)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(biphenyl-4-yl)-1-((furan-2-ylmethyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (614 mg) in CH2Cl2 (6 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and azeotroped (three times) with toluene and dried under high vacuum. The crude (S)-2-amino-3-(biphenyl-4-yl)-N-(furan-2-ylmethyl)-N-methylpropanamide TFA salt (721 mg) was used for next step without further purification. HPLC retention time=1.37 minutes (condition B); MS (m+1)=335.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1.CCOC(C)=O>C(Cl)(Cl)Cl>[Br:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
4-Ethylphenylamine (1.00 g, 7.52 mmol, 1 equiv) was dissolved in chloroform (40 mL) and placed into an ice bath. NBS (1.34 g, 1 equiv) was then added into the solution in small portions. The mixture was warmed to room temperature and stirred for 2 hours. EtOAc (˜200 mL) was added and the mixture was filtered. The filtrate was washed with saturated aqueous K2CO3 (200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexanes to afford the title compound as light brown oil (1 g). MS (ES) m/z 200.0 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([CH2:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[N:28]=[CH:27][C:26](/[CH:29]=[C:30](\[O:36][CH2:37][CH3:38])/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)=O)(C)(C)C.O>ClCCl>[CH2:37]([O:36]/[C:30](=[CH:29]\[C:26]1[CH:27]=[N:28][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][CH3:15])[CH:18]=2)=[CH:24][CH:25]=1)/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:38]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)nc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.2 %

Procedure:
0.62 mL (7.0 mmol) of trifluoroacetic acid is added to a solution of 0.30 g (0.7 mmol) of ethyl (Z)-3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrid-3-yl}-2-ethoxyacrylate in 10 mL of dichloromethane. The reaction mixture is stirred at room temperature for 20 hours. The reaction is stopped by addition of 10 mL of water and extraction with dichloromethane. The organic phases are combined and then dried over magnesium sulfate. After filtration, the solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture to give 0.19 g (86%) of ethyl (Z)-2-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]acrylate in the form of a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C.CCO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][O:22][C:20]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[C:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH:4]=[O:3])[CH:21]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(CC=O)c2ccccc2)c2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a −78° C. solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester CXVII (0.39 g, 1.2 mmol) in DCM (10 ml) was added DIBALH (1M in hexane, 4.0 ml, 4.0 mmol). After stirring for 90 minutes at −78° C., more DIBALH (1M in hexane, 1.2 ml, 1.2 mmol) was added. The resulting mixture was stirred for 2.25 hours, after which EtOH (2 ml) and a saturated solution of NaHCO3 (2 ml) were added. The mixture was then stirred at room temperature for 30 min, filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated and washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionaldeyde CXVIII as a colorless syrup (0.27 g, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13].[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)c1ccc(-c2ccccc2)cc1
Yield: 75.6 %

Procedure:
N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-fluoro-1H-indol-3-yl)ethanamine (0.100 g, 0.561 mmol), biphenyl-4-carbonyl chloride (0.130 g; 0.589 mmol), and triethylamine (0.095 mL; 0.673 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.152 g (76%) of N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][C:19](=O)[CH:18]([CH2:22][O:23][CH3:24])[O:17][C:16]=3[CH:25]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH2:22][O:23][CH3:24])[O:17][C:16]=3[CH:25]=2)(=[O:11])=[O:10])=[CH:31][CH:32]=1
Reactant: COCC1Oc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc2NC1=O
Solvent: C1CCOC1
Solvent: CSC
Product: COCC1CNc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-(methoxymethyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (500 mg, 1.05 mmol) in THF (10 mL) was added BH3.DMS (0.15 mL, 1.57 mmol, Aldrich) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was quenched with methanol (7 mL) and was azeotroped with methanol (3×15 mL). The solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (silica: 100-200; elution: 30% ethyl acetate in hexane) to get pure N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (350 mg, 71.6%) as a brown solid. m/z (ESI) 462.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O:14][CH2:15][C:16]([NH2:18])=[S:17])(=O)C.Cl>O1CCOCC1>[OH:14][CH2:15][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)OCC(N)=S
Agent: Cl
Solvent: C1COCCO1
Product: OCc1nc(-c2ccccc2)cs1
Reaction time: 0.5 h

Procedure:
2-Bromoacetophenone (39.9 g; 0.2 mole) and 2-acetoxythioacetamide (30 g; 0.225 mole) were dissolved in dioxan (150 ml). The mixture was stirred and heated on a steam bath for 15 minutes, yielding a mass of crystals. Aqueous 5N HCl (40 ml) was added and the heating continued for a further 30 minutes. The dioxan was evaporated under vacuum and the residue neutralised with aqueous Na2CO3 solution. The solid was collected, washed with water and dried. After recrystallisation from benzene the product weighed 33.5 g (87%) and had a m.p. of 88°-9° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:25]2[N:26]=[C:27]([CH3:30])[O:28][CH:29]=2)[C:22](O)=[O:23])[C:11]1=[O:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:25]2[N:26]=[C:27]([CH3:30])[O:28][CH:29]=2)[C:22]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:23])[C:11]1=[O:31]
Reactant: CC[C@@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1coc(C)n1
Reactant: C1COCCN1
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CCOCC1)c1coc(C)n1

Procedure:
Similarly was prepared from intermediate 4 and morpholine
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([CH:15]([C:18]2[C:23]([CH2:24][CH3:25])=[C:22]([O:26][CH3:27])[N:21]=[C:20]([O:28][CH3:29])[N:19]=2)C#N)[CH:11]=[C:12]([CH3:14])[CH:13]=1)(C)(C)C.[H-].[Na+].O.C1(C)C=CC(S(O)(=O)=[O:42])=CC=1>CN(C=O)C.CO>[CH2:24]([C:23]1[C:18]([C:15]([C:10]2[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH2:7][OH:6])[CH:9]=2)=[O:42])=[N:19][C:20]([O:28][CH3:29])=[N:21][C:22]=1[O:26][CH3:27])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(OC)nc(OC)nc1C(C#N)c1cc(C)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(CO)c1
Reaction time: 0.33 h
Yield: 628.3 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-phenyl]-(5-ethyl-2,6-dimethoxy-pyrimidin-4-yl)-acetonitrile (3.74 g, 8.47 mmol) in anhydrous DMF (40 ml), was added 60% sodium hydride (373 mg, 9.32 mmol). After 20 min., oxygen was bubbled into the reaction mixture for 3 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was stirred with p-toluenesulfonic acid monohydrate (152 mg, 0.8 mmol) in methanol (10 ml) for 2 hr. at room temperature. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:1 to 3:2)) to afford 1.59 g (59%) of a white solid. m.p. 101-103° C.; 1H NMR (200 MHz, CDCl3) δ 1.05 (3H, t, J=7.4 Hz), 2.35-2.48 (5H, m), 3.93 (3H, s), 4.06 (3H, s), 4.63 (2H, br. S), 7.40 (1H, s), 7.56 (1H, s), 7.60 (1H, s).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:11]([CH2:12]O)=[CH:10][C:9]([CH3:14])=[CH:8][N:7]=1>C(Cl)Cl>[Cl:5][C:6]1[C:11]([CH2:12][Cl:3])=[CH:10][C:9]([CH3:14])=[CH:8][N:7]=1
Reactant: Cc1cnc(Cl)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cnc(Cl)c(CCl)c1
Reaction time: 6 h
Yield: 92 %

Procedure:
Thionyl chloride (2.73 g, 0.023 moles) was added slowly to a well-stirred solution of 2-chloro-3-hydroxymethyl-5-methylpyridine (1.2 g, 0.0076 moles) in methylenechloride (20 ml) at 0° C. temperature over a period of 20 minutes. The reaction mass was further stirred for 6 hours at the same temperature. The solvent and excess thionylchloride was removed under reduced pressure and the mass was quenched with water (25 ml). The mass was extracted with methylene chloride (2×50 ml) and the layers separated. The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure. The residue so obtained was subjected to chromatographic purification on silica gel to give 2-chloro-3-chloromethyl-5-methylpyridine as a solid in 92% yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>O1CCCC1>[CH3:16][S:17]([N:5]1[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]1[Br:3])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Br)n(S(C)(=O)=O)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of 195 milligrams (mg) (8.13 mM) of sodium hydride in 20 ml of anhydrous tetrahydrofuran was added, in portions, 2 g (8.13 mM) of the isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 931 mg (8.13 mM) of methanesulfonyl chloride was added dropwise. The reaction mixture was stirred overnight at room temperature. The precipitated sodium chloride was removed by filtration and concentration of the filtrate in vacuo gave 2.4 g of desired product, isopropyl N-methylsulfonyl-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil (93% yield).