Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](N2CCCCC2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:10]3[CH2:37][CH2:36][CH:7]([CH:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCCCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(bis(4-fluorophenyl)methylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 64% overall yield. FDMS m/e=476 (M+ of free base). α[D]589 =-9.85 (c=0.89, methanol).
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[O:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].[OH-].[K+]>C1COCC1.O.C(O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[O:19][CH:18]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]4)[C:21]=2[CH:22]=1
Reactant: CCOC(=O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2n1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
101 (7.7 g, 16.3 mmol) is dissolved in 15 ml of a 1:1:1 mixture of THF/water/ethanol and after addition of KOH pellets (5.4 g, 81.9 mmol) the mixture is stirred for 2 h at 85° C. Then the organic phase is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, acidified with 2M HCl and filtered off. The crude product is purified by crystallisation from ethyl acetate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:34]([NH:33][C:25]2[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:30]([CH3:32])[CH3:31])=[O:35])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(=O)OCCc1ccc(NCc2ccccc2)cc1
Product: CC(=O)OCCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 15.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using 2-(4-benzylaminophenyl)ethyl acetate (5.0 g) and 2,6-diisopropylphenyl isocyanate (5.7 g) as starting materials, 2-{4-[1-benzyl-3-(2,6-diisopropylphenyl)ureido]phenyl}ethyl acetate (1.39 g) was obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23]O.CS([Cl:29])(=O)=O.O>ClCCl>[Cl:29][CH2:23][C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10]
Reactant: OCC1=C(c2ccccc2F)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1C1=C(CCl)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14.7 mL) was added to a solution of [2-(2-fluorophenyl)cyclohex-1-enyl]methanol obtained in Preparation Example 1-(3) (8.88 g) in dichloromethane (300 mL). Methanesulfonyl chloride (4.00 mL) was added dropwise to the reaction solution in an ice bath. The reaction solution was gradually warmed to room temperature and stirred overnight. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (5.88 g).
Reaction SMILES: [O:1]1[C@H:3]2[C:4]3[CH:13]=[C:12]([S:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)(=[O:16])=[O:15])[CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[C@@:2]12[CH3:25].[NH3:26]>C(O)C>[NH2:26][C@H:3]1[C@@:2]([OH:1])([CH3:25])[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)(=[O:16])=[O:15])=[CH:13][C:4]1=2
Reactant: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H]2O[C@]2(C)C(C)(C)O3)c1
Reactant: N
Solvent: CCO
Product: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H](N)[C@](C)(O)C(C)(C)O3)c1
Temperature: 50 °C

Procedure:
(3S ,4S)-3,4-Dihydro-3,4-epoxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (2.0 g) (see Preparation 17) was dissolved in ethanol (15 ml) and 35% aqueous ammonia solution (10 ml) was added. The mixture was heated at 50° C. for 48 hours before adding further ammonia solution (5 ml) and heating for another 8 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using 5:95 methanol: dichloromethane as the eluent to yield (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.9 g) as a foam. Found: C,58.65; H,5.77; N,3.29. C19H23NO5S, 0.22 CH2Cl2 requires C,58.28; H,5.96; N,3.53%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:8]1.[CH:22](OCC)=[O:23]>O>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:11][CH:10]([CH2:17]3)[N:9]3[C:5](=[N:6][C:7]([C:18]([O:20][CH3:21])=[O:19])=[C:8]3[CH:22]=[O:23])[C:4]=2[CH:3]=1
Reactant: CCOC=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Solvent: O
Product: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxylate (4 g) was reacted with ethyl formate similar to as described in Example 8 or Example 9 to give (2.3 g) of methyl 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylate following triteration from water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: COCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCNC(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(2-methoxyethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=486.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH:22][S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=S(=O)(CC(F)(F)F)NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(3-benzyloxyphenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 70:30 to 60:40 DCM/ethyl acetate, evaporated, and then triturated with diethyl ether to give the title compound. Anal Calcd for C21H19F3N2O3S: C, 57.79; H, 4.39; N, 6.42. Found: C, 57.60; H, 4.47; N, 6.41. 1H NMR (400 MHz) 3.77 (2H, q, J=9.0 Hz), 4.86 (2H, d), 4.99 (2H, d), 6.82 (2H, m), 6.95 (1H, m), 7.25 (2H, m), 7.34-7.40 (5H, m), 7.67 (1H, td, J=2.0, 8.0 Hz), 8.32 (1H, bs), 8.50 (1H, d, J=4.0 Hz). MS found 437.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.[OH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:29]([N:44]3[CH2:45][CH2:46][CH:41]([OH:40])[CH2:42][CH2:43]3)=[O:31])[S:11][C:7]=2[C:6]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(-c2csc(C)n2)c2sc(N)nc12
Reactant: OC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2csc(C)n2)c2sc(NC(=O)N3CCC(O)CC3)nc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 0.070 g of 4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-ylamine (0.00025 Mol) in THF (4 ml) at room temperature were added 0.054 ml N-ethyl-diisopropylamine (0.00031 Mol) and 0.001 g DMAP. 0.025 g of triphosgen (0.000085 Mol) were added and the whole mixture was heated to 70° C. for 1 hr. Then another 0.054 ml N-ethyl-diisopropylamine (0.00031 Mol) and 0.031 g of 4-hydroxy-piperidin (0.00031 Mol) were added and the reaction mixture was stirred at 70° C. for 1.5 hrs. Upon cooling to room temperature a precipitation formed, which was filtered and washed with THF. The filtrate was evaporated and the residue was subjected to column chromatography (silicagel, CH2Cl2/MeOH 9:1). The title product was obtained as a white solid (11%); F.p.: 145-150° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1([CH3:21])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:18]=[C:19]=[O:20])[C:12]=2[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:29]([NH:31][NH2:32])C>C1(C)C=CC=CC=1.C(O)C>[CH3:29][N:31]1[C:1]([CH3:2])=[C:4]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[CH2:11][CH2:10][C:9]3([CH3:21])[CH3:8])=[O:20])[C:5]([CH3:6])=[N:32]1
Reactant: CCNN
Reactant: CC1(C)CCc2c(N=C=O)cccc21
Reactant: CC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1CCC2(C)C
Yield: 70.1 %

Procedure:
To a solution of 600 mg (6.0 mmol) of acetylacetone and 1.12 g (6.0 mmol) of 1,1-dimethylindane-4-yl isocyanate in 10 ml of toluene was added dropwise 730 mg (7.2 mmol) of triethylamine at room temperature with stirring, followed by further stirring at room temperature for 12 hours. Then the reaction solution was concentrated under reduced pressure to obtain crude 3-(1,1-dimethylindane-4-yl carbamoyl)pentane-2,4-dione. Then, thus obtained crude 3-(1,1-dimethylindane-4-yl carbamoyl)pentane-2,4-dione was dissolved in 10 ml of ethanol. To the solution was added 276 mg (6.0 mmol) of ethylhydrazine, followed by stirring at room temperature for 6 hours and then for further one hour under reflux with heating. After left standing for cooling, the solvent was distilled off under reduced pressure and the residue was recrystallized with methanol to obtain 1.25 g of 1,3,5-trimethyl-N-(1,1-dimethylindane-4-yl)pyrazole-4-carboxamide which had a melting point of 151.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].I[CH2:33][CH:34]([F:36])[F:35].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:33][CH:34]([F:36])[F:35])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: FC(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(CC(F)F)CC1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.23 mmol) and 2-iodo-1,1-difluoroethane (53 mg, 0.45 mmol) in DMF (2 mL) was added NaH (18 mg, 0.45 mmol, 60%) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 60° C. for 7 h. Excess of NaH was quenched by adding water and the mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by HPLC to obtain 5-cyclohex-1-enyl-3-[[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-(trans-4-methylcyclohexanecarbonyl)amino]-thiophene-2-carboxylic acid methyl ester (43 mg, 38%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCNCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.57 g of tert-butyl (2-bromoethyl)carbamate (7.0 mmol, 0.7 equivalents) were initially charged in 98.5 ml of acetonitrile, 0.87 ml of 2-methoxyethylamine (750 mg, 10.0 mmol, 1 equivalent) and 3.5 ml of N,N-diisopropylethylamine (2.58 g, 20 mmol, 2 equivalents) were added and the mixture was stirred at 80° C. overnight. The mixture was concentrated and the residue was purified on a silica gel column (mobile phase: dichloromethane/methanol gradient: from 50:1 to 30:1 to 10:1, then dichloromethane/2 N ammonia in methanol: 10:1). This gave 1.69 g (99% of theory; purity about 90%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C[O:37][CH2:36]C1.CO.[OH-].[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH2:31][CH2:32][O:37][CH3:36])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C=CS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCCS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1 M aqueous NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHCl3 was added to the reaction mixture, which was washed with water and saturated brine, and dried over Na2SO4. Then, the organic layer was concentrated under reduced pressure to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine (353 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][CH2:7][CH:8]=O)([O-])=O.CCCN1[C@@H]2CCC3C=CC(O)=CC=3[C@H]2[O:20]CC1.C(OCC)C>CS(C)=O.N1CCC[C@H]1C(O)=O.CO.[Pd]>[NH:1]1[C:4]2[C:5](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][C@@H:7]([OH:20])[CH2:8]1
Reactant: CCCN1CCO[C@@H]2c3cc(O)ccc3CC[C@H]21
Reactant: O=CCCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCOCC
Product: O[C@H]1CNc2ccccc2C1
Reaction time: 0.33 h

Procedure:
To the stirred solution of o-nitrohydrocinnamaldehyde 4a-e (6 mmol) and PhNO (6 mmol) in DMSO (20 mL), L-proline (20 mol %) was added at 25° C. and allowed to stir for 20 min. After completion of reaction, as indicated by the change in color from green to yellow, large excess (200 mL) of diethyl ether was poured into the reaction mixture and stirred for additional 10 min. The combined organic mixture was washed with H2O (5×20 mL). The organic layer was separated and aqueous layer was extracted with diethyl ether (2×50 mL). Combined organic layers were washed with brine (5×50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude α-aminooxylated aldehyde was dissolved in MeOH (20 mL) and to this mixture 10% Pd/C (5 wt %) was added. The reaction mixture was then stirred at 25° C. for additional 6 h. After the completion of reaction (monitored by TLC), it was filtered through celite (MeOH eluent) and the solvent evaporated under reduced pressure. Chromatographic purification of the crude product [flash silica gel (230-400 mesh) and petroleum ether:EtOAc:Et3N (60:38:2)] gave the pure (R)-tetrahydroquinolin-3-ol derivatives to 5a-e.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]#[N:11].C(N)(=[S:14])C>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[S:14])[NH2:11]
Reactant: CC(N)=S
Reactant: Cn1c([N+](=O)[O-])cnc1C#N
Product: Cn1c([N+](=O)[O-])cnc1C(N)=S
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-methyl-5-nitro-2-cyanoimidazole (0.6 mole) was dissolved in this mixture at 40° C. Thioacetamide (1.2 mole) was added and stirring continued for 3 hours at 40° C. The resultant solution was poured on to 4 liters of ice/water mixture and stirred for 30 minutes. The precipitate was collected, slurried with water, filtered and dried to yield 1-methyl-2-thiocarbamyl-5-nitroimidazole, m.p. 148°-50° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:8])([OH:7])[CH3:6].N1C(C)=CC=CC=1C.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:8])([O:7][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(O)CCCBr
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(CCCBr)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
To a −50° C. cooled solution of alcohol 8 (3 g, 16.6 mmol) in anhydrous CH2Cl2 (50 mL) was added 2,6-lutidine (2.32 mL, 2.13 g, 19.89 mmol) followed by TBSOTf (4.57 mL, 5.26 g, 19.9 mmol). The solution was stirred at 0° C. for 15 min and water (10 mL) was added. The mixture was extracted with CH2Cl2 (3×40 mL), and combined organic phases were washed with 1N aqueous solution of NaOH (40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (1% ethyl acetate/hexane) to give 3.9 g (13.2 mmol, 80%) of 9. 1H NMR (400 MHz, CDCl3) δ: 0.07 (6H, s), 0.85 (9H, s), 1.21 (6H, s), 1.55 (2H, m), 1.95 (2H, m), 3.41 (2H, t, J=6.8 Hz)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.CCOCC>O1CCCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-iodophenol (10 g, 45.45 mmol) in 200 ml of anhydrous tetrahydrofuran was treated at 0° C. with sodium hydride (2.36 g, 60% dispersion, 59.09 mmol) for 5 minutes. To the resulting mixture was slowly added over a 5-minute period methoxyethoxymethyl chloride (8.3 ml, 72.73 mmol). The mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred under nitrogen for 24 hours. The solvent was removed under reduce pressure. The residue was taken into 500 ml of ether, washed with 200 ml of 5% sodium hydroxide (4×200 ml), water (4×200 ml), saturated sodium chloride (1×200 ml), and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave an oily product in 14.1 g. TLC (silica gel, ether): Rf 0.5.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:5].O.[NH2:19][NH2:20]>CO>[NH:19]([C:3](=[O:2])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:5])[NH2:20]
Reactant: COC(=O)C(=O)Nc1cccc(C(=O)OC)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(NC(=O)C(=O)NN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of methyl 3-{[methoxy(oxo)acetyl]amino}benzoate (100 mg, 0.42 mmol) in MeOH (8 mL) was added hydrazine hydrate (0.2 mL). After stirring for 0.5 h at rt, the reaction mixture was filtered. Washing with MeOH (2×1 mL) and water (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave 82 mg of the title compound (82%) as a white solid in 97.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([CH2:10][C:11]2([CH2:14]O)[CH2:13][CH2:12]2)[CH2:9][CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[ClH:3].[Cl:3][CH2:14][C:11]1([CH2:10][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:13][CH2:12]1
Reactant: OCC1(CN2CCCC2)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: ClCC1(CN2CCCC2)CC1
Temperature: 110 °C
Yield: 111.2 %

Procedure:
Thionyl chloride (1 mL, 13.7 mmol) was added to a solution of (1-pyrrolidin-1-ylmethyl-cyclopropyl)-methanol (1.45 g, 9.3 mmol) in toluene (20 mL) to give a pale brown suspension. The suspension was heated, 110° C., for ˜3 hrs. to give a dark brown suspension. The resulting suspension was allowed to cool and concentrated to a brown solid. Tritruation with diethyl ether (40 mL) gave the desired intermediate, 1-(1-chloromethyl-cyclopropylmethyl)-pyrrolidine hydrochloride as a brown powder 1.6 g, 82%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][CH:22]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][CH2:22][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CO
Product: c1ccc(CN2CCN(Cc3ccccc3)C(CCN3CCCCC3)C2)cc1
Reaction time: 0.5 h

Procedure:
In methanol (10 mL) were dissolved 1,4-dibenzyl-2-(formylmethyl)piperazine (600 mg) and piperidine (200 mg). After stirring for 30 minutes, the solvent was concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL), followed by the addition of sodium borohydride (147 mg). The resulting mixture was stirred. Five hours later, the solvent was distilled off under reduced pressure. Chloroform was added to the residue and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=10:1→5:1), whereby the title compound (640 mg) was obtained as a colorless oil.