Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:47][S:44]([NH:43][C:41]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]([C:25]1[CH:24]=[C:23]([NH:22][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH:28]=[CH:27][CH:26]=1)[C:38]([CH3:40])([CH3:39])[CH2:37]2)=[O:42])(=[O:45])=[O:46]
Reactant: O=C(O)c1cnccn1
Reactant: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
A solution of pyrazine-2-carboxylic acid (42 mg, 0.34 mmol) and 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then a solution of N-[2-(3-Amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (130 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded pyrazine-2-carboxylic acid [3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (12 mg, 7%) as a white solid: LC/MS m/e calcd for C24H25N5O4S (M+H)+: 480.56, observed: 480.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].C(OCC)(=O)C>CS(C)=O>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
6-Nitroindole (1.0 g) and benzyl chloride (2.2 g) are dissolved in dimethylsulfoxide (10 ml), and thereto is added potassium hydroxide (1.0 g), and the mixture is stirred at room temperature for 12 hours. To the mixture is added ethyl acetate, and the organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-benzyl-6-nitroindole (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C=O)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]([O:38][CH2:39][CH2:40][CH3:41])[CH:28]=[C:29]4[C:34]=3[O:33][CH2:32][CH2:31][CH2:30]4)[N:25]([CH2:42][C:43](O)=[O:44])[CH:24]=2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(N(CC)CC)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]([O:38][CH2:39][CH2:40][CH3:41])[CH:28]=[C:29]4[C:34]=3[O:33][CH2:32][CH2:31][CH2:30]4)[N:25]([CH2:42][C:43]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[O:44])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)O)c13)OCCC2
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)NCCN4CCOCC4)c13)OCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
4-(2-Aminoethyl)morpholine (217 mg, 1.7 mmol) was added to a DMF solution (10 ml) of [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetic acid (580 mg, 1.39 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU, 790 mg, 2.1 mmol) and triethylamine (5 ml). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. Water and ethyl acetate were added to the residue, followed by separation. The thus-obtained organic layer was washed with water and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a pale brown powder of 2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (115 mg, yield: 16%).
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:37]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:38][C:39]([O-])=[O:40].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:39](=[O:40])[CH2:38][C:37]([O:43][CH2:44][CH3:45])=[O:42])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2C1C(=O)OCC
Yield: 74 %

Procedure:
A solution of ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.72 g), monoethyl malonate (0.94 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 g), triethylamine (1.78 g) in dichloromethane (20 ml) is stirred overnight at room temperature. The reaction mixture is washed with water and dried over sodium sulfate and then evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.57 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.[C:19]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:7]3[C:3]([C:2]([F:1])([F:18])[F:17])=[CH:4][CH:5]=[N:6]3)=[CH:16][CH:15]=2)=[CH:28][CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-n3nccc3C(F)(F)F)cc2)cc1
Temperature: 65 °C

Procedure:
The product from Example 37A (37.3 mg, 0.146 mmol), 4-tert-butylaniline (28 μL, 0.18 mmol), PS-DCC (1.27 mmol/g, 0.342 g, 0.435 mmol), HOBT (20.2 mg, 0.149 mmol), and triethylamine (0.062 mL, 0.45 mmol) in DMF (1.5 mL) were combined and heated at 65° C. for 16 hours. The mixture was allowed to cool to room temperature, filtered, and the filtrate was diluted with diethyl ether (20 mL). The diethyl ether was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 2H), 7.83 (br s, 1H), 7.76 (m, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 7.41 (d, 2H), 6.87 (m, 1H), 1.33 (s, 9H); MS (m/z) 388.
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[OH:32].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[O:32][CH:2]([CH3:3])[C:1]([OH:4])=[O:5]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O
Yield: 44.3 %

Procedure:
β-Propiolactone (0.186 mL, 2.66 mmol) was added to a stirred, room temperature solution of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.5 g, 2.66 mmol), potassium tert-butoxide (0.314 g, 2.66 mmol) in THF (33 mL) under a dry nitrogen atmosphere. After 2 days the reaction mixture was added to water, acidified with 10% aqueous HCl and extracted with ethyl acetate. To the ethyl acetate phase was added acid washed (2% phosphoric acid in methanol) silica gel and the solvent was removed. The adsorbate was flash chromatographed (2% phosphoric acid in methanol treated silica gel ; eluent: gradient: 9:1 to 8:2 petroleum ether:ethyl acetate) to provide the title compound as an off-white solid (0.748 g, 44%): mp 218-220° C.: NMR (DMSO-d6);δ12.48 (broad s, 1H), 8.28 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (s, 2 H), 7.79 (ddd, J=7, 6, 1 Hz, 1 H), 7.64-7.57 (m, 2 H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.31 (ddd, =8, 7, 1 Hz, 1 H), 6.69 (d, J=8 Hz, 1 H), 4.44 (t, J=6 Hz, 2 H), 2.89 (t, J=6 Hz, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 632 (30%), 634 (70%) 636 (80%) 638 (40%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.68, H, 2.36, N, 0.01.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:16])=[C:8]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CCCCCC>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:16])=[C:8]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
1.66 g (6.77 mmol) of N-(5-acetyl-2-fluoro-phenyl)-N-methyl-methanesulfonamide were dissolved in 3.35 ml (3.0 g) (25.18 mmol) of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 2.5 hours. The mixture was cooled at room temperature. To the solid formed was added 20 ml of n-hexane and filtered to yield a solid which was crystallized from ethyl acetate. 1.37 g of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide as a yellowish-white solid were obtained (yield 67.4%).
Reaction SMILES: CS(O[C@@H:6]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[C@@H:7]1OS(C)(=O)=O)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+].C(O)(=O)C>CO>[N:32]([C:6]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:33]=[N-:34]
Reactant: C[C@]12CCC(=O)C=C1[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1C(N=[N+]=[N-])=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Conversion of 6α,7α-dihydroxy-4-androstene-3,17-dione to the corresponding 6α,7α-dimethanesulfonate ester by treatment with methanesulfonyl chloride in pyridine in a manner similar to that described in Example 22B followed by treatment of the resulting 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in dimethylformamide in a manner similar to that described in above Example 22C does not yield an identifiable amount of 6-azido-4,6-androstadiene-3,17-dione. Similarly, treatment of 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in aqueous methanol in the presence of acetic acid in a manner similar to that described in Example 6, does not yield an identifiable quantity of 6-azido-4,6-androstadiene-3,17-dione.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22][CH3:23])=[O:7])[CH3:2]
Reactant: CCI
Reactant: CCOc1ccc(C(=O)O)c(OCC)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC)nc1OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the compound prepared in Example 294 (1.75 g) and cesium carbonate (2.70 g) in N,N-dimethylformamide (21 mL) was stirred at room temperature for 2 hours. Ethyl iodide (0.663 mL) was added and stirring continued at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to obtain the title compound (1.6 g) having the following physical data.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH2:30])[CH2:19][CH2:18][C:17]3[C:13](=[CH:14][N:15]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[N:16]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH:41]2[CH2:43][O:42]2)[CH:35]=[C:36]([F:38])[CH:37]=1>C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:30][CH2:43][CH:41]([OH:42])[CH2:40][CH2:39][C:34]3[CH:35]=[C:36]([F:38])[CH:37]=[C:32]([F:31])[CH:33]=3)[CH2:19][CH2:18][C:17]3[C:13](=[CH:14][N:15]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[N:16]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC(N)(c2cccc(C(C)(C)C)c2)C3)cc1
Reactant: Fc1cc(F)cc(CCC2CO2)c1
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC(NCC(O)CCc2cc(F)cc(F)c2)(c2cccc(C(C)(C)C)c2)C3)cc1
Temperature: 50 °C
Yield: 41 %

Procedure:
To a sealed tube was added a solution of 5-(3-tert-butyl-phenyl)-2-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (0.41 g, 1.0 mmol) in isopropyl alcohol followed by 2-[2-(3,5-difluoro-phenyl)-ethyl]-oxirane (0.18 g, 1.0 mmol). The reaction was heated at 50° C. overnight and no product was formed. After heating at 100° C. for an additional 3.5 h the reaction was complete. The reaction mixture was concentrated and the crude product was purified by flash chromatography, eluting with 3% methanol in CHCl3 to afford 0.25 g (0.41 mmol, 42%) of 1-[5-(3-tert-butyl-phenyl)-2-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol: retention time (min)=2.15, method [1]. MS (ESI) 608.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C([O-])(O)=[O:15].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: Fc1ccccc1C1=CCCCC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccccc1C12CCCCC1O2
Reaction time: 2 h

Procedure:
1-(2-Fluorophenyl)cyclohexene of Example 1(a) [6.76 g; 0.038 mole] was dissolved in a two-phase system consisting of 350 ml of CH2Cl2 and 110 ml of 0.5M NaHCO3. m-Chloroperbenzoic acid (7.80 g of 85%; 0.38 mole) was then added portionwise with vigorous mechanical stirring. After 2 hours TLC indicated that the reaction was complete. The organic layer was separated and washed with 100 ml of N NaOH and 100 ml of water. Drying and concentration under reduced pressure gave an oil which amounted to 6.34 g (86%) after distillation, b.p. 113°/0.075 mm (Kugelrohr). A small portion was chromatographed over silica gel (CHCl3) to remove traces of polar impurities and distilled again to provide the sample of 1-(2-fluorophenyl)cyclohexene oxide.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([O:16][CH2:17][CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[CH2:17]([O:16][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19])[CH3:18]
Reactant: CCON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CCON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 50 %

Procedure:
3-[Ethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 53-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (50% yield); mp 113–114° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.30 (3H, t, J=7.1 Hz, CH3), 3.12 (3H, s, NCH3), 3.96 (2H, q, J=7.1 Hz, OCH2), 4.16 (2H, s, NCH2), 4.86 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.33 (2H, m, aromatics), 11.65 (1H, broad s, OH). Anal. calcd for C15H17FN2O4: C, 58.43; H, 5.55; N, 9.08. Found: C, 58.30; H, 5.55; N, 9.03.
Reaction SMILES: [CH:1]1([CH2:9][NH2:10])[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.[CH2:11]1[O:13][CH2:12]1>CO>[OH:13][CH2:12][CH2:11][NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][CH:1]([CH2:9][NH2:10])[CH2:2][CH2:3]1
Reactant: NCC1CCC(CN)CC1
Reactant: C1CO1
Solvent: CO
Product: NCC1CCC(CNCCO)CC1

Procedure:
A solution of 14.2 gm. (0.1 mole) of 1,4-cyclohexanebis(methylamine) in 150 ml. anhydrous methyl alcohol and under an atmosphere of nitrogen is warmed to 45°-50° C. In a 20 minute period, there is introduced with good agitation and beneath the liquid surface a total of 1.1 gm. (0.025 mole) of ethylene oxide in gaseous form. The reaction temperature is maintained at 45°-50° C. for an additional one-half hour after stopping the addition of ethylene oxide. The methyl alcohol is removed by distillation at atmospheric pressure; excess 1,4-cyclohexanebis(methylamine) is readily separated from the product by fractionation under reduced pressure. Only monoethoxylated compound remains and can be used as such or further purified by distillation at reduced pressure.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][CH:17]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[O:13]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.16 g) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carbonitrile (2.0 g) in dry dimethylformamide (40 ml) under nitrogen. After 0.5 hour. benzyl chloride was added and after a further 2 hours the mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of the washed (H2O) and dried (MgSO4) extract gave a red oil which was triturated with ether and then crystallised from ethanol to give the title compound as yellow microcrystals (1.2 g) m.p. 182°-4° C. T.L.C. Silica, ether Rf 0.45.
Reaction SMILES: [OH:1][C:2]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC2C=CC=CC=2)[CH2:11][CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].B(Br)(Br)Br>ClCCl.CO>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:2]([C:4]2[S:5][CH:6]=[CH:7][N:8]=2)([OH:1])[CH3:3])[CH2:10][CH2:11]1
Reactant: CC(O)(c1nccs1)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}-carbamate (895 mg, 2.48 mmol) in dichlormethane at −78° C. was added boron tribromide (1.0 M in dichloromethane, 2.7 mL, 2.7 mmol) dropwise. After one hour, the solution was warmed to 0° C. Another portion of boron tribromide (1.0 M in dichloromethane, 2.7 mL, 2.7 mmol) was then added dropwise and the reaction was allowed to warm to room temperature. The solution was then carefully diluted with methanol and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(trans-4-aminocyclohexyl)-1-(1,3-thiazol-2-yl)ethanol. MS ESI calc'd. for C11H19N2OS [M+H]+ 227. found 227. 1H NMR (500 MHz, DMSO-d6) δ 7.67 (d, J=3.3, 1H), 7.51 (d, J=3.2, 1H), 5.69 (s, 1H), 2.46-2.39 (m, 1H), 1.80-1.65 (m, 3H), 1.63-1.50 (m, 1H), 1.43 (s, 3H), 1.40-1.32 (m, 1H), 1.24-1.11 (m, 1H), 1.03-0.86 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:23])[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[OH-].[Na+].[CH2:26]([OH:29])[CH2:27][OH:28]>O>[OH:28][CH2:27][CH2:26][O:29][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:23])[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: OCCO
Reactant: Cc1ccc(N2C(=O)c3cccc4c(Br)ccc(c34)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(N2C(=O)c3cccc4c(OCCO)ccc(c34)C2=O)cc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 6-bromo-2-p-tolyl-benzo [de] isoquinoline-1, 3-dione (4.0 g), sodium hydroxide (0.65 g), and 1,2-ethylene glycol (50 ml) was maintained under reflux with stirring at 120° C. for 10 hrs. The reaction mixture was then cooled to room temperature and water (100 ml) was added to the mixture. The solid that separated out was filtered, washed with water, and dried at 100° C. for 8 hours (Yield=2.71 g). The crude product was purified using 120 ml monochlorobenzene and 0.25 g activated charcoal to obtain pure product weighing 1.32 g. H1-NMR: 2.39 δ (s, 3 protons); 3.92 δ (m, 2 proton); 4.35 δ (t, 2 protons); 5.13 δ (t, 1 proton); 7.22 δ (m, 2 protons); 7.31 δ (m, 3 protons); 7.83 δ (t, 1 proton); 8.44δ (m, 2 protons); 8.68 δ (d, 1 proton).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16](/[CH:30]=[CH:31]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:17](OS(C4C=CC(C)=CC=4)(=O)=O)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16](/[CH:30]=[CH:31]/[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[C:17]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
The tert-butyl (E)-3-{8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-{[(4-methylphenyl)sulfonyl]oxy}-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (9.0 mg, 0.0152 mmol) obtained in (A) was dissolved in dimethylformamide (0.75 ml), added with morpholine (13.2 μl, 0.152 mmol), and stirred overnight at room temperature. The reaction mixture was concentrated, and then the residue was purified by thin layer chromatography (n-hexane:ethyl acetate=1:1, v/v) to obtain the title compound (6.7 mg, 87%).