Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([F:17])[CH:16]=1)[O:13][C:12](=[O:18])[CH2:11][CH2:10]2.[O:19]1[CH2:23][CH2:22][O:21][CH:20]1[CH:24]1[CH2:29][CH2:28][CH:27]([CH:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1>C1COCC1.[Br-].[Zn+2].[Br-]>[F:17][C:15]1[CH:16]=[C:7]([C:33]2([OH:36])[CH2:34][CH2:35][CH:30]([CH:27]3[CH2:26][CH2:25][CH:24]([CH:20]4[O:21][CH2:22][CH2:23][O:19]4)[CH2:29][CH2:28]3)[CH2:31][CH2:32]2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:18])[CH2:11][CH2:10]2
Reactant: O=C1CCC(C2CCC(C3OCCO3)CC2)CC1
Reactant: O=C1CCc2cc(Br)cc(F)c2O1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C1CCc2cc(C3(O)CCC(C4CCC(C5OCCO5)CC4)CC3)cc(F)c2O1
Temperature: -100 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
Butyllithium (1.6 ml, 1.5 M) was added dropwise to a solution of 6-bromo-8-fluoro-3,4-dihydrocoumarin (4.8 g) in THF (50 ml) as cooled at −100° C. in an argon gas stream. After completion of the dropwise addition, the temperature of the reaction mixture was raised to −78° C., and a solution of zinc bromide (5 g) in THF (100 ml) was added dropwise thereto. After completion of the dropwise addition, the temperature of the reaction mixture was raised to −30° C., and a solution of 4-(4-(1,3-dioxolan-2-yl)cyclohexyl)cyclohexanone (5.0 g) in THF (50 ml) was added dropwise thereto. After completion of the dropwise addition, the temperature of the reaction mixture was raised to room temperature, followed by stirring for 18 hours. The reaction mixture was added in ice water, extracted with toluene, washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a colorless crystal of 1-(8-fluoro-3,4-dihydrocoumarin-6-yl)-4-(4-(1,3-dioxolan-2-yl)cyclohexyl)cyclohexanol (4.5 g).
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[Br:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Iodoethane (3.7 ml) was added to a mixture of 2-bromo-4-nitrophenol (4 g) and potassium carbonate (5.1 g) in N,N dimethylformamide (20 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water (300 ml) and ethyl acetate. After extraction with EtOAc. the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5 increasing to 90:10) to give the title compound as an oil (3.4 g). 1H NMR (250 MHz, CDCl3) δ 1.54 (3H, t, J=9.1 Hz), 4.21 (2H, q, J=7 Hz), 6.93 (1H, d, J=9.1 Hz), 8.19 (1H, dd, J=9.1, 2.7 Hz), and 8.47 (1H, d, J=2.7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][O:15][C:14]3=[O:22])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[CH3:24][N:25](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:22]=[C:14]1[N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[N:25])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][O:15]1
Reactant: O=C1OCC(C(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2csc(N3C(=O)OCC3C(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 72 %

Procedure:
3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(trifluoromethyl)-1,3-oxazolidin-2-one, prepared in step 3 of Example 64, (0.455 g, 1.15 mmol) and zinc cyanide (81 mg, 0.69 mmol) were dissolved in 12 mL of DMF. The mixture was purged with nitrogen for 15 min and then tetrakis(triphenylphosphine)palladium(0) (66.5 mg, 0.058 mmol) was added and the mixture was heated to 120° C. for 1.5 h. The mixture was cooled and diluted with ethyl acetate and poured into 200 mL of water. The mixture was extracted with ethyl acetate, the organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 1% acetone/hexane to 10% acetone/hexane) afforded racemic 4-{2-[2-oxo-4-(trifluoromethyl)-1,3-oxazolidin-3-yl]-1,3-thiazol-4-yl}benzonitrile (278 mg, 72%) as a white solid.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:12][O:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5](/[CH:4]=[CH:3]/[CH2:2][OH:1])[CH:6]=2)=[CH:18][CH:17]=1
Reactant: OC/C=C/c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(COc2cccc(/C=C/CO)c2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of (E)-3-(3-Hydroxy-propenyl)-phenol (0.5 g, 3.33 mmol), methyl 4-(bromomethyl) benzoate (763 mg, 3.33 mmol) and potassium carbonate (1.8 g, 13.3 mmol) in acetone (40 ml) was stirred at room temperature over night. The reaction mixtyre was added water (30 ml) and acidified with 1N HCl and extracted with ethyl acetate (90 ml). The organic phase was washed with water, brine and dried with sodium sulphate and evaporated and dried in vacuo yielding 954 mg (96%) (E)-4-[3-(3-Hydroxy-propenyl)-phenoxymethyl]-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[CH:21](=O)[CH2:22][CH3:23].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:17]1([CH3:18])[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:9]1[C:4]2[C:5](=[O:8])[NH:6][N:7]=[C:2]([NH:1][CH2:21][CH2:22][CH3:23])[C:3]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNc1n[nH]c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 4-amino-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (50 mg, 0.19 mmol), propionaldehyde (0.034 ml, 0.47 mmol), AcOH (0.013 ml, 0.224 mmol) and dichloromethane (10 ml) was stirred for 30 min before addition of NaBH(OAc)3 (99 mg, 0-47 mmol). The mixture was stirred for 3 hours, then washed with saturated sodium bicarbonate (20 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (1:1-1:2) to give 19.4 mg (34%) of the title compound as crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[S:4].[IH:15].[CH3:16]I>CO>[IH:15].[IH:15].[CH3:1][NH:2][C:3](=[N:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[S:4][CH3:16]
Reactant: CNC(=S)NCCCCc1nccs1
Reactant: CI
Agent: I
Solvent: CO
Product: CNC(=NCCCCc1nccs1)SC

Procedure:
N-Methyl-N'-[4-(2-thiazolyl)butyl]thiourea was converted into its hydriodide salt with 66% hydriodic acid. This salt was dissolved in methanol, methyl iodide added and the solution heated under reflux for 2 hours. Concentration and crystallisation of the resultant oil gave N,S-dimethyl-N'-[4-(2-thiazolyl)butyl]isothiourea dihydriodide. Reaction of this isothiourea with hydroxylamine by the procedure of Example 1 (ii) gave the title product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:25][N:26]=[C:27]=[O:28]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:27]([NH:26][CH3:25])=[O:28])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Solvent: ClCCl
Product: CNC(=O)NC(C)c1ccc(-c2nnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of Example 24G (0.044 g, 0.122 mmol) in CH2Cl2 (2 mL) was treated with methyl isocyanate (0.035 g, 0.61 mmol). The reaction was stirred at 25° C. for 1 hour and was concentrated under reduced pressure on a rotary evaporator. The residual white solids (0.046 g) were purified by flash chromatography on silica gel eluting with a solvent gradient from 50% to 70% ethyl acetate in hexanes to provide 0.025 g (49%) of the title compound as a white solid, 1H NMR (300 MHz, DMSO-d6) δ ppm 7.48 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.96 (dd, J=3.86, 0.92 Hz, 1H) 6.53 (d, J=8.09 Hz, 1H) 5.75 (q, J=4.78 Hz, 1H) 4.94-5.05 (m, 1H) 4.63 (heptet, J=5.88 Hz, 1H) 2.56 (d, J=4.78 Hz, 3H) 1.42 (d, J=6.99 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 419 (M+H+.
Reaction SMILES: C(C1C(=O)O[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]=2)(=O)C.[CH3:20][C:21]([C:23]1[C:32](=[O:33])[O:31][C:30]2[C:25](=[CH:26][C:27]3[CH2:40][CH2:39][CH2:38][N:37]4[C:28]=3[C:29]=2[CH2:34][CH2:35][CH2:36]4)[CH:24]=1)=[O:22]>C(O)C>[CH2:17]([N:14]([CH2:15][CH2:16][N:37]1[CH2:28][CH2:29][CH2:34][CH2:35][CH2:36]1)[C:9]1[CH:8]=[CH:7][C:12]([CH:13]=[CH:20][C:21]([C:23]2[C:32](=[O:33])[O:31][C:30]3[C:25](=[CH:26][C:27]4[CH2:40][CH2:39][CH2:38][N:37]5[C:28]=4[C:29]=3[CH2:34][CH2:35][CH2:36]5)[CH:24]=2)=[O:22])=[CH:11][CH:10]=1)[CH3:18]
Reactant: CCN(CC)c1ccc2cc(C(C)=O)c(=O)oc2c1
Reactant: CC(=O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Solvent: CCO
Product: CCN(CCN1CCCCC1)c1ccc(C=CC(=O)c2cc3cc4c5c(c3oc2=O)CCCN5CCC4)cc1

Procedure:
10-(3-(N-ethyl-N-(2-piperidinoethyl)-4-aminophenyl)propenoyl)-1H,2H,3H,5H,6H,7H,11H-[1]benzopyrano[6,7,8-ij]quinolizin- 11-one (9) was prepared according to the procedure of Example 4 wherein 3-acetyl-7-diethylaminocoumarin was replaced by Coumarin 334 (Eastman Kodak, Rochester, N.Y.); λmax (ethanol)=503 nm ##STR14##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH:21]=O)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:24]1[CH2:27][CH:26]([N:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:24]2[CH2:27][CH:26]([N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25]2)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CN(C2CNC2)CCS1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(C[C@@H](CCN1CC(N2CCSCC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
tert-Butyl [(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]methylcarbamate (see WO 95/05377; 610 mg, 1.8 mmol) was dissolved in 1,2-dichloroethane (20 mL) and to the resultant solution was added 4-azetidin-3-ylthiomorpholine hydrochloride (430 mg, 1.9 mmol) followed by the addition of sodium triacetoxyborohydride (480 mg, 2.2 mmol). The mixture was stirred at room temperature for 5 h and then triethylamine (0.73 mL, 5.2 mmol) was added. The reaction mixture was stirred for 2 h and then partitioned between CH2Cl2 and NaHCO3 aq. The organic layer was washed with water and the combined organic solutions were dried over MgSO4. The solvent was removed by evaporation to yield an oil, which was chromatographed on a reversed phase column using a mixture of acetonitrile and 0.1 M ammonium acetate aq. The appropriate fractions were extracted with ether. The organic solution was dried over MgSO4 and then the solvent was removed by evaporation. There was obtained 266 mg (31%) of tert-butyl [(2S)-2-(3,4-dichlorophenyl)-4-(3-thiomorpholin-4-ylazetidin-1-yl)butyl]methylcarbamate as an oil. 1H NMR (400 MHz, CDCl3): 1.4 (s, 9H), 1.5-3.5 (c m, 23H), 7.0 (dd, 1H), 7.3 (d, 1H), 7.4 (d, 1H); LCMS: m/z 488 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[N:14][C:15]=4[CH:16]=[CH:17][C:18]=3[F:21])[CH2:10]2)[CH2:4][CH2:3]1.[CH:23]([C:25]1[N:41]=[CH:40][C:28]2[O:29][CH2:30][CH2:31][N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:27]=2[CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][C:12](=[O:22])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][CH2:23][C:25]5[N:41]=[CH:40][C:28]6[O:29][CH2:30][CH2:31][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:27]=6[CH:26]=5)[CH2:7][CH2:6]4)[C:19]=1[C:20]=23
Reactant: CC(C)(C)OC(=O)N1CCOc2cnc(C=O)cc21
Reactant: NC1CCN(CC2Cn3c(=O)cnc4ccc(F)c2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2cnc(CNC3CCN(CC4Cn5c(=O)cnc6ccc(F)c4c65)CC3)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
A solution of 6-[(4-amino-1-piperidinyl)methyl]-7-fluoro-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-3-one (95 mg, 0.31 mmol) and 1,1-dimethylethyl 7-formyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (83 mg, 0.31 mmol) in chloroform/methanol (1:1, 8 ml) was stirred with molecular sieves overnight, then heated under reflux for 3 h. After cooling, sodium triacetoxyborohydride (164 mg) was added and the mixture was stirred for 5 h at room temperature. The mixture was basified and the aqueous phase was extracted with 10% methanol/dichloromethane. Combined organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% (2M ammonia in methanol)/dichloromethane, gave impure material. Further chromatography on silica, eluting with 0-10% methanol/dichloromethane, gave the pure product (91 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:22][CH2:21][CH2:20][OH:23])=[O:18])=[CH:12][CH:11]=1
Reactant: OCCO
Reactant: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Solvent: O
Product: COC(=O)CCCCCOc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
6-(4-Isocyanato-phenoxy)-hexanoic acid methyl ester 36 (15 g, 57 mmol) was added to ethylene glycol (50 ml) at room temperature. The reaction was exothermic and the temperature rose to 46° C. The reaction mixture was allowed to cool to room temperature and later stirred at room temperature for 16 hours. Water (150 ml) was added and crude 37 was filtered, dried and recrystallised from toluene to get pure 37 (12 g, 84%) as a white powder. M.p: 69.5-71.5° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 68.7 %

Procedure:
A 200 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (1.36 g, 5.20 mmol), potassium carbonate (2.16 g, 15.6 mmol), 2-chloro-4-ethylbenzothiazole (1.23 g, 6.20 mmol) and 14 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (750 mL) and washed with brine (6×250 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 1.51 g (69%) of the title compound as an amorphous foam. FDMS: m/e=422. α[D]589 =62.74 (c=0.67, chloroform).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10](Cl)=[O:11])[CH2:2][CH2:3][CH3:4].Br.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCc1oc2ccccc2c1C(=O)Cl
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.9 %

Procedure:
2-Butyl-benzofuran-3-carbonyl chloride (2.22 g, 9.36 mmol), prepared in step 2 of Example 4, in 40 mL of anhydrous THF was added under nitrogen dropwise over 20 minutes to a mixture of the HBr salt of 4′-amino-biphenyl-4-ol (3.26 g, 12.3 mmol), prepared in the previous step, and triethylamine (3.42 mL, 24.5 mmol) in 100 mL of anhydrous THF at ice bath temperature. After the addition the reaction was stirred at room temperature for 20 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give a solid. Purification of the solid on 1 Kg of silica gel (230-400 mesh) using 30% ethyl acetate-hexane as the eluent gave 2-butyl-N-(4′-hydroxy[1,1′-biphenyl]-4-yl)-1-benzofuran-3-carboxamide (2.27 g, 48%) as an off-white solid, mp 181-183° C.; MS (APCI) m/z 386 [M+H]+. Elemental Analysis for C25H23NO3: Calc'd: C, 77.90; H, 6.01; N, 3.63; Found: C, 77.48; H, 5.86; N, 3.56.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]1=[O:16].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]1=[O:16]
Reactant: COC(=O)c1cc2cccnc2n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2cccnc2n(CBr)c1=O
Reaction time: 4 h
Yield: 72.5 %

Procedure:
10.71 g (49.0 mmol) of methyl 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in carbon tetrachloride (200 mL), and 8.64 g (49.0 mmol) of N-bromosuccinimide and 0.1 g of 1,2-azobis(2-methylpropionitrile) were added thereto. While the mixture was irradiated with light, the mixture was stirred for 4 hours. 3.0 g (17.0 mmol) of N-bromosuccinimide was further added to the mixture, and the resulting mixture was stirred for 3 hours while the mixture was irradiated with light. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:chloroform=1:19), and thus 10.56 g (yield: 73%) of the title compound was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2nc(CC(=O)OCC)cs2)cc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-n-butoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (11.8 mg) with purity >90%. LCMS (pos) m/z 399.2.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3ccc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-quinoline. MS (ESI) mass calcd. for C26H23N3OS, 425.56; m/z found, 426.2 [M+H]+.
Reaction SMILES: CO[C:3](=[N:13][N+:14]([O-:16])=[O:15])[NH:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[CH3:17][NH2:18]>O>[Cl:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][NH:4][C:3]([NH:18][CH3:17])=[N:13][N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=1
Reactant: CN
Reactant: COC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 89.1 %

Procedure:
To a mixture of O-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea (970 mg, 3.96 mmol) and water (30 ml) was added 40% aqueous solution of methylamine (0.7 ml, 7.92 mmol, 2.0 equivalents) at room temperature with stirring. After 1.5 hours of stirring at room temperature, the resulting crystals were collected. The crystals were washed with water and methanol, and dried. As a result, 860 mg (89.1% yield) of 1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24].CN(C)C=O>O>[Cl:22][C:23](=[CH2:24])[CH2:25][O:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: CCCCCCNc1nc(C)cc(O)n1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)COc1cc(C)nc(NCCCCCC)n1
Temperature: 25 °C

Procedure:
42.0 g 6-Hydroxy-4-methyl-2-n-hexylamino-pyrimidin (0.2 Mol), 27.6 g K2CO3 (0.2 Mol), 24.4 g 2,3-dichloro-1-propene (0.22 Mol) and 150 ml dimethylformamide are charged in a sulphonation flask. The mixture is heated for about 3 hours at a bath temperature of 110°, then cooled to room temperature and thereafter poured in 500 ml water. This mixture is extracted with ether, the ether extract dried with Na2SO4 and concentrated with the aid of a flask rotary vacuum evaporator at a temperature of up to 60°. The impure title compound is obtained as a brown oil, which is purified chromatographically with ether/hexane 1:3 on silicagel to give a yellow oil that slowly crystallises. m.p. 36°-37°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)cc1

Procedure:
4-Aminobenzenesulfonamide (6.80 g), tetrahydropyran-4-carboxaldehyde (4.96 g), and sodium triacetoxyborohydride (16.74 g) in tetrahydrofuran (300 mL) and acetic acid (15 mL) were stirred at room temperature for 24 hours. The reaction was concentrated and taken up in ethyl acetate. The resulting solution was washed with water and brine, concentrated, and chromatographed on silica gel with 50% ethyl acetate/hexanes.