Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[F:29][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1ccc(C(O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 63c (0.97 mmol, 300 mg) in CH2Cl2 was added DAST (1.015 mmol, 0.133 mL) dropwise at −78° C. under N2. The reaction was kept at −78° C. for 30 min and then quenched with aqueous NaHCO3 solution at low temperature. Additional CH2Cl2 was added to the reaction and the organic solution was concentrated. The crude material was purified flash column chromatography (silica gel, 10% EtOAc/hexanes) to give 63d.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(F)(F)F)nn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)nn1
Yield: 13.5 %

Procedure:
A mixture of 3-methyl-6-(trifluoromethyl)pyridazine (70 mg), N-bromosuccinimide (84 mg), azobisisobutyronitrile (14.1 mg), and CCl4 (3 ml) was heated under reflux for 2 days. The solvent was evaporated to dryness under vacuum. The residue obtained was purified by chromatography column on silica gel (AIT, Flashsmart BP-SUP, 20-40 μm) using a mixture of EtOAc/hexane as eluent to give 14 mg (14%) of the title compound along with 15.3 mg (11%) of the dibrominated derivative.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[N:4]=1.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([O:9][C:5]1[N:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)=[O:14]
Reactant: Oc1cccc(O)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(Oc1cccc(O)n1)c1ccc(Cl)cc1Cl
Yield: 77.7 %

Procedure:
The general procedure of Example 81 was followed using 3.00 g of 2,6-dihydroxypyridine hydrogen-chloride and 4.26 g of 2,4-dichlorobenzoyl chloride, thereby producing 4.49 g of the title compound in a yield of 78%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]C)[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:5][C:4]=2[N:3]=1>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCCNS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(CCCNS(C)(=O)=O)ccc3c21
Reaction time: 18 h
Yield: 53.2 %

Procedure:
A solution of N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}methanesulfonamide (630 mg, 1.45 mmol) in dichloromethane (125 mL) was sealed with a septum and purged with nitrogen gas. A 1.0 M solution of boron tribromide in dichloromethane (7.3 mL) was added via syringe. The resulting mixture was stirred for 18 hours. Methanol (50 mL) was added and the solution was concentrated under reduced pressure. The resulting solid was dissolved in a 2.0 M solution of ammonia in methanol (75 mL) and then concentrated under reduced pressure. This step was repeated two more times with silica gel (1 tbsp) being added prior to final concentration. The crude product absorbed on silica was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient; 0-25% CMA over 1200 mL, followed by 25-40% CMA over 1900 mL). The solid product was washed with water, filtered, and dried to provide 325 mg of N-{3-[4-amino-2-(hydroxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}methanesulfonamide as a white solid, mp 202-205° C.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C:3]([C:2](=[O:22])[CH3:1])=[CH:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
5α-Pregna-2,16-dien-20-one (3.0 g.) in chloroform (50 ml.) was treated with m-chloroperbenzoic acid (85%, 2.0 g.). The solution was stirred at room temperature overnight, diluted with more chloroform (50 ml.), washed with dilute potassium bicarbonate solution and with water, dried over sodium sulphate and evaporated to an oil which crystallised on standing. Recrystallisation from ethyl acetate/petrol gave title compound (2.75 g.) as colourless plates, m.p. 145°-149° [α]D + 74.5°, λmax. 238 nm (ε 8970).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([S:25]([CH3:28])(=[O:27])=[O:26])([CH3:24])[CH3:23])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CO.O.C(OCC)(=O)C>[CH3:28][S:25]([C:22]([C:14]1[CH:15]=[C:16]2[C:21](=[C:12]([C:8]3[CH:7]=[C:6]([CH2:5][CH:4]([C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=4)[C:3]([OH:39])=[O:2])[CH:11]=[CH:10][CH:9]=3)[CH:13]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)([CH3:24])[CH3:23])(=[O:26])=[O:27]
Reactant: COC(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(c1cc(-c2cccc(CC(C(=O)O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 21 °C

Procedure:
To a solution of Example 7 (130 mg, 0.23 mmol) in THF/MeOH/H2O (2:2:1, 5 mL) was added LiOH (2M, 0.35 mL, 0.69 mmol). The resulting mixture was stirred at 21° C. 18 h, acidified with HCl 10% and diluted with ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. The title compound was obtained as a white powder after sonication in ether/hexane and filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C=O)C.CCOC(C)=O>[Si:15]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=1)[NH2:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: Cc1ccc(CO)cc1N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3-amino-4-methylphenyl)methanol (1.0 g, 7.3 mmol) in DMF (7.3 mL) was added tert-butyldimethylchlorosilane (1.2 g, 8.1 mmol) and imidazole (0.65 g, 9.5 mmol). The reaction stirred at room temperature for 18 hours and then was poured into a separatory funnel with water and EtOAc. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-40% EtOAc/heptane) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:20]2[CH:22]=[C:4]([C:5]3[CH:28]=[C:9]([C:10](=[O:27])[NH:11][C@H:12]([C:24](O)=[O:25])[CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][CH2:18][S:19]2)[C:8]([CH3:29])=[CH:7][C:6]=3[CH3:30])[N:3]=1.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[NH2:1][C:2]1[N:21]=[C:20]2[CH:22]=[C:4]([C:5]3[CH:28]=[C:9]([C:10](=[O:27])[NH:11][C@H:12]([CH2:24][OH:25])[CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][CH2:18][S:19]2)[C:8]([CH3:29])=[CH:7][C:6]=3[CH3:30])[N:3]=1
Reactant: Cc1cc(C)c2cc1C(=O)N[C@H](C(=O)O)CCNC(=O)CCSc1cc-2nc(N)n1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c2cc1C(=O)N[C@H](CO)CCNC(=O)CCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
(S)-4-Amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (550 mg, 1.28 mmol) obtained in Example 2-13 was dissolved in a mixture of tetrahydrofuran (13 ml) and methanol (1.5 ml). Isobutylchloroformate (250 μl, 1.92 mmol) and N-methylmorpholine (141 μl, 1.28 mmol) were added to the solution at room temperature. After stirring at room temperature for one hour, the mixture was cooled to 0° C. and an aqueous solution (1.5 ml) of sodium borohydride (97 mg, 2.56 mmol) was added thereto. The mixture was warmed to room temperature, and then diluted with ethyl acetate. The solution was sequentially washed with water and a saturated aqueous sodium chloride solution. The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=10:1) to yield (S)-4-amino-14-hydroxymethyl-18,20-dimethyl-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-10,16-dione (Compound 68) (205 mg) as a white solid material.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccc(C)cc1)c1csc(N)n1
Yield: 38.7 %

Procedure:
Ethyl 4-chloro-2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 19.88 g.), thiourea (5.59 g.), sodium acetate (9.99 g.), water (45 ml.) and ethanol (45 ml.) were treated in a similar manner to that of Example P-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)-acetate (syn isomer, 8.25 g.).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=2)=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(N(C)C)=O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=2)[N:1]=1)[CH3:16]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C=O
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 813 mg of 2-ethylsulfanylbenzaldehyde, 764 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 8 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.49 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.N.[Li].C(O)C>CCOCC>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH2:8][CH2:7]1
Reactant: CNCCCC1C=Cc2ccccc21
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CNCCCC1CCC2=C1CC=CC2
Yield: 97.9 %

Procedure:
A solution of 40 g of 1-[3-(methylamino)propyl]indene in 200 ml of absolute ether is added to 2.5 liters of liquid ammonia at -33°C. Lithium ribbon (35 g) is added over 1.5 hours. The bronze mixture is stirred for 1 hour, and treated with absolute ethanol over 2 hours until the blue color is discharged. The ammonia is evaporated overnight, whereupon water and ether are added with cooling in an ice bath. The layers are separated, the aqueous layer reextracted, and the organic layers are dried (potassium carbonate) and evaporated to give 40 g of 4,7-dihydro-1-[3-(methylamino)propyl]indan as an oil. The crude diene is taken up in 400 ml of toluene and treated with 24 g of phenoxypropylbromide in 100 ml of toluene. The mixture is refluxed for 18 hours, cooled, diluted with ether, and washed several times with water. The organic layers are then shaken with excess 10% hydrochloric acid. The bottom colorless aqueous phase of the 3-phase mixture is drawn off, the toluene-ether layer is decanted, and the isolated middle layer washed with distilled water. The oily hydrochloride is then shaken with excess 10% sodium hydroxide and ether and the organic phase is separated and dried (potassium carbonate). Evaporation gives 25 g of N-methyl-N-phenoxypropylaminopropyl-4,7-dihydroindan.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][C:29]=3[S:36](=[O:39])(=[O:38])[NH2:37])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](O)=[O:44].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][C:29]=3[S:36](=[O:39])(=[O:38])[NH:37][C:43](=[O:44])[C:42]3[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=3[Cl:40])=[CH:26][CH:27]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 80 %

Procedure:
The reaction of 5-n-butyl-2-[2-chloro-5-nitrophenyl]-2,4-dihydro-4-[(2'-sulfamoyl-5'-ethylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step B) with 2-chlorobenzoic acid (3 equivalents), CDI (3 equiv), and DBU (3 equiv) was carried out according to the procedure of Example 51 to give an 80% yield of the title compound as a yellow solid; minor impurity by TLC in 95:5 CH2Cl2 --MeOH but suitable for use without further purification; mass spectrum (FAB) m/e 708 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][O:5][C:6]=1[CH3:7].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:8][C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[O:5][N:4]=1)(=[O:18])=[O:17]
Reactant: Cc1onc(N)c1C
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1onc(NS(=O)(=O)c2ccccc2Br)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4,5-dimethyl-3-isoxazolamine (1.62 g, 13.00 mmol, prepared as described in T. Konoike et al., Tetrahedron Letters, 37, 3339 (1996)) and 4-dimethylaminopyridine (159 mg, 1.3 mmol) in 6.5 ml pyridine at 0° C., 2-bromobenzenesulphonyl chloride (3.65 g, 14.3 mmol) was added in portions over 10 minutes. After stirring at room temperature overnight, the mixture was added dropwise to 40 ml 6N HCl at 0° C. The mixture was extracted with 3×50 ml EtOAc. The combined organic extracts were washed with 30 ml each of 1N HCl and brine and dried and concentrated. The residue was dissolved in 160 ml MeOH and 160 ml 3% aqueous NaHCO3 solution was added and the mixture was concentrated in vacuo to remove most of the MeOH. The solid was filtered off and the aqueous filtrate was acidified to pH 2 with solid NaHSO4, and extracted with 3×100 ml of EtOAc. The extracts were washed with brine, dried and concentrated to give the title compound of this step (3.0 g, 70%). Rf=0.57, silica gel, 1:1 hexane/EtOAc.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:12])=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:26]([O:30][C:31]([NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:26]([O:30][C:31]([NH:33][C@H:34]1[CH2:35][CH2:36][C@@H:37]([NH:40][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4]([CH3:12])=[CH:5][N:6]=[CH:7]3)[CH2:38][CH2:39]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1cncc2cccc(Br)c12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cncc2cccc(N[C@H]3CC[C@@H](NC(=O)OC(C)(C)C)CC3)c12
Temperature: 120 °C

Procedure:
According to the method of Example 15, Step A, the title compound was synthesized from Intermediate 93. That is, under nitrogen atmosphere, a suspension of Intermediate 93 (602 mg), tris(dibenzylideneacetone)dipalladium(0) (124 mg), tri(tert-butyl)phosphine (0.5 ml, Kanto Chemicals), cis-N-(tert-butoxycarbonyl)-1,4-cyclohexanediamine (697 mg) and sodium tert-butoxide (390 mg) in toluene was stirred with heating at 120° C. for 16.5 hours. The reaction mixture was cooled to room temperature and added with ethyl acetate (10 ml), and the insoluble matters were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (45 mg).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:12])[CH:10]=[CH2:11])=[CH:3][CH:2]=1
Reactant: C=CC(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC)cc1
Yield: 98.8 %

Procedure:
Anisole (108 mg), acryloyl chloride (154 mg), and aluminium chloride (199 mg) were reacted in dichloromethane (1.5 mL) at from −20° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (160 mg).
Reaction SMILES: [CH2:1](I)[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:19]([NH2:21])=[O:20])[O:16][S:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:8]=[CH:9][C:10]=1[Cl:11].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:14]1[C:13](=[O:18])[C:12]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=2)([C:19]([NH2:21])=[O:20])[O:16][S:15]1=[O:17])[CH3:2]
Reactant: CCI
Reactant: NC(=O)C1(c2ccc(Cl)c(Cl)c2)OS(=O)NC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C(N)=O)(c2ccc(Cl)c(Cl)c2)OS1=O
Yield: 69.7 %

Procedure:
31.2 g (0.2 mole) of ethyl iodide are added to a solution of 6.2 g (0.02 mole) of 5-(3,4-dichlorophenyl)-5-aminocarbonyl-1,2,3-oxathiazolidin-4-one-2-oxide and 2.02 g (0.02 mole) of triethylamine in 50 ml of acetonitrile. The solution is heated to the boil for four hours and then evaporated down under reduced pressure. The residue is taken up in 50 ml of dichloromethane, and the solution is washed with three times 20 ml of water. The organic phase is evaporated down and the residue is triturated with diethyl ether. In this manner, 4.7 g (70% of theory) of 3-ethyl-5-(3,4-dichlorophenyl)-5-aminocarbonyl-1,2,3-oxathiazolidin-4-one-2-oxide of melting point 127°-128° C. are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C@@:14]4([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:11]([CH2:12][CH2:13]4)[C:10]=3[C:9](=[O:20])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:19][C@@:14]12[C:16]([CH3:17])([CH3:18])[C@@H:11]([C:10]3[C:9](=[O:20])[N:8]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:15]=31)[CH2:12][CH2:13]2
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)[nH]n1-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.7 %

Procedure:
A mixture of (4S,7R)-1-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 8; 1.00 g, 3.7 mmol), phenyl-boronic acid (0.94 g, 7.5 mmol), and copper(II) acetate (1.03 g, 5.6 mmol) in dichloromethane (10 mL) and pyridine (0.6 mL, 7.5 mmol) was stirred at room temperature for 2 days and then heated at reflux for 2 h. The reaction mixture was diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed with water, 10% copper(II) sulfate solution, water, and brine. The solution was then dried (magnesium sulfate), filtered, evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 90 g column, eluting with 10-50% ethyl acetate/hexanes to give (4S,7R)-7,8,8-trimethyl-1,2-diphenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (0.57 g, 44%) as a light brown solid. ES(+)-MS (M+H) 345.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCc1ccccc1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCCc1ccccc1
Yield: 87.7 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.0 g (15.1 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 3.17 g of the desired compound (yield: 87.8%).