Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[Li]CCCC.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([N:7]([CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=2)[C:8]([NH2:10])=[O:9])=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: NC(=O)NCc1cccc(C(F)(F)F)c1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC(=O)N(Cc1cccc(C(F)(F)F)c1)C(=S)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-trifluoromethyl benzyl urea (218 mg, 1 mmol) in dry THF (2 mL) under nitrogen was added dropwise n-BuLi (2.5 M in hexane, 0.4 mL). The mixture was stirred at RT for 30 min and then 3,4-dichlorophenyl isothiocyanate (204 mg, 1 mmol) in dry THF (2 mL) was added dropwise. HPLC analysis after 5 min revealed complete reaction to the expected product. Saturated NaHCO3 (5 mL) and Et2O (15 mL) were added and the phases were separated. The aqueous phase was extracted with Et2O (2×15 mL). The combined organic phases were washed with brine (5 mL) and were dried over MgSO4. Concentration in vacuo gave 412 mg of a yellow oil. Purification by flash chromatography (silica, 20-30% EtOAc in n-hexane) gave 193 mg (46%) of pure product according to 1H NMR.
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[Si:13]([O:20][CH2:21][C@H:22]([CH3:25])[CH:23]=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CCOCC>[Si:13]([O:20][CH2:21][C@H:22]([CH3:25])[CH:23]=[N+:8]([O-:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: C[C@H](C=O)CO[Si](C)(C)C(C)(C)C
Reactant: ONCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Product: C[C@H](C=[N+]([O-])Cc1ccccc1)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of N-benzylhydroxylamine prepared by the method as described in J. Am. Chem. Soc., 93, 2897 (1971) (368 mg; 3.0 mmol) and calcium chloride (3.30 mg; 3.0 mmol), anhydrous ether (30 ml) was added in argon stream, and (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropanal (600 mg; 3.0 mmol) was added dropwise thereto at 0° C. Stirring was continued at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The oily residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (5:5-0:10) to give (R)-(-)-N-(3-t-butyldimethylsilyloxy-2-methylpropylidene)benzylamine-N-oxide (658 mg; 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[CH:3]=1.[O:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][CH:17]3[CH2:16][CH2:15][O:14][CH2:19][CH2:18]3)=[CH:22][CH:23]=2)=[CH:3][C:4]1=[O:13]
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)cc2)OC1(C)C
Reactant: CC(C)CCn1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CCn1ccc(-c2ccc(NC3CCOCC3)cc2)cc1=O
Temperature: 150 °C
Yield: 98.9 %

Procedure:
A suspension of intermediate D4 (0.46 g, 1.9 mmol), intermediate D7 (0.69 g, 2.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.19 mmol) in a mixture of dioxane (4 ml) and saturated aqueous sodium carbonate (4 ml) was heated at 150° C. for 10 minutes, under microwave irradiation. The crude was filtered over diatomaceous earth and washed with EtOAc. The organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 and finally EtOAc as eluent). The desired fractions were collected and evaporated in vacuo to yield D8 (0.64 g, 95%) as a yellow solid.
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[C:12]([C:23]([OH:25])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO>[CH2:3]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C@H:12]([C:23]([OH:25])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C1=C(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: O=O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
A 185-ml stainless steel autoclave was charged under argon in a glove box (O2 content≦2 ppm) with 1-benzyl-4-(3,4-dichloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.00 g, 2.87 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP)] (0.22 mg, 0.29×10−6 mol, S/C 10′000) and methanol (30 ml). The asymmetric hydrogenation was run for 20 h at 80° C. under 40 bar of hydrogen (99.8% conversion). After the pressure was released, the formed white suspension was evaporated to dryness to yield 1.03 g (>99%) of crude (S,S)-Ib with 98.0% purity and 97.6% ee.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH2:26][CH2:27][CH2:28][C:29]3[N:30]=[CH:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:33]=3)[CH:20]=2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH2:4][CH2:3]1.C1(O)C=CC=CC=1.Cl[Si](C)(C)C>ClCCCl>[N:32]1[CH:33]=[C:29]([CH2:28][CH2:27][CH2:26][S:25][C:21]2[CH:20]=[C:19]([CH:9]([O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:10]3[NH:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)[CH:24]=[CH:23][CH:22]=2)[NH:30][CH:31]=1
Reactant: CN1CCC(OC(c2cccc(SCCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2)c2nc3ccccc3[nH]2)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Solvent: Oc1ccccc1
Product: CN1CCC(OC(c2cccc(SCCCc3cnc[nH]3)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of 2-((1-methylpiperidin-4-yloxy){3-[3-(1-trityl-1H-imidazol-4-yl)propylsulfanyl]phenyl}methyl)-1H-benzimidazole (200 mg) in 1,2-dichloroethane (7 mL) are added phenol (270 mg) and chlorotrimethylsilane (0.37 mL). The reaction mixture is heated at reflux overnight. Volatiles are removed under reduced pressure and the residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give 2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([O-:3])=[O:2].[CH3:11][Al](C)C>CCCCCC>[N+:1]([CH2:4][CH:5]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:11])([O-:3])=[O:2]
Reactant: C[Al](C)C
Reactant: O=[N+]([O-])C=Cc1ccsc1
Solvent: CCCCCC
Product: CC(C[N+](=O)[O-])c1ccsc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
When R2 is H the 3-(2-nitroethenyl)thiophene (1 eq) was suspended in hexane, cooled in an ice bath under nitrogen and slowly treated with 2N trimethylaluminum in hexane (2.6 eq). After 30 minutes, the solution was quenched with 3N HCl, diluted with ether and filtered. The organic layer was dried (Na2SO4) and condensed under reduced pressure to afford the crude product. This material was purified by flash silica gel column chromatography using 70% hexane in methylene chloride. The product was obtained as a colorless oil (80%); MH+ at m/z 172.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[Cl:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:16]([CH2:15][Cl:14])(=[O:18])=[O:17])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: O=S(=O)(Cl)CCl
Product: CNC(=O)Oc1ccc(NS(=O)(=O)CCl)c(C)c1

Procedure:
According to the procedure of Example 2, 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole) was reacted with chloromethanesulfonyl chloride (1.63g., 0.011 mole). The product, recrystallized from ethanol/water, was an orange-red solid (m.p. 136.5°-38.5° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:4][CH:3]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
The title compound was prepared from [4-(4-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and phenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid: MS (ES) m/z 510.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(O[C:16](=[O:21])[C:17]([F:20])([F:19])[CH3:18])C.[Br:22][CH2:23][Br:24]>C1COCC1>[Br:22][CH:23]([Br:24])[C:16](=[O:21])[C:17]([F:19])([F:20])[CH3:18]
Reactant: CCOC(=O)C(C)(F)F
Reactant: BrCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(F)(F)C(=O)C(Br)Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To N,N-diisopropylamine (4.06 ml, 2.93 g, 29.0 mmol) in THF (20 ml) was added n-butyllithium (11.6 ml of a 2.5 M solution in hexanes; 29.0 mmol) dropwise, maintaining the temperature of the mixture below 5° C. throughout the addition. The resulting solution was stirred at 0° C. for 15 min, and was then added dropwise to a solution of 2,2-difluoropropionic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 5,859,051) (2.00 g, 14.5 mmol) and dibromomethane (2.02 ml, 5.04 g, 29.0 mmol) in THF (20 ml) over 30 min with stirring, maintaining the temperature of the mixture below −60° C. throughout the addition. The solution was stirred for 15 min at −78° C. under nitrogen, and was then quenched by the addition of 5 N hydrochloric acid (10 ml). The mixture was allowed to warm to room temperature, and was diluted with water (10 ml). The aqueous phase was separated and washed with diethyl ether (2×30 ml). The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel, eluting with 10% to 20% diethyl ether in 40-60 petroleum ether (UV detection), yielding 1,1-dibromo-3,3-difluorobutan-2-one as a yellow oil (1.65 g, 43%): 1H NMR (360 MHz, CDCl3) δ 1.90 (3H, t, J 19.2 Hz), 6.39 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[ClH:13]>>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Reactant: Cl
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Temperature: 25 °C

Procedure:
5-Bromo-2-methyl-4-nitropyridine oxide (7.0 g, 30 mmol) was refluxed in conc. HCl (80 mL) for 16 hrs. The mixture was allowed to cool to rt, partially concentrated and then neutralized by NaOH (10N) to pH 7. The crude was partitioned between CHCl3 and water. The organic solution was separated, dried and concentrated to yield 5-bromo-4-chloro-2-methylpyridine oxide as a white solid (6.71 g). MS [M+H]+: 223.7; tR=1.91 min. (method 1).
Reaction SMILES: Br[CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>[I-].[K+].Cl>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cccc(C)c1NCC(C)Br
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: Cc1cccc(C)c1NCC(C)Nc1c(C)cccc1C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of 106.8 g (0.441 moles) of N-(β-bromopropyl)-2,6-dimethyl-aniline, obtained as described in point (a) above, 110 ml (107.4 g, 0.88 moles) of 2,6-dimethylaniline and 1.6 g (10 mmoles) of potassium iodide is stirred at 100° to 105° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool, 600 ml of 10% aqueous hydrochloric acid are added, and the resulting mixture is allowed to stand at room temperature overnight. The separated precipitate, which is a mixture of the hydrochloride and the hydrobromide of the expected product, is filtered off, washed with water, dried, and then treated as described in point (b) of Method (b) above in order to liberate the base. In this way 93.8 g (75.3%) of 1,2-bis(2',6'-dimethylphenyl-amino)-propane are obtained; m.p.: 54°-56° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1/[CH:18]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 90 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3. Yellow solid, 90% yield, mp 148–150° C. 1H-NMR (CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.92 (br, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z=477 ([M+H]+, 100%). HRMS (ES+) Calcd. for C26H24NO5S: 477.1484. Found: 477.1487.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:39])[S:27]([N:30]1[CH:34]=[CH:33][C:32]([Sn](C)(C)C)=[N:31]1)(=[O:29])=[O:28]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:32]2[CH:33]=[CH:34][N:30]([S:27](=[O:29])(=[O:28])[N:26]([CH3:25])[CH3:39])[N:31]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)n1ccc([Sn](C)(C)C)n1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2ccn(S(=O)(=O)N(C)C)n2)sc1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) in toluene (3.0 mL) was sequentially added a solution of Pd(PPh3)4 (12 mg, 0.01 mmol) in toluene (1.0 mL) and 3-Trimethylstannanyl-pyrazole-1-sulfonic acid dimethylamide (prepared according to J. Med. Chem (1998), 41, p-2019) (75 mg, 0.2 mmol, 2.0 eq), and heated the resulting overnight at 80° C. It was then cooled to room temperature, the solvent was evaporated and the crude was purified on preparative TLC using EtOAc/hexane (1:5). 5-(1-Dimethylsulfamoyl-1H-pyrazol-3-yl)-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (35 mg, 66.5% yield) was isolated. 1H NMR (CDCl3, 400 MHz) 9.93 (s, 1H), 8.11 (d, J=0.7 Hz, 1H), 8.02 (dd, J=6.7, 1.32 Hz, 1H), 7.84 (d, J=0.7 Hz, 1H), 7.45 (dt, J=7.5, 1.3 Hz, 1H), 7.31 (t, J=8.2 Hz, 2H), 7.26 (d, J=1.0 Hz, 1H), 2.98 (s, 6H), 2.7 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7](=[S:10])SC)([OH:3])=[O:2].[OH-].[Na+].O.[N-:14]=[N+:15]=[N-:16].[Na+]>CCOCC>[C:1]([CH2:4][CH2:5][N:6]1[C:7]([SH:10])=[N:16][N:15]=[N:14]1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCn1nnnc1S

Procedure:
To a mixture of 25.37 g. (0.143 mol.) of methyl 2-carboxyethyldithiocarbamate and 5.6 g. (0.143 mol.) of sodium hydroxide in 210 ml. of water was added 9.25 g. (0.143 mol.) of sodium azide. The reaction mixture was refluxed for one hour then cooled, diluted with 100 ml. of ether and acidified to pH 1.7. The layers were separated, the aqueous phase was extracted with ether and the combined extracts were dried (MgSO4) and evaporated to dryness to give a residue which was recrystallized from acetone-chloroform to give 1-(2-carboxyethyl)tetrazole-5-thiol, m.p. 158°-160° C.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.CO>[C].[Pd].C(O)(=O)C>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCCCN2)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To an acetic acid (5 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.12 g), 10% palladium-carbon (0.060 g) was added, followed by stirring under hydrogen pressure (5 kg/cm2) at 80° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and methanol and acetic acid were added thereto. The insoluble substance was removed by filtration, and the solvent was removed under reduced pressure. Chloroform and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.062 g of tert-butyl 2-(2-hydroxy-5-(piperidin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH2:24][CH3:25])=[CH:18][C:17]=2[F:26])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][CH2:24][CH3:25])=[CH:18][C:17]=1[F:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Product: CCOc1cc(F)c(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
0.25 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-ethoxyphenyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography (stationary phase: silica gel, developing solvent: hexane/ethyl acetate=3/1), to obtain 0.16 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-ethoxyphenyl)-6-methylpyridazine (hereinafter, referred to as compound (vi) of the present invention).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][CH2:17][C:18]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:19]=1[O:20][C:21]1[C:22]([CH2:38][C:39]([O:41]CC3C=CC=CC=3)=[O:40])=[C:23]([O:36][CH3:37])[CH:24]=[CH:25][C:26]=1[C:27]2([CH3:35])[CH3:34])=[O:15])[CH3:13])=O)C1C=CC=CC=1>C(O)C(F)(F)F.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][CH2:17][C:18]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:19]=1[O:20][C:21]1[C:22]([CH2:38][C:39]([OH:41])=[O:40])=[C:23]([O:36][CH3:37])[CH:24]=[CH:25][C:26]=1[C:27]2([CH3:35])[CH3:34])=[O:15])[CH3:13]
Reactant: COc1ccc2c(c1CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: COc1ccc2c(c1CNC(=O)[C@H](C)N)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C

Procedure:
A solution of 0.3 g of benzyl 5-[(N-benzyloxycarbonyl-L -alanyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate in 85 ml of trifluoroethanol was stirred under hydrogen for 15 minutes in the presence of palladium/charcoal (10%). The catalyst was filtered off and rinsed with trifluoroethanol. The filtrate and wash solution were brought to dryness and the combined residue was chromatographed over silica gel in chloroform/methanol/water, whereby 0.1.8 g 5-(L-alanylaminomethyl)-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid was obtained as a colourless foam; IR 3450-2400, 1679, 1606, 1575, 1493 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH:8]3[CH:14]([NH2:15])[C:13]([CH3:16])([C:5]=2[CH:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH2:19](C12C(=O)C(CC3C=CC(OC)=CC=31)CCCC2)C>>[CH2:16]([C:13]12[C:14](=[NH:15])[CH:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=31)[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH3:19]
Reactant: COc1ccc2c(c1)C1(C)CCCCC(C2)C1N
Reactant: CCC12CCCCC(Cc3ccc(OC)cc31)C2=O
Product: CCC12CCCCC(Cc3ccc(OC)cc31)C2=N

Procedure:
Using a procedure analogous to that described in Example XXVIIA for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine there is obtained from 3.5 g. of 5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one, oxime 1.6 g. of the title product, b.p. 150°-160° C. (0.5 mm.).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[NH:25][NH2:26])[CH:20]=[CH:21][CH:22]=1>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:20]=[CH:21][CH:22]=1
Reactant: NNC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1cccc(C(F)(F)F)c1

Procedure:
ninhydrin, 4-(3-trifluoromethyl phenyl)-semicarbazide hydrochloride