Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[CH2:29][O:28]C(C)(C)[O:26][CH2:25][C:24]=2[CH:32]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.O>[O:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:29][OH:28])=[C:24]([CH2:25][OH:26])[CH:32]=1)[Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC1(C)OCc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OCc1ccc(CO)c(CO)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.175 g (13.825 mM) of tert-butyl-(7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocyclohepten-2-yl)methoxydiphenylsilane in 50 ml of tetrahydrofuran-water (4:1) was added 2 ml of trifluoroacetic acid with ice-cooling and the mixture was stirred at room temperature for 4 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [Na].[CH2:2]([N:8]1[C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]([CH3:19])[C:9]1=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl[CH2:21][P:22](=[O:25])([CH3:24])[CH3:23]>>[CH2:2]([N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:21][P:22](=[O:25])([CH3:24])[CH3:23])[CH:14]=[N:13][C:12]=2[N:11]([CH3:19])[C:9]1=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CP(C)(=O)CCl
Reactant: CCCCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [Na]
Product: CCCCCCn1c(=O)c2c(ncn2CP(C)(C)=O)n(C)c1=O

Procedure:
The title substance was prepared from 26 g (0.1 mol) of 1-hexyl-3-methylxanthine sodium salt and chloromethyldimethylphosphine oxide analogously to Example 59 and crystallized from hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2]
Reactant: CCOC(=O)CC[C@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H]1CC[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl trans-2-(3-ethoxy-3-oxopropyl)-5-hydroxypiperidine-1-carboxylate (625 mg, 2.07 mmol, step 3 of Example 5) and triethylamine (252 mg, 2.49 mmol) in dichloromethane (9.0 mL) was added methanesulfonyl chloride (285 g, 2.49 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then stirred at room temperature for 20 h. The mixture was quenched with water (30 mL), extracted with dichloromethane (30 mL×4). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 790 mg (quant.) of the title compound as a yellow oil. The resulting residue was used for the next reaction without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>C(Cl)(Cl)Cl>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-aminopropyl)-4-(4-chlorobenzhydryl)piperazine (1.7 g) and triethylamine (0.7 g) in chloroform (20 ml) was dropwise added benzoyl chloride (0.7 ml) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate and water, and then extracted with 10% hydrochloric acid. After neutralizing the aqueous extract with aqueous sodium carbonate, the desired product was extracted with ethyl acetate. The organic extract was washed with water, dried and evaporated in vacuo to give an oil. According to a conventional manner, the oily product was converted to fumaric acid salt, which was recrystallized from a mixture of ethanol and diethyl ether to afford 1-(3-benzoylaminopropyl)-4-(4-chlorobenzhydryl)piperazine fumarate (0.82 g) as white crystals. mp: 173°-175° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.228 mmol) and 4-(bromomethyl)benzenesulfonamide (370 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 4-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzenesulfonamide crude product as a solid.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:3]1.O.[NH2:13][NH2:14]>CCO>[F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]2[NH:14][N:13]=[C:8]([NH2:9])[CH:7]=2)[CH2:3]1
Reactant: NN
Reactant: N#CCC(=O)C1CC(F)(F)C1
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CC(F)(F)C2)[nH]n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a solution of 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile (12.5 g, 78.6 mmol) in EtOH (250 mL) was added hydrazine hydrate (5.9 g, 117.9 mmol) and the resulting mixture was stirred at 75° C. overnight. After concentrating the reaction mixture in vacuo, the residue was redissolved in EtOAc (500 mL) and washed with satd. aq. NaHCO3. The aqueous layer was extracted with EtOAc and the combined extracts washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (10:1) to afford 3.46 g (39%) of 85 as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.20 (br s, 1H), 5.23 (s, 1H), 4.65 (br s, 2H), 3.16-3.13 (m, 1H), 2.88-2.84 (m, 2H), 2.64-2.57 (m, 2H); MS (ESI+) m/z=174 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](S)[N:5]([CH2:7][C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=1.O>C(O)C.[Ni]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=1
Reactant: Cc1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c(S)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
4-methyl-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole-2-thiol (0.6 g, 1.44 mmol) was dissolved in ethanol (20 mL), water (5 mL) was added, and the mixture was cooled in ice. Raney nickel (4 g) was added, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was filtered though Arbocel® and concentrated in vacuo to provide a brown oil. This was purified by flash chromatography on silica gel eluting with ethyl acetate:diethylamine (95:5) to provide the title compound (0.086, 16%) as a clear oil. 1H NMR (400 MHz CDCl3) δ 1.80-1.90 (m, 6H), 2.08-2.18 (m, 7H), 2.65-2.80 (m, 6H), 3.50 (t, 2H), 3.80 (m, 2H), 3.90 (s, 2H), 4.05 (t, 2H), 6.10 (s, 1H), 6.70 (s, 1H), 6.89 (d, 2H), 7.0 (d, 2H). LRMS ESI+ m/z 384 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([OH:34])=O)=[CH:31][C:26]=2[O:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:44])=O>ClCCl>[Cl:44][C:32]([C:30]1[CH:29]=[CH:28][C:27]2[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:24][O:25][C:26]=2[CH:31]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)O)ccc12
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)Cl)ccc12

Procedure:
To a solution of 3-(2-(1(S)-(tert-butoxycarbonylamino)-2-(pyridin-2-yl)ethyl) -phenyl)benzo[d]isoxazole-6-carboxylic acid (Compound 18a) (45 mg) dissolved in dry dichloromethane (2 mL) under nitrogen, cooled with ice bath, was added triethylamine (127 μL) then thionyl chloride (35.5 μL). After 10 min the solvents were removed under reduced pressure to give the title product.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1
Yield: 7 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-phenylpyridazin-4(1H)-one (crude 620 mg, 2.30 mmol) in 20 mL of methanol was added phenylhydrazine (996 mg, 9.22 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-phenyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (50 mg, yield 7% for two steps) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([OH:29])=O)([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].[NH2:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][OH:40])=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C.O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@:8]([CH2:26][C:27]([NH:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][OH:40])=[CH:37][CH:36]=2)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[C:7]1=[O:30])[CH3:2]
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reactant: Nc1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(CN1C(=O)[C@](CC(=O)Nc2ccc(CO)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N′-(4-methylphenyl)ureido)indolin-2-one (compound described in “Example 174(1)” of Japanese Patent Application Laid-Open No. 7-48349, 300 mg) was dissolved in acetonitrile (10 mL), and after adding p-aminobenzylalcohol (100 mg) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (151 mg) in that order, the mixture was stirred at 15-30° C. for 18 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting reaction mixture was purified by column chromatography to obtain 324 mg of the title compound (yield: 88%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>C1COCC1.O>[Cl:17][C:18]1[N:19]=[C:20]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:21]=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Sodium hydride (225.6 g, 5.64 mol) is dispersed into THF (3 L) and the temperature is lowered to 0-5° C. A solution of (R)-3-hydroxy-1-boc piperidine (891.6 g, 4.43 mol) in THF (3 L) is added over 1 h while maintaining the temperature between 0-5° C. The reaction is stirred for 1 h. 2,6-Dichloropyrazine (600 g, 4.03 mol) as a solution in THE (3 L) is added dropwise over 1.5 h maintaining the same temperature. The reaction is stirred for 2 h at 25-30° C., and then poured onto ice. The mixture is diluted with water and extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate, filtered, and concentrated. The residual oil is triturated with 5% dichloromethane in hexane to give the product as a white solid. The solid is collected by filtration and dried, to give 1538 g crude material. The crude product is retriturated with 5% dichloromethane in hexanes to give a white solid in quantitative yield. ES/MS m/z 314.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])=[CH:4][CH:3]=1.[CH:21]([C:23]1[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=1)=O.[O:32]1CCCC1>>[C:29]([NH:28][C:25]1[S:26][CH:27]=[C:23]([CH:21]=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:7][C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:9])=[O:32])=[CH:19][CH:20]=2)[N:24]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NNC(=O)NCc1ccc(N)cc1
Reactant: C1CCOC1
Reactant: CC(=O)Nc1nc(C=O)cs1
Product: CC(=O)Nc1nc(C=Nc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-[(4-aminobenzyl)carbamoyl]hydrazinecarboxylate (700.7 mg, 2.500 mmol) in anhydrous tetrahydrofuran (10 ml) was added N-(4-formyl-1,3-thiazol-2-yl)acetamide (425.5 mg, 2.500 mmol). The mixture was heated under reflux for 1 hr, cooled to room temperature, and concentrated under reduced pressure. Tetrahydrofuran (5 ml) and tert-butyl methyl ether (10 ml) were added to the residue and the mixture was stirred. The resulting solid was collected by filtration, washed twice with tert-butyl methyl ether and dried under reduced pressure to give tert-butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methylidene}amino)benzoyl]carbamoyl}hydrazinecarboxylate (1.097 g, quantitative) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O.C(OCC)(=O)C>O1CCCC1>[N:14]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:4])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-bromo-4′-nitroacetophenone (4.0 g) in dry tetrahydrofuran (60 mL) was treated with morpholine (2.84 mL). After stirring at room temperature for a further 30 minutes the reaction mixture was treated with water (100 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (100 mL), then dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give the title compound (2.72 g) as a yellow solid, Rf 0.60 (dichloromethane:methanol:triethylamine, 85:10:5). 1H NMR [(CD3)2SO]: δ 8.32 (d, 2H), 8.20 (d, 2H), 3.90 (s, 2H), 3.58 (t, 4H) and 2.48 (t, 4H).
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+].Br[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=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[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
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: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc([N+](=O)[O-])cn4)cc3CC[C@@H]12
Yield: 72.7 %

Procedure:
A 15 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 (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-bromo-5-nitropyridine (93 mg, 0.46 mmol) and 1.5 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 (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 106 mg (73%) of the title compound as an amorphous foam. mp 188°-191°. FDMS: m/e=383. α[D]589 =+57.07 (c=0.68, chloroform).
Reaction SMILES: ClCCl.CC1(C)C(C)(C)OB([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[N:16][CH:17]=2)O1.[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@H:29]([OH:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@@H:29]([C:30]1[CH:31]=[CH:32][C:33]([C:12]2[CH:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=2)=[CH:34][CH:35]=1)[OH:37])=[O:26]
Reactant: CC1(C)OB(c2ccc(CCC#N)nc2)OC1(C)C
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 60 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (30.2 mg, 0.037 mmol) is added to a degassed mixture of the product of step 1, Example 21 along with 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (150 mg, 0.369 mmol), and cesium carbonate (482 mg, 1.48 mmol) in N,N-dimethylformamide (2.76 mL) at room temperature. The reaction mixture is heated at 60° C. for 4 hours. After cooling to room temperature the reaction mixture is concentrated under high vacuum, and the residue slurried in ethyl acetate. The slurry is filtered through solka floc washing the cake with ethyl acetate. The combined filtrates were concentrated and the brown residue purified by chromatography on silica gel eluting with a gradient of 50-80% ethyl acetate in hexanes to afford the title compound (72.5 mg): 1H NMR (300 MHz, DMSO-d6) δ 2.92-2.97 (m, 2H), 3.08-3.13 (m, 2H), 4.23-4.28 (m, 1.5 H), 4.41-4.46 (m, 0.5H), 4.54-4.58 (m, 0.5H), 4.69-4.74 (m, 0.5H), 4.89-4.92 (m, 1H), 5.98 (d, 1H), 6.53 (s, 1H), 7.42-7.49 (m, 3H), 7.79 (d, 2H), 8.03-8.06 (dd, 1H), 8.62 (d, 1H), 8.83-8.84 (m, 1H). MS (ESI+) m/z of 410.0/412.0 [M+H].
Reaction SMILES: [C:1]([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[OH:17].IC>C1COCC1.CCCCCC>[CH3:1][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[OH:17]
Reactant: [Li]C(C)(C)C
Reactant: Oc1c(Br)cccc1C(F)(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cccc(C(F)(F)F)c1O
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
t-Butyllithium (1.7 ml of a 1.8M solution of hexane; 3 equiv.) is added to THF (1 ml) and cooled to -78° C. under argon with stirring, and a solution of 2-bromo-6-trifluoromethylphenol in dry THF (1 ml; 1 mmol) is added dropwise via syringe. The reaction is stirred 30 minutes, and then iodomethane (340 mg; 2.4 equiv.) is added dropwise via syringe at -78° C. under argon, with stirring. The mixture is allowed to warm to 0° C. with stirring over 15 minutes, and stirring is continued for 45 minutes more. The reaction is then quenched with 1N HCl (3 ml) and extracted from 1N HCl (10 ml) with 3×10 ml portions of ether. The combined ether portions are washed with water (3×20 ml portions: pH tests neutral), and the solution is then dried (MgSO4), filtered, and concentrated in vacuo to give crude 2-methyl-6-trifluoromethylphenol, which is chromatographed on silica gel with 5% ether in petroleum ether to give pure product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:24][NH2:25].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[NH:24]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:25]
Reactant: O=C(CCCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Agent: O=C(O)c1cc(O)ccc1O
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc2c(nn1)CCN(C(=O)CCCc1ccccc1)C2

Procedure:
11.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-phenylbutyryl)pyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 50° for 53 hours with the addition of 50 cc of dioxane. The mixture is worked up as described in Example 10. The gentisinate of the title compound has a M.P. of 203°-205° (decomp., from methanol/water 2:1).