Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[N:21]([NH:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[Pd].[OH-].[OH-].[Pd+2]>[CH:31]1([NH:30][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]([OH:29])=[C:19]([C:14]3[NH:13][C:12]4[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][C:11]=4[S:16](=[O:17])(=[O:18])[N:15]=3)[C:20]2=[O:36])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NC1CCCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NC1CCCC1
Yield: 98.7 %

Procedure:
The product of Example 305B (0.122 g, 0.23 mmol) in tetrahyrofuran (15 mL) was reacted with a catalytic amount of palladium hydroxide on carbon, a catalytic amount of 5% palladium on carbon, and ammonium formate (0.080 g, 1.27 mmol) at 60° C. for 2 hours. The warm reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give the title compound (0.10 g, 100%). MS (ESI−) m/z 439 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 4 H) 1.78 (m, J=2.94 Hz, 2 H) 2.58 (m, 2 H) 3.91 (m, 1 H) 6.25 (m, 1 H) 7.13 (m, 2 H) 7.45 (m, 1 H) 7.54 (d, J=9.19 Hz, 1 H) 7.85 (m, 1 H) 8.12 (m, 2 H) 10.45 (s, 1 H) 14.00 (s, 1 H) 15.25 (s, 1 H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)#[N:2].S(Cl)([Cl:16])=O>>[C:1]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)#[N:2]
Reactant: N#CCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: N#CCCc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 17.5 parts of 4-(2-cyanoethyl) benzoic acid and 120 parts of thionyl chloride are refluxed for 15 minutes. The surplus thionyl chloride is then eliminated under reduced pressure and the 4-(2-cyanoethyl) benzoyl chloride is obtained which is liquid at atmospheric temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccc(Br)cc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and 4-methoxybenzyl chloride (0.045 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:ethyl acetate/hexane=1/10) to obtain N-(4-bromophenyl)-N-(4-methoxybenzyl)pyrimidin-2-amine (107 mg).
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]([CH2:13]Cl)([CH2:11]Cl)[CH2:9][CH3:10]>C(O)C>[OH:5][CH2:4][CH2:3][S:2][CH2:7][C:8]([CH2:13][S:2][CH2:3][CH2:4][OH:5])([CH2:11][S:2][CH2:3][CH2:4][OH:5])[CH2:9][CH3:10]
Reactant: CCC(CCl)(CCl)CCl
Reactant: OCCS
Agent: [Na]
Solvent: CCO
Product: CCC(CSCCO)(CSCCO)CSCCO

Procedure:
To 300 parts of ethanol were successively added 6.9 parts of metallic sodium, 23.4 parts of 2-mercaptoethanol and 18.9 parts of 1,1,1-tris(chloromethyl)propane in this order, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium chloride was removed, and the solution was concentrated to obtain 1,1,1-tris(2-hydroxyethyl-thiomethyl) propane. This compound was added to 50 parts of chloroform, and 45 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the solvent by distillation to obtain 1,1,1-tris(2-chloroethylthiomethyl)propane. To this compound were successively added 0.3 part of phosphoric acid and 60 parts of 30% aqueous hydrogen peroxide, and the resulting medium mixture was heated under reflux and then cooled to deposit 1,1,1-tris(2-chloroethylsulfonylmethyl)propane. The deposited compound was recovered by filtration and dissolved in 200 parts of acetone, and the resulting acetone solution was incorporated with 30 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and the acetone solution was concentrated to deposit white solids. The solids were recrystallized from ethanol-acetone to obtain 1,1,1-tris(vinylsulfonylmethyl)propane.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1.[H-].[Na+]>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CCCCCCc2ccccc2)c1
Yield: 54.1 %

Procedure:
By working in a way similar to that described in example 2 but using toluen-4-sulphonic acid 6-phenyl-hexyl ester (5.4 g, 16.24 mmoles), obtained as described in example 11, 3-methoxy-phenyl-acetonitrile (2.39 g, 16.24 mmoles), NaH (55-65%, 715 mg, 17.86 mmoles) and DMF (25 ml), 2.7 g of the title compound were obtained (yield: 54.1%).
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:3]\[C:4]([OH:6])=[O:5].C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)S(O)(=O)=O.C1(SC)C=CC=CC=1.C1C(O)=CC=CC=1C.CCOCC>CN(C=O)C.FC(F)(F)C(O)=O.O>[C:10]([OH:12])(=[O:11])[CH:1]=[C:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)/C=C(\CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=C(CC(=O)O)C(=O)O

Procedure:
Trans-aconitic acid (0.17 g, 1.0 mmol) and trifluoroacetic acid salt of β-Ala--Arg(Mts)--Leu--Asp(OBn)--Ser(Bn)--NH--iPr (SEQ ID NO:11) (3.23 g, 3.0 mmol) were condensed with CDI in DMF. The product was treated as in Example 73 to obtain the objective compound in the protected form (0.67 g, 0.22 mmol). The protected compound was dissolved in trifluoroacetic acid (10 ml), added with a trifuluoroacetic acid solution of 1M-trifluoromethanesulfonic acid/thioanisole/m-cresol with ice cooling at 0° C. and allowed to react for 1 hour to eliminate the protective group on the side chains and at the terminal of the peptide. The reaction mixture was poured into ether, and resulted oily precipitate was dissolved in distilled water, washed with ethyl acetate, passed through an anion-exchange resin column (Amberlite IRA400; C1 form) to convert the product into hydrochloride and lyophilized to obtain the objective aconitic acid (β-Ala--Arg--Leu--Asp--Ser--NH--iPr)3 (SEQ ID NO:11)3 (0.29 g, 0.15 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:16]#[N:17])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.[C-:18]#[N:19].[Na+]>CN(C)C=O.O>[C:18]([CH2:2][CH2:3][CH2:4][C:5]1([C:16]#[N:17])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:19]
Reactant: [C-]#N
Reactant: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(C#N)(CCCC#N)CC1
Temperature: 140 °C
Yield: 88.3 %

Procedure:
To a solution of ethyl 4-(3-chloropropyl)4-cyano-1-piperidinecarboxylate (12.7 g) in dimethylformamide (250 ml) was added sodium cyanide (24 g) under nitrogen, with stirring. The mixture was warmed at 140° C. overnight and then cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution and water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was chromatographed, eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to give 10.8 g (88.5%) of product. A portion was distilled to give the analytical sample, bp196-201° C. (4 mm of mercury).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:16][CH2:15]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 3-nitrobenzoyl chloride (4.5 g, 24.25 mmol) in THF (30 ml) was added 1-methylpiperazine (8.50 g, 85 mmol). The reaction was stirred for 20 min at room temperature. The reaction mixture was diluted with 50 mL water and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine (50 mL). The brine was back extracted with ethyl acetate (2×50 mL) and all the organic layers were combined, dried over magnesium sulphate, filtered, and concentrated under vacuum give the title product (5.2 g).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:44]([C:46]1[N:47]=[CH:48][N:49]2[C:54](=[O:55])[N:53]([CH2:56][O:57][CH3:58])[N:52]=[N:51][C:50]=12)=O>C(Cl)Cl>[NH:43]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:44]1[C:46]1[N:47]=[CH:48][N:49]2[C:54](=[O:55])[N:53]([CH2:56][O:57][CH3:58])[N:52]=[N:51][C:50]=12
Reactant: COCn1nnc2c(C(=O)Nc3ccccc3N)ncn2c1=O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COCn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
Triflic anhydride (820 μL; 4.85 mmol) was added to a solution of triphenylphosphine oxide (1.35 g; 4.85 mmol) in DCM (15 mL) at 0° C. and the mixture stirred for 20 minutes, then added to a suspension of N-(2-aminophenyl)-3-(methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.500 g; 1.61 mmol—combined batches) in DCM (15 mL). The solution was stirred for 96 hours, and the precipitate filtered. This was the triflate salt of the desired product (550 mg). This salt was dissolved in a mixture of MeCN (19 mL) and MeOH (1 mL) and triethylamine (750 μL) added. The resulting precipitate was filtered, and washed with ethyl acetate to give the title compound as a yellow powder (269 mg; 56%). Concentration of the filtrate, and washing the residue with ethyl acetate yielded a further 48 mg of pure material. δH (DMSO d6): 13.09 (1H, s), 7.75 (1H, d, J=7.5), 7.58 (1H, d, J=7.1), 7.30-7.22 (2H, m), 5.64 (2H, s), 3.45 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>O.C1COCC1.C(OCC)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([O:36][CH2:37][C:38]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=3)=[O:39])(=[O:34])=[O:35])=[CH:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=C(Cl)COS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(COS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A mixture of p-aminosalicylic acid (43 mg, 0.278 mmol) and NaOH (11 mg, 0.278 mmol) in water (6 ml) was stirred at room temperature for 10 min until all of the solid material had dissolved. Na2CO3 (25 mg, 0.231 mmol) was then added and the mixture cooled to 0° C. A suspension of 14 (105 mg, 0.306 mmol) in THF (2 ml) was injected rapidly and the resulting solution allowed to warm to room temperature and stirred for 2 h. Then reaction mixture was poured into a separating funnel containing diethyl ether. The phases were separated and the aqueous phase washed with a further portion of diethyl ether. The aqueous phase was acidified to pH 1 by addition of 1N HCl solution and the product extracted into ethyl acetate. The ethyl acetate was washed twice with 1N HCl solution and the organic phase was dried (Na2SO4) and filtered. The product was found to be in both the diethyl ether and ethyl acetate fractions so these organic phases were combined and the solvent removed in vacuo. The product was purified by column chromatography over silica gel (Rf=0.27, 10% MeOH in ethyl acetate) affording 15 as a yellow powder (45 mg, 35%). An analytical sample was obtained by further purification by recrystallization from EtOAc/MeOH. δH (400 MHz, MeOD) 4.72 (2H, s, CH2), 6.89 (1H, dd, J=8.6 Hz and 1.8 Hz, ArH), 7.13 (1H, d, J=1.8 Hz, ArH), 7.46 (2H, d, J=8.4 Hz, ArH), 7.58 (2H, d, J=8.4 Hz, ArH), 7.70 (1H, d, J=8.6 Hz, ArH), 7.82 (2H, d, J=8.4 Hz, ArH), 8.03 (2H, d, J=8.4 Hz, ArH); MS (ES−) 401.9 (100%), 459.8 (75%, [M−H]−).
Reaction SMILES: ON[C:3]([CH2:5][N:6]([CH2:20]C(C)C)[C:7](=[O:19])[CH2:8][CH:9]([CH2:15]C(C)C)[C:10]([N:12](C)C)=[O:11])=[O:4].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:45]([O:52]N)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH2:45]([O:52][C:3]([CH2:5][N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH:9]([CH3:15])[C:10]([NH2:12])=[O:11])=[O:4])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC(CC(=O)N(CC(=O)NO)CC(C)C)C(=O)N(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(CC(=O)N(C)CC(=O)OCc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 40.9 %

Procedure:
N4 -(Hydroxycarbamoyl-methyl)-2,N4 -diisobutyl-N1,N1 -dimethyl-succinamide (1.30 g, 0.0041 mol) was dissolved in DMF (10 ml) and treated at 0° C. with NMM (0.56 g, 0.0041 mol) followed by EDC (0.95 g, 0.005 mol) and HOBt (0.67 g, 0.005 mol). The reaction mixture was allowed to stir at 0° C. for 20 minutes and then at ambient temperature for 2 hours before O-benzylhydroxylamine (0.76 g, 0.0062 mol) was added. The reaction mixture was allowed to stir at room temperature for a further 1.5 hours. The solvent was removed under reduced pressure and the resulting crude oil was taken up in ethyl acetate (100 ml). The solution was washed consecutively with saturated aqueous NaHCO3, 1M HCl and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to a crude oil. The crude oil was purified by flash chromatography (silica gel, gradient elution with 5% to 10% methanol in dichloromethane) to give the title compound as a white solid (0.49 g, 29%). 1H NMR: δ(CD3OD), 7.38-7.21 (5H, br m). 4.75 (2H, s), 4.11-3.65 (2H, br m), 3.25 (1H, br m), 3.17-2.97 (2H, br m), 3.07 (3H, s), 2.81 (3H, s), 2.79-2.24 (2H, br m), 1.75 (1H, br m), 1.55-1.25 (3H, br m) and 0.91-0.64 (12H, br m).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=O)=[CH:5]2)[CH2:3][CH2:2]1.C([N:22](CC)CC)C.ClC(OCC)=O.N>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([NH2:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (1.00 g, 3.77 mmol) was dissolved in dimethylformamide (15 ml), added with triethylamine (0.788 ml, 5.66 mmol) and ethyl chloroformate (0.538 ml, 5.66 mmol) under ice cooling, and stirred for 1 hour. The reaction mixture was warmed to room temperature, stirred for 30 minutes, and further stirred at 0° C. for 1 hour. The reaction mixture was added with concentrated aqueous ammonia (0.75 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (1.23 g, quantitative) as white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:17]2[CH2:16][CH2:15][C@@:12]2(C=O)[C@H:8]3[C@@H]3C[C@@H]3[CH2:11]2)[CH2:3]1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[O:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C(OCC)C>[CH2:41]1[C@@H:43]2[C@H:44]([OH:40])[C@:12]3([CH2:15][CH2:16][C@H:17]4[C@@H:7]([CH2:6][CH:5]=[C:4]5[C@:18]4([CH3:21])[CH2:19][CH2:20][C@H:2]([OH:1])[CH2:3]5)[C@@H:8]3[C@H:42]12)[CH3:11]
Reactant: C1CCOC1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C[C@@]3(C=O)CC[C@@H]12
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2O

Procedure:
A solution of 21 g of 3β-hydroxy-15β,16β-methylene-5-androsten-18-one in 210 ml of tetrahydrofuran was stirred with 21 g of lithium tri-tert.-butoxyaluminohydride for 1 hour at room temperature. The mixture was then diluted with diethyl ether, washed with 2N sulfuric acid and water, dired, and evaporated, thus obtaining 19 g of 15β,16β-methylene-5-androstene-3β,17β-diol, used without further purification in the subsequent stage.
Reaction SMILES: [NH:1]([CH2:3][CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6])[NH2:2].[Cl:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([CH2:16][CH2:17][C:18](O)=[O:19])=O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O>[OH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[CH2:3][N:1]1[C:18](=[O:19])[CH2:17][CH2:16][C:14]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:22][CH:21]=2)=[N:2]1
Reactant: CC(C)C(O)CNN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(O)CN1N=C(c2ccc(Cl)cc2)CCC1=O
Yield: 92.1 %

Procedure:
A mixture of 9.5 grams (0.085 mol) of 1-hydrazino-3-methyl-2-butanol, 14.4 grams (0.070 mol) of 3-(p-chlorobenzoyl)-propanoic acid and 100 milliliters of toluene are stirred in a flask equipped with a condenser and Dean-Stark water collecting apparatus at reflux for about 2.0 hours during which 2.8 milliliters of water is collected in the Dean-Stark tube. The toluene solution is washed with 50 milliliters of 2 N sodium hydroxide solution, 25 ml. of 2 N hydrochloric acid and then water. The toluene layer is then dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The solid obtained is crystallized from methylene chloride-petroleum ether to yield 19.0 grams of 2-(2-hydroxy-3-methylbutyl)-6-(p-chlorophenyl)4,5-dihydropyridazine-3(2H)-one, (m.p. 90°-92° C.)
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CN1C(=O)CCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:2]3=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]3[CH:4]=[N:19]2)=[CH:14][CH:13]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a dry 16×100 mm CHEMGLASS® reaction tube under N2 was added 2-fluoro-4-iodonicotinaldehyde (600 mg, 2.390 mmol), (4-fluorophenyl)hydrazine (332 mg, 2.63 mmol), and anhydrous NMP (3.2 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temperature, and then placed in a 185° C. oil bath for 2 h. The reaction mixture was then allowed to stir at room temperature for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was extracted with water (5×50 mL), brine (1×50 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by BIOTAGE® Silica gel chromatography on a 90 g Thompson Single Step silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 12 column volumes to give 480 mg (59.2%) of the title compound, Intermediate 1A, as an off white solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.22-8.28 (3 H, m), 8.15 (1 H, s), 7.78 (1 H, d, J=4.88 Hz), 7.25-7.37 (2 H, m). LC/MS (Condition A): 100% purity; ret. T=2.9 min, (M+H)+ 339.97.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[CH:13](=[O:15])[CH3:14].[OH-].[Na+].C(OC(=O)C)(=O)C.C(OC)(=O)C>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:14][CH:13]=[O:15])[CH:2]=1
Reactant: CC=O
Reactant: O=Cc1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: O=CC=Cc1cnc2ccccc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a 500-mL round-bottom flask, equipped with mechanical stirrer, dropping funnel and temperature bath was charged 30.9 g (0.2 mol) quinoline 3-carboxaldehyde and acetaldehyde (50 mL). The mixture was cooled to −10° C. and a solution of sodium hydroxide (500 mg) in methanol (8 mL) was added dropwise keeping the temperature below 10° C. The mixture was stirred at 0° C. for 30 min. Acetic anhydride (50 mL) was added and the mixture was heated to 70° C. (methyl acetate formed in the reaction was removed). After 1 hour, the mixture was cooled to 30° C. and 100 mL 3N HCl (50 mL conc. HCl in 100 mL water) was added. The mixture was heated to 80° C. for 45 min. and neutralized with 10% sodium carbonate solution. (The organic layer, containing product, was checked by TLC, system isopropyl acetate, visualize under short UV). At the end of the reaction, the mixture was cooled to <30° C., diluted with 200 mL water and it was washed with 2×150 mL isopropyl acetate. To the aqueous layer was then added isopropyl acetate (500 mL) and the pH was brought to >8 by neutralization with sodium carbonate. The organic layer was separated and concentrated to a small volume until the product starts to crystallize. The mixture was stirred for 30 min. filtered and dried to give 18.5 g product as a light yellow solid. A second crop (5.4 g) was collected by concentration of the mother liquor and filtration of the solid product followed by washing with MTBE (25 mL). Total yield, 23.9 g (66%). The NMR of the product was consistent with the proposed structure.