Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH:21]([C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1)([CH3:23])[CH3:22]>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[NH:28][N:27]=2)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)c1cc(N)n[nH]1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2nc(Cl)nc3c2CCC3)n[nH]1
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, Compound (i) (8 g, 42 mmol) in isopropanol (100 mL) was added N,N-diisopropylethyl amine (8.67 g, 67 mmol) followed by 5-isopropyl-1H-pyrazol-3-amine, Compound (ii) (5.89 g, 47 mmol). The reaction mixture was heated to reflux at 100° C. for 16 h. The reaction mixture was cooled to RT. The precipitated product was filtered and washed with hexane to afford 2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine, Compound (iii) (5 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (d, 6H), 1.96-2.07 (m, 2H), 2.70-2.81 (m, 4H), 2.88-3.01 (m, 1H), 6.38 (s, 1H), 9.60 (s, 1H), 12.11 (brs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[CH:11]=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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:13]1([C:2]2[N:7]=[C:6]3[CH:8]=[CH:9][S:10][C:5]3=[CH:4][C:3]=2[CH:11]=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc2sccc2nc1Cl
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc2sccc2nc1-c1ccccc1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of 5-chlorothieno[3,2-b]pyridine-6-carbaldehyde (396 mg, 2.01 mmol) in DME/water (10 mL/2 mL) was added phenylboronic acid (306 mg, 2.51 mmol), K2CO3 (833 mg, 6.03 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol). The mixture was degassed before being heated in a sealed tube at 100° C. for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (25 mL), washed with water (2×10 mL) and washed with brine (10 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 0-40% EtOAc in heptane) to give the title compound (416 mg, 86%) as a white solid. δH (CDCl3) 10.15 (s, 1H), 8.88 (s, 1H), 8.97 (d, J 6 Hz, 1H), 7.69 (d, J 6 Hz, 1H), 7.50-7.65 (m, 5H). LCMS (ES+) 240.2 (M+H)+, RT 3.46 minutes (Method 2).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[CH:15]1([N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]5[CH:41]=[CH:40][C:39]([CH2:42][CH:43]6[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]6)=[CH:38][N:37]=5)[N:29]=4)[CH:25]=[C:26]([F:27])[C:21]=3[N:20]=[C:19]2[CH3:49])[CH2:17][CH2:16]1.ClCCCl>C(O)(=O)C>[CH:15]1([N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]5[CH:41]=[CH:40][C:39]([CH2:42][CH:43]6[CH2:48][CH2:47][N:46]([CH2:1][CH3:2])[CH2:45][CH2:44]6)=[CH:38][N:37]=5)[N:29]=4)[CH:25]=[C:26]([F:27])[C:21]=3[N:20]=[C:19]2[CH3:49])[CH2:17][CH2:16]1
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CC5CCNCC5)cn4)ncc3F)cc2n1C1CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1CCC(Cc2ccc(Nc3ncc(F)c(-c4cc(F)c5nc(C)n(C6CC6)c5c4)n3)nc2)CC1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
Add sodium triacetoxyborohydride (720 mg) to a mixture of [4-(3-cyclopropyl-7-fluoro-2-methyl-3H-benzoimidazol-5-yl)-5-fluoro-pyrimidin-2-yl]-(5-piperidin-4-ylmethyl-pyridin-2-yl)-amine (110 mg), 1,2 dichloroethane (1.14 mL) and acetic acid (2709 μL). Heat at 60° C. for 1 h. Remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2M (3%) to afford 80 mg of the title compound. MS (ES+): m/z=504 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[CH:29]=[CH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(NC(=O)OC(C)(C)C)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)c(F)c2)c(F)c1NC(=O)OC(C)(C)C
Yield: 65.7 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-3-chloro-6-(4-chloro-3-fluorophenyl)-5-fluoropicolinate (1.5 g, 3.46 mmol), tributyl(vinyl)stannane (2.196 g, 6.92 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.365 g, 0.519 mmol) were combined in 1,2-dichloroethane (4.62 mL) and irradiated in a microwave at 130° C. in a sealed vial for 30 min. The cooled reaction mixture was applied directly to a silica gel column and eluted with a 5-40% ethyl acetate/hexanes gradient to provide methyl 4-(tert-butoxycarbonylamino)-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-vinylpicolinate (0.966 g, 2.274 mmol, 65.7%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH:17]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])c(C)c2)cn1
Reaction time: 36 h
Yield: 74.1 %

Procedure:
A mixture of 5-fluoro-2nitrotoluene (1.05 g), 4-methylimidazole (556 mg) and sodium carbonate (753 mg) in dimethylformaldehyde (23 ml) was heated under stirring for 36 hours. The reaction mixture was distilled under reduced pressure to remove solvent. The residue was dissolved in water and the solution was acidified with 4N HCl solution to pH 5 and extracted with chloroform. The water layer was made to pH 10 with 2.5N sodium hydroxide solution, extracted with chloroform, dried with MgSO4 and filtered. The solution was distilled to give 1.09 g (74%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([O:25][CH:26]([F:28])[F:27])=[N:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.[H][H]>[Pd].C1COCC1>[F:28][CH:26]([F:27])[O:25][C:13]1[C:12]2[C:16](=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=2)[N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[N:14]=1
Reactant: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(OCc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Tert-butyl 6-(benzyloxy)-3-(difluoromethoxy)-indazole-1-carboxylate (262.5 mg) which can be prepared according to the method described in Reference example 33, etc. and 5% palladium on carbon-STD-type-50% wet with water (109.9 mg; manufactured by N. E. Chemcat Corp.) were suspended in dehydrated THF (3.4 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (197.2 mg).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.C([O-])(=O)C.[Na+].[H][H]>O.[Pd].C(O)(C)C>[CH3:17][C:16]([CH2:15][CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[CH:2]=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][C:8]=2[CH:7]=1)=[O:18]
Reactant: [H][H]
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
49.44 Grams (0.154 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 12.24 g (0.149 moles) of anhydrous sodium acetate, 4 g of a 50% suspension in water of 5% palladium on carbon, equivalent to 0.00094 moles of palladium and 400 ml of isopropanol are put into a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2.5 atmospheres. For a period of time of 9 hours the temperature of reaction is kept at 50° C., then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered in order to eliminate the catalyst. The solution is concentrated to 130 ml, diluted with 45 ml of water, heated to 60° C. and added with 18.2 g of sodium metabisulfite. The reaction mixture is kept for one hour at 60° C. and then is cooled to 0° C. The so obtained suspension is kept at 0° C. for two hours and then is filtered; the solid is washed with 60 ml of isopropanol cooled to 0° C. and then is suspended in a mixture made by 70 ml of a 10% aqueous solution of sodium hydroxide and 270 ml of toluene. The reaction mixture is stirred for one hour and half at room temperature, then is heated at 60° C. and the layers are separated. The organic phase is washed with 60 ml of water and is concentrated under vacuum at 60° C. until an oil is obtained which solidifies by cooling. The solid is dissolved at 60° C. in 40 ml of isopropanol and the resulting solution is cooled to 0° C. in two hours. The obtained suspension is kept for one hour at this temperature, filtered, washed with 10 ml of cold isopropanol and dried in oven under vacuum until constant weight. 26.3 Grams of nabumetone are obtained with a yield equal to 74.8%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.45 g, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.16 g, 0.9 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 195 mg, 35%). MS (H+), 628.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[C:6]([O:10][C:11]([NH:13][N:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)(=O)C>[C:6]([O:10][C:11]([NH:13][N:14]1[CH2:18][CH2:17][N:16]([Si:2]([CH3:4])([CH3:3])[CH3:1])[C:15]1=[O:19])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NN1CCNC1=O
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1CCN([Si](C)(C)C)C1=O
Reaction time: 8 h
Yield: 91.1 %

Procedure:
While cooling, 10.55 g (97.1 mmol) of trimethylsilylchloride was dropped into a solution of 19.55 g (97.1 mmol) of 1-[(t-butoxycarbonyl)amino]-2-imidazolidinone and 9.83 g (97.1 mmol) of triethylamine in 900 ml of absolute ethyl acetate. After stirring overnight, the salt was filtered off and the filtrate evaporated in vacuo to yield 24.18 g of 1-[(t-butoxycarbonyl)amino]-3-(trimethylsilyl)-2-imidazolidinone, melting point 132.1° C.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:38])[C:11]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:15]([C:26](=O)[CH2:27][S:28](=[O:34])(=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:14]([CH3:36])[NH:13][C:12]=2[CH3:37])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)(C)C.CN(C)C=O>[C:1]1([C@H:7]([O:9][C:10](=[O:38])[C:11]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:15](/[CH:26]=[CH:27]/[S:28](=[O:34])(=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:14]([CH3:36])[NH:13][C:12]=2[CH3:37])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(C(=O)CS(=O)(=O)NC(C)C)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@H](C)c2ccccc2)=C(C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC1=C(/C=C/S(=O)(=O)NC(C)C)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@H](C)c2ccccc2)=C(C)N1
Yield: 78.2 %

Procedure:
Analogously to Example 18, 1.08 g of (S)-1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid (R)-1-phenylethyl ester were treated with 0.08 g of sodium borohydride in a mixture of 10 ml of isopropanol and 2 ml of dimethylformamide. The product was chromatographed with methylene chloride/ethyl acetate (4:1) as the elution agent and then recrystallized from ethanol. There was obtained 0.82 g of (S)-1,4-dihydro-5-[(E)-2-(isopropylsulfamoyl)vinyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid (R)-1-phenylethyl ester in the form of yellow crystals, m.p. 198°-201°, specific rotation: [α]54620 =-290° (c=1.0% w/v, chloroform).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([OH:22])[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([OH:22])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccc3cccc(O)c3n2)cc1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.683 g of 2-amino-8-hydroxyquinoline, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.45 g of 2-[(4-nitrophenyl)amino]quinol-8-ol (11) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:20])[CH:15](Cl)[C:16](=O)[CH3:17])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:16]=1[CH3:17])=[O:20])[CH3:12]
Reactant: NC(=S)c1ccc(F)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(F)cc2)nc1C
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 4-fluoro-thiobenzamide (1.25 g, 8.04 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (1.11 mL, 8.20 mmol) in ethanol (18 mL) was heated at refluxed for 16 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (1.99 g): MS: (+) m/z 266.03 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:11]
Reactant: Br
Reactant: CCC(=O)c1cnccc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)C(C)Br
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methylpyridin-3-yl)propan-1-one (4.72 g) in acetic acid (35 ml) was added hydrobromic acid (5.5 ml) and the mixture was cooled to 10° C. A solution of bromine (5.0 g) in acetic acid (15 ml) was gradually added to the reaction mixture and the mixture was stirred at 80° C. for one hr. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give the title compound (5.56 g) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=O)[NH:7]2.Cl.Cl.Cl.[N:18]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:18]1([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=4)=[O:14])[CH2:31][CH2:32]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
A solution of 4-Methoxy-1H-indole-2-carboxylic acid (930 mg, 4.86 mmol), amine 5 (1.63 g, 4.86 mmol) and DIEA (2.5 ml, 14.58 mmol) in 20 ml of DMF is treated with solid TBTU (1.56 g, 4.86 mmol). The mixture is stirred over night and then evaporated. The crude residue is dissolved in EtOAc and washed twice with sodium bicarbonate (10%). The aqueous layers are re-extracted with DCM, the combined organic layers are washed with brine and dried over sodium sulfate. The crude product is then purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 0% to 2%).
Reaction SMILES: [ClH:1].[F:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4]1=[O:27])[C@:17]1([CH3:18])[C:12]2(O[CH:13]2[C:14](=[O:23])[CH:15]=[C:16]1[CH3:22])[C:11](=[CH2:25])[C@H:10]3[CH3:26].O>C(O)(=O)C>[F:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4]1=[O:27])[C@:17]1([CH3:18])[C:12](=[C:13]([Cl:1])[C:14](=[O:23])[CH:15]=[C:16]1[CH3:22])[C:11](=[CH2:25])[C@H:10]3[CH3:26]
Reactant: Cl
Reactant: C=C1[C@@H](C)[C@H]2[C@@H]3C[C@@H](F)C(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C(C)=CC(=O)C3OC132
Solvent: CC(=O)O
Solvent: O
Product: C=C1C2=C(Cl)C(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C

Procedure:
Gaseous hydrogen chloride is introduced for about 30 min into a solution of 16α-fluoro-4,5-epoxy-1,7α-dimethyl-6-methylenandrost-1-ene-3,17-dione (359 mg) in glacial acetic acid (5 ml). Thereupon water is added, the precipitate filtered off, washed with diethylether and chromatographed on silica gel to yield pure 16α-fluoro-4-chloro-1,7α-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione (264 mg). Found: C 70.05, H 6.89, Cl 9.32, F 4.99. C22H26ClFO2 requires: C 70.11, H 6.95, Cl 9.41, F 5.04.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH2:8][CH2:9][OH:10])[CH3:7].[Na]>>[C:1]([CH2:2][CH2:3][O:10][CH2:9][CH2:8][N:6]([CH3:7])[CH3:5])#[N:4]
Reactant: C=CC#N
Reactant: CN(C)CCO
Agent: [Na]
Product: CN(C)CCOCCC#N
Reaction time: 24 h

Procedure:
530 g of acrylonitrile are added dropwise to 890 g (10 mols) of dimethylaminoethanol and 0.3 g of dissolved sodium at room temperature. The mixture is left to stand for 24 hours and low-boiling constituents are distilled off.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:6]1)[CH2:12]2)=[O:4].[Br:27][C:28]([CH3:33])([CH3:32])[C:29](Br)=[O:30]>>[Br:27][C:28]([CH3:33])([CH3:32])[C:29]([N:15]([CH:8]1[CH:9]2[CH2:10][CH:11]3[CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:6][CH:7]1[CH2:13]3)[CH2:14]2)[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:30]
Reactant: COC(=O)C12CC3CC(C1)C(NNC(=O)OCc1ccccc1)C(C3)C2
Reactant: CC(C)(Br)C(=O)Br
Product: COC(=O)C12CC3CC(C1)C(N(NC(=O)OCc1ccccc1)C(=O)C(C)(C)Br)C(C3)C2

Procedure:
Benzyl 2-(5-methoxycarbonyladamantan-2-yl)hydrazinecarboxylate and 2-bromoisobutyrylbromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-(5-methoxycarbonyladamantan-2-yl)hydrazinecarboxylate was obtained as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:18])[CH:17]=1)[N:14]=[CH:13][C:12]([C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:20])=[C:11]2[OH:30])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:18])[CH:17]=1)[N:14]=[CH:13][C:12]([C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:20])=[C:11]2[OH:30]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 1 h

Procedure:
To a flask containing tert-butyl-3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinylcarbamate from Preparation No. 25 (0.06 g) and dichloromethane (2 mL) is added trifluoroacetic acid (2 mL). The reaction mixture is stirred 1 hour then concentrated under reduced pressure. The residue is triturated with toluene (3×) and dried in vacuo. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% MeOH:CH2Cl2 to 6% MeOH:CH2Cl2. The product-containing fractions are evaporated to give 0.04 g of the title compound as a tan solid.