Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[O:3]1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]2=[O:12])[CH2:19][CH2:20][CH3:21]
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
A solution of 50 g (0.26 mol) of 2,2-dimethyl-6-hydroxychroman-4-one (Example 28a) in 500 ml of DMF was added dropwise to a suspension of 9.0 g (0.3 mol) of 80% sodium hydride in 500 ml of DMF. After stirring at RT for 90 min, 49 g (0.265 mol) of iodobutane were added and the mixture was stirred at RT for a further 90 min. The reaction mixture was then concentrated in vacuo, the residue was treated with water and the mixture was extracted several times with EA. The organic phases were washed with 5 M sodium hydroxide solution, stirred with activated carbon and magnesium sulfate, filtered and concentrated. 57.6 g of 6-butoxy-2,2-dimethylchroman-4-one were obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([CH:24]([CH3:26])[CH3:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:28])[CH2:23][CH2:22][C@@H:21]([CH:24]([CH3:26])[CH3:25])[C@@H:12]32)[C:3]1([CH3:32])[CH3:33]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 91.9 %

Procedure:
To a solution of (1S,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (3 g, 6.54 mmol) and potassium carbonate (1.808 g, 13.08 mmol) in DMF (60 mL) was added (bromomethyl)benzene (0.816 mL, 6.87 mmol). The reaction mixture was heated up to 60° C. for 3 h. LCMS indicated the starting material was consumed. The reaction mixture was quenched with 60 ml water, a white precipitate was observed. The white solid was collected through filtration and washed with distilled water. The solid was dried in the air to provide the title compound as white solid (3.3 g, 92%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.42-7.28 (m, 5H), 5.27-5.01 (m, 2H), 3.18 (dt, J=11.22, 5.53 Hz, 1H), 2.40-2.09 (m, 3H), 1.91-1.73 (m, 2H), 1.72-0.78 (m, 21H), 0.95 (s, 3H), 0.91 (s, 3H), 0.84 (d, J=7.02 Hz, 3H), 0.80 (s, 3H), 0.75 (s, 3H), 0.73 (s, 3H), 0.73 (d, J=6.71 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[CH:9]=1)(O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[BH4-].[Na+].Cl>C1COCC1.O>[F:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]([CH2:1][OH:2])[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(CO)c(=O)n(CC(C)C)n2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 4-carboxy-6-(3-fluoro-4-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-one (4.53 g, 14.9 mmol) in THF (40 mL) was added triethylamine (1.66 g, 16.4 mmol). To the ice-cooled mixture was added dropwise a solution of ethyl chlorocarbonate (1.78 g, 16.4 mmol) in THF (5 mL), and the mixture was stirred for 30 minutes. Triethylamine hydrochloride was filtered off. An ice-cold solution of sodium borohydride (564 mg, 14.9 mmol) in water (1 mL) was added to the filtrate, and then, the mixture was stirred at room temperature for 10 minutes. Thereafter, 2 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel [silica gel 300 g, chloroform/methanol (100/1→50/1)) to yield the title compound as a colorless crystalline powder (1.08 g, 25.0%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[CH:25]1([CH:31]=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=CC1CCCCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=CC1CCCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.115 g, 0.30 mmol) was reacted with cyclohexanecarbaldehyde (0.336 g, 3.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36].C(OCC)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35](=[O:37])[CH3:36])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 1 ml of pyridine, 268 mg of acetic anhydride and 10 mg of 4-dimethylaminopyridine were added to the solution, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. By recrystallizing the resulting residue from ethanol, 139 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]acetamide was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=[O:37])[CH3:36]>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:35](=[O:37])[CH3:36])[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (101 mg), 4M hydrogen chloride/ethyl acetate (1 mL) and ethyl acetate (1 mL) was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was mixed with acetic anhydride (1 mL) and pyridine (1 mL), and the obtained mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol), and recrystallized (hexane/ethyl acetate) to give the title compound (53.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Reactant: CNc1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccccc1Br
Temperature: 25 °C
Yield: 24 %

Procedure:
To a reaction vial charged with 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride (0.05 g, 0.2 mmol) and 2-bromo-N-methylaniline (0.044 g, 0.24 mmol) was added a catalytic amount of DMAP. Pyridine in methylene chloride (1.2 M, 0.66 mL) was added and the reaction was stirred at room temperature with LC/MS monitor. The reaction was complete in a couple hours. After aqueous work up, the reaction mixture was concentrated in vacuo, taken into DMF at 100 mg/ml and purified by preparative RP-HPLC to give 162bp. Yield=24% of theoretical. MS: (ESI+)=419.5
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N[C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+].IC1C=CC=CC=1>O1CCOCC1.[Cu]I>[C:11]1([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Ic1ccccc1
Product: c1ccc(-n2ccc3cnccc32)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-azaindole (780 mg, 6.60 mmol), copper(I) iodide (25.1 mg, 132 μmol), (1S,2S)-(+)-1,2-diaminocyclohexane (162 μl, 1.35 mmol) and potassium phosphate (2.52 g, 11.9 mmol) in dioxane (24 ml) was added iodobenzene (739 μl, 6.60 mmol). The reaction mixture was stirred overnight at 110° C. The mixture was then cooled to room temperature, filtered through silica gel, and the silica gel washed with EA. The combined filtrates was evaporated under reduced pressure, and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. Yield: 1.28 g.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH:17]=O.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:33]([O:32][C:31]([N:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:24]2[O:19][CH2:20][CH2:21][O:22][C:23]=2[CH:28]=1)[CH:38]1[CH2:43][CH2:42][N:41]([CH2:17][CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]2=[O:1])[CH2:40][CH2:39]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To 24 mL of dichloromethane suspension containing 0.8 g of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 1.1 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.24 mL of acetic acid was added, at room temperature and stirred at room temperature for 1 hour. To the reaction mixture, 1.0 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate], to give 1.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylate as a slight yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 3 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (90 mg, 0.289 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (62 mg, 0.304 mmol), DL-10-Camphorsulfonic acid (84 mg, 0.362 mmol) and isopropanol (3 mL) in a microwave tube. Microwaved reaction at 120° C. for 20 minutes. Evaporated off solvent and purified with normal phase chromatography to yield an off-white solid, 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3,N-dimethyl-benzamide (4.2 mg, 3%). LCMS: m/z=479.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.06 (d, 1H, J=1.3 Hz), 7.39 (m, 4H), 7.27 (m, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 6.66 (d, 1H, J=8.6 Hz), 6.10 (m, 1H), 2.92 (m, 3H), 2.34 (m, 2H), 2.25 (s, 3H), 2.05 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.C=O.[CH:29]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH3:29])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C[O-]
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cc1c(N2CCN(C)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To 1-cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) are added formic acid (3 ml), 37% formalin (3 ml) and sodium formate (0.4 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is poured into ice water and adjusted to below pH 8 with aqueous sodium hydrogen carbonate, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from ethyl acetate to give 1-cyclopropyl-7-(3,4-dimethyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.12 g), as pale yellow powder, m.p. 181°-183° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:35][C:36]([F:53])([F:52])[C:37]1[N:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:36]([F:35])([F:52])[F:53])[N:42]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)n2)OC1(C)C
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: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C(F)(F)F)n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 1g (1.09 mg, 2.13 mmol) in dimethoxyethane (15 ml), was added 6-(Trifluoromethyl)pyridine-2-boronic acid pinacol ester (750 mg, 2.56 mmol), and 2M Na2CO3 (2.1 mL, 4.26 mmol). The mixture was degassed, tetrakis(triphenylphosphine)palladium (0) (490 mg, 0.426 mmol) was added and the mixture was degassed, and then heated to 80° C. After 1 hr, the reaction was cooled to room temperature, diluted with EtOAc and washed with NaHCO3 and brine. Purification by column chromatography gave the title compound (987 mg, 91%). Calcd for C27H25F6NO2 (M+H) 509.44, Found 510.3.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[O:28]C)[N:13]=2)=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[O:28]=[C:18]1[NH:17][CH:16]=[CH:15][C:14]2[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=3)[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]1=2
Reactant: COc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-methoxy-3-phenyl-1,6-naphthyridine (25 g, 66 mmol) in dioxane (66 mL) was added 4M HCl (66 mL). The reaction mixture was stirred overnight, poured carefully into saturated NaHCO3 (900 mL), and filtered to give 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde as a white solid. 1H NMR: (500 MHz, CDCl3) δ 11.58 (br s, 1H), 10.00 (s, 1H), 8.74 (s, 1H), 7.80 (d, 2H), 7.61 (d, 2H), 7.43 (d, 1H), 7.33-7.21 (m, 6H), 6.93 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[S:9])[NH2:8].OO>CO>[N:1]1[S:9][C:7]([NH2:8])=[C:3]2[S:4][CH:5]=[CH:6][C:2]=12
Reactant: NC(=S)c1sccc1N
Agent: OO
Solvent: CO
Product: Nc1snc2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of crude 3-aminothiophene-2-carbothioamide in MeOH (5 mL) was added H2O2 (30%, 0.6 mL), after stirring at room temperature for 15 min, it was concentrated to remove most of MeOH, and then diluted with EtOAC, organic layer was washed with brine, concentrated to give crude pdt, purification by column chromatography (DCM/EtOAC=3:1) gave thieno[3,2-c]isothiazol-3-amine (334 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH2:21])[CH3:14].N>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH:21][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:12])=[N:11][C:3]=1[O:2][CH3:1])[CH3:14]
Reactant: COc1nc(Cl)ccc1C(=O)Cl
Reactant: CCN1CCCC1CN
Agent: N
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCN1CCCC1CNC(=O)c1ccc(Cl)nc1OC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
5.02 g (0.025 mole) of crude 2-methoxy-6-chloronicotinoyl chloride are dissolved in 75 ml of absolute chloroform and the solution is added dropwise in the course of 30 minutes at 25°-30° C to a solution of 7.7 g (0.06 mole) of 1-ethyl-2-(aminomethyl)-pyrrolidine in 75 ml of absolute benzene. The reaction mixture is stirred for 3 hours at 50° C, cooled, and 10 ml of a 5 N ethanolic ammonia solution are added thereto. The organic solvents are evaporated in vacuo and the residual crude base is chromatographed through a column of basic silica gel with benzene which contains 0.5% of methanol. Pure N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxy-6-chloronicotinamide is obtained as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH:10]([C:25]([O:27][CH3:28])=[O:26])[CH2:9]1)(OC(C)(C)C)=O.[ClH:29]>C(OCC)(=O)C>[ClH:29].[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[C:25]([O:27][CH3:28])=[O:26])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][O:16][C:15]1=[O:24]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)OCc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1CNCCC1N1C(=O)OCc2ccccc21

Procedure:
Methyl 1-Boc-4-(3,1-benzoxazin-2-one-1-yl)-3-piperidine carboxylate from Step 3 above (0.6 g, 1.5 mmol) was stirred in ethyl acetate in an ice bath, then saturated with HCl gas and stirred another 15 min in the cold. The mixture was evaporated in vacuo. Three portions of ethyl acetate were successively added and evaporated in vacuo to give methyl 4-(3,1-benzoxazin-2-one-1-yl)-3-piperidine carboxylate hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH3:32])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][CH3:32])([O-:29])=[O:28]
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: CCC[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.100 g, 0.52 mmol) and CDI (0.169 g, 1.04 mmol) were added together and then reacted with nitropropane (0.070 g, 0.78 mmol) and DBU (0.198 g, 1.30 mmol) according to the general procedure. Purification by column chromatography gave 0.059 g (43%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.17 (m, 3H), 5.04 (dd, J=4.4, 9.6 Hz, 1H), 2.60 (m, 4H), 1.62 (m, 6H), 1.31 (m, 2H) 1.02 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.3, 142.5, 128.6, 128.5, 126.0, 95.8, 39.5, 35.9, 31.3, 28.7, 23.5, 23.3, 10.6 ppm; IR νmax (cm−1) 2922, 2855, 1730, 1559, 1454, 1363, 1030, 747, 699; HRMS (FAB) calcd for C15H21NO3 (MNa+) 286.1414, found 286.1410.