Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:43])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:42][C:26]4([CH2:29][C:28]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:27]4)[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.C(O)(=O)C.[H][H]>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C@:2]12[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:49])[CH3:48])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:43])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([CH:24]2[CH2:25][C:26]4([CH2:29][C:28]([C:30]([O:32][CH:33]([CH3:34])[CH3:35])=[O:31])([C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[CH2:27]4)[CH2:42]2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC2(CC(C3=CC[C@]4(C)[C@H]5CC[C@@H]6[C@H]7[C@H](C(C)C)CC[C@]7(N)CC[C@@]6(C)[C@]5(C)CC[C@H]4C3(C)C)C2)C1
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (0.057 g, 0.085 mmol) in ethanol (2 mL), 1,4-dioxane (2 mL) and acetic acid (0.02 mL, 0.349 mmol) was added palladium hydroxide (20% on carbon) (0.072 g, 0.103 mmol). The mixture as stirred under 1 atm of hydrogen overnight. After stirring the mixture for 15 h, it was filtered through a plug of celite (washed with MeOH) then the filtrate was concentrated under reduced pressure. The residue was diluted with 15 mL of sat. aq. NaHCO3 and extracted with dichloromethane (3×15 mL). The combined organic layers were dried with sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give diisopropyl 6-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]heptane-2,2-dicarboxylate (0.057 g, 0.085 mmol, 100% yield) as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ=5.33 (d, J=5.7 Hz, 1H), 5.11-5.02 (m, 2H), 3.80-3.72 (m, 1H), 3.68-3.60 (m, 1H), 2.66 (s, 2H), 2.44 (s, 2H), 2.99-0.64 (m, 62H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-butoxycarbonyl)-4-piperidone (5.00 g) and 4-butoxyaniline (3.95 g) was treated in the same manner as described in Preparation Example 37 to give brown powder of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO.O1CCCC1>[C:23]1([C:18]2[C:17]([NH:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:12][CH:11]=3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CCCc1ccc(OCCNc2cccnc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(OCCNc2cccnc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
4-{4-[2-(2-phenylpyridinylamino)ethoxy]phenyl}butanoic acid methyl ester (149 mg) from the previous step was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and 2N sodium hydroxide aqueous solution (0.6 mL) was added, then stirred overnight at room temperature. The reaction solution was concentrated with 2N hydrochloric acid (0.6 mL), then the residue was purified by silica gel flash column chromatography (developing solvent: chloroform:methanol=19:1) to give the above-identified compound (115 mg, yield 80%) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-fluoropiperidin-1-yl)quinolin-7-yl]ethanone (0.0364 g, 0.119 mmol) and ammonium acetate (0.0915 g, 1.19 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.297 mL, 0.297 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H20ClFN3 (M+H)+: m/z=308.1; Found: 308.1.
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:19])[C:9]([CH3:18])([CH3:17])[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[CH:1]1([O:7][C:8](=[O:19])[C:9]([CH3:17])([CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)OC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a mixture of 2,2-dimethylmalonic acid t-butyl ester cyclohexyl ester (817 mg) and dichloromethane (7.5 mL), TFA (1.5 mL) was added, and the resulting mixture was stirred at room temperature for 2.5 hours. To the resulting mixture, ethyl acetate (100 mL) was added. The resulting mixture was sequentially washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and toluene (10 mL) was added to the filtrate obtained, after which the filtrate was concentrated under reduced pressure to obtain the captioned compound (571 mg).
Reaction SMILES: CO[C:3](=[O:39])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[C:6]([F:37])[C:5]=1[OH:38].[CH3:40][NH:41][CH3:42]>C1COCC1>[F:37][C:6]1[C:5]([OH:38])=[C:4]([CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=1)[C:3]([N:41]([CH3:42])[CH3:40])=[O:39]
Reactant: CNC
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)cc(F)c1O
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(O)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
22 mg (40 μmol) of 3-fluoro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester was dissolved in 2 ml of a 2 M solution of dimethylamine in THF. The solution was heated to 100° C. in a closed vial for 24 h and then concentrated. The residue was dissolved in 2 ml of methanol and 350 μl of 50% w/v aqueous potassium hydroxide added. The mixture was left at ambient temperature for 1 h and then neutralized by addition of glacial acetic acid. The crude was directly purified by mass triggered reverse phase HPLC purification to afford 6.0 mg (14 μmol; 37% yield) of 3-fluoro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as an ivory solid. 1H-NMR (d6-DMSO): δ 11.91 (s, 1H), 8.51 (d, 1H), 8.14 (d, 1H), 7.73 (d, 1H), 7.64 (d, 1H), 7.62 (dd, 1H), 7.32-7.25 (m, 2H), 7.14 (d, 1H), 7.05 (m, 1H), 3.82 (s, 3H), 2.99 (s, 3H), 2.87 (s, 3H). MS: m/z 406 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[CH2:23]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1Nc1ccccc1
Yield: 45.4 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (4.0 g, 13.6 mmol) and piperazine (4.7 g, 54.6 mmol) in 40 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (3.5 g, 86%) was obtained by flash column chromatograph (10% methanol in dichoromethane). A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), benzyl bromide (0.2 g, 1.7 mmol) and triethylamine (0.60 ml, 4.19 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(5-(4-benzylpiperazin-1-yl)-2-nitrophenyl)benzenamine (0.30 g, 43%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.54 (t, J=5.0 Hz, 4H), 3.32 (t, J=2.0 Hz, 4H), 3.56 (s, 2H), 6.34 (dd, J=9.7, 2.1 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 7.22-7.44 (m, 9H), 8.14 (d, J=9.7 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 47.3, 53.0, 63.3, 96.2, 106.2, 124.9, 125.8, 127.8, 128.9, 129.3, 129.6, 130.1, 138.0, 139.5, 145.9, 156.1.
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.COC1C=CC(C[O:23][NH:24][C:25](=[O:33])[CH2:26][N:27]2[C:31]([SH:32])=[N:30][N:29]=[N:28]2)=CC=1>>[SH:32][C:31]1[N:27]([CH2:26][C:25]([NH:24][OH:23])=[O:33])[N:28]=[N:29][N:30]=1
Reactant: COc1ccc(CONC(=O)Cn2nnnc2S)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Cn1nnnc1S)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a mixed solvent of trifluoroacetic acid (15 ml) and anisole (15 ml) is added 5-mercapto-1H-tetrazole-1-acetohydroxamic acid p-methoxybenzyl ester (3 g), and the mixture is stirred at room temperature for 2 hours under nitrogen gas. The reaction mixture is concentrated under reduced pressure, and the resultant material is dissolved in water and passed through a column of synthetic resin adsorbent (Diaion HP-20 distributed by Mitsubishi Chemical K.K.) (95 ml). The resin is washed with water. The fractions containing the main product are combined and concentrated under reduced pressure. The resultant solid is crystallized from a mixture of ether and hexane to give the title compound (1.83 g). mp. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1C(=O)NCCO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (1.3 g, 4.4 mmol), 2-amino-N-(2-hydroxyethyl)benzamide (838 mg, 4.65 mmol), di-isopropyl-ethylamine (925 μL, 5.31 mmol) and 15 mL isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N-(2-hydroxyethyl)benzamide (1.3 g, 89%):
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][NH2:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])(=O)C.[Cs+].CS(C)=O>C(OCC)(=O)C.[Cu]>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:9][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:22]([NH2:23])=[N:13]2)[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](NN)C1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2nc(N)c3cccnc32)C1
Temperature: 100 °C

Procedure:
Tert-butyl(trans-3-hydrazinylcyclobutyl)carbamate (4 g, 19.87 mmol), 2-chloro-3-cyanopyridine (3 g, 21.65 mmol), cesium acetate (14 g, 72.9 mmol), and copper powder (0.126 g, 1.987 mmol) were placed under nitrogen. Dry dimethylsulfoxide (20 mL) was added and the mixture stirred at 100° C. After 1 hour the mixture was cooled and diluted with ethyl acetate (300 mL). The mixture was filtered through a pad of celite and the filtrate washed with 10% saturated sodium bicarbonate (500 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (10% (2 N ammonia in methanol) in dichloromethane) gave the desired tert-butyl(trans-3-(3-amino-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)carbamate (2.72 g, 8.97 mmol, 45.1% yield).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH:16]S(O)(=O)=O>>[C:1]([N:5]=[N:6][C:7]([C:14](=[O:16])[NH2:15])([CH3:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)O
Product: CC(C)(C)N=NC(C)(CCC(=O)O)C(N)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To 20 ml of 95% H2SO4 cooled to -10°C in a 50 ml round bottom flask immersed in an ice-salt bath, was added 6.0 grams (0.0284 moles) of 4-t-butylazo-4-cyanovaleric acid (from Example X) in small portions over one-half hour holding the temperature at -10°C. After the addition was complete, the mixture was stirred for an additional 4 hours at -5° to -10°C. After 3 hours, the reaction mixture was poured into 75 ml of ice water and the product extracted with 50 ml of methylene chloride. The methylene chloride layer was washed with 100 ml of cold water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure to leave 4.3 grams (66% yield) of a white-yellow solid. The solid was slurried in 50 ml of pentane, filtered and the filter cake air dried. The purified material had a melting point of 97° -102°C (dec.) and its infrared spectrum was in agreement with the structure of 4-t-butylazo-4-carbamylvaleric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:14][CH:15]([F:21])[C:16](OCC)=[O:17].C[O-].[Na+].[O-]CC.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:11](=[O:13])[CH2:12][C:16](=[O:17])[CH:15]([F:21])[F:14])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(F)F
Reactant: CCOC(=O)c1ccc(C(C)=O)s1
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(C(=O)CC(=O)C(F)F)s1
Yield: 85 %

Procedure:
Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester and ethyl difluoroacetate by the method described in Preparative Example 3. Sodium methoxide was substituted with sodium ethoxide. The product was obtained as a crude oil (5.4 g, 85%). An approx. 5:1 isomer mixture was observed in the NMR spectra of product. 1H NMR (CDCl3) 1.41 (t, J=7.0, 3 H), 3.63 (q, J=7.0, 2 H), 5.98 (t, minor isomer, J=53.2, 1 H), 6.05 (t, major isomer, J=54.0, 1 H), 6.45 (s, 1 H), 7.74 (d, J=4.0, 1 H), 7.80 (d, J=4.0, 1 H). 19F NMR −127.8 (minor isomer, J=53.5), −127.1 (major isomer, J=55.5). LC/MS 5.18 min, [M+1]+ 277.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.CCC([O-])(C)C.[Na+].C1(C)C=CC=CC=1>CS(C)=O>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 75.8 %

Procedure:
18.2 g (0.05 mole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone, 33.0 g (0.30 mole) of sodium tert-pentoxide and 100 ml of toluene were subjected to the treatments described sub letter (a). After addition of 15 ml of DMSO, heating at 110° for 4 hours and final treatments as indicated hereinabove, there were isolated 7.75 g (76% yield) of the desired compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:23][C:17]1([CH3:24])[CH2:18][C:19]([CH3:21])([CH3:22])[CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16]1
Reactant: CC1(C)C=C(c2ccc(OCc3ccccc3)cc2)CC(C)(C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To 10% Pd/C (0.17 g) under N2 was added 1-benzyloxy-4-(3,3,5,5-tetramethyl-cyclohex-1-enyl)-benzene (1.7 g, 5.3 mmol), prepared by a substantially similar procedure to that of Step 1 of Example 18, in MeOH (15 mL) and EtOAc (15 mL). This mixture was stirred under H2 (1 atm) overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the title compound as a white solid (1.19 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]=1[O:14]C(=O)C)[C:8]([OH:10])=O)(=O)C.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][CH2:22][NH:21][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([OH:14])=[C:5]([OH:4])[CH:6]=1
Reactant: NCCCO
Reactant: CC(=O)Oc1cc(C(=O)O)cc([N+](=O)[O-])c1OC(C)=O
Product: O=C(NCCCO)c1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The procedures described in Examples 43 and 44 were repeated using 3,4-diacetoxy-5-nitrobenzoic acid and 3-aminopropan-1-ol. Yield 85%, m.p. 160°-163° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[O:13][CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(I)c(O)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Methyl 3-cyano-4-hydroxy-5-iodobenzoate (11.29 g) was dissolved in N,N-dimethylformamide (230 mL), and potassium carbonate (49.20 g) and dimethylsulfuric acid (17.0 mL) were added to the solution, and then the mixture was stirred at room temperature for 18 hours. After the reaction solution was filtered, water was added and the precipitated crystal was collected by filtration to obtain the title compound (8.99 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4]([CH3:6])=[CH2:5].CCOCC.S(=O)(=O)(O)O.[CH2:18](O)[CH2:19][CH2:20]C>>[C:3]([O:2][CH2:1][CH2:18][CH2:19][CH3:20])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A 148.2g (2.0 mols) amount of n-butanol, 400.5g (4.0 mols) of methylmethacrylate, 0.5g of hydroquinonemonomethyl ether and 2.45g (0.025 mol) of concentrated sulfuric acid were added to a flask to conduct a reaction in the same manner described in Example 1. The reaction was carried out for 6 hours. The reaction results obtained were an 89.9% conversion of n-butanol and an 88.2% yield of n-butyl methacrylate. However, it was found by gas chromatography that a high boiling point by-product was present and 0.004 mol of methacrylic acid (2740 ppm. on n-butyl methacrylate) was produced as a by-product.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.CC1CCC[NH:30]1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:30]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CC1CCCN1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 252.2 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. 2-Methyl-pyrrolidine (0.207 g, 1.800 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.300 g (88%) of the indole-amine was obtained as a white solid. This was converted to the HCl. salt. LC/MS (ESI+) 377 (M+1); Anal. Calcd for C24H28N2O2.1HCl.0.75H2O: C, 67.59; H, 7.21; N, 6.57; Found: C, 67.79; H, 7.16; N, 6.50.
Reaction SMILES: [NH2:1][C@H:2]([CH:20]([CH3:22])[CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]([CH3:19])([CH3:18])[CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[N:39]([CH:42]([CH3:44])[CH3:43])=[C:40]=[O:41]>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:40]([NH:39][CH:42]([CH3:44])[CH3:43])=[O:41])[CH:20]([CH3:22])[CH3:21])[CH2:6][C:7]2([CH3:18])[CH3:19])=[CH:12][CH:13]=1
Reactant: CC(C)N=C=O
Reactant: CC(C)[C@@H](N)C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)N[C@@H](C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-amino-1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methylbutan-1-one, TFA (30 mg, 0.07 mmol) and DIPEA (0.14 mmol) in CH2Cl2 (1 mL), was added 2-isocyanatopropane (7.00 mg, 0.08 mmol). The mixture was stirred at rt for 2 h and concentrated. The residue was purified by preparative HPLC to afford (R)-1-(1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-isopropylurea (11 mg, TFA salt) as a white solid. MS found 409.15 (M+H)+.