Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Nc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(-c2sc3cc(O)ccc3c2Nc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.4 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-3-[N-[4-[2-(1-piperidinyl)ethoxy]phenyl]amino]-6-methoxybenzo[b]thiophene hydrochloride (0.70 g, 1.25 mmol) in 40 mL of anhydrous CH2Cl2 under N2 10° C. was added BBr3 (0.36 mL, 3.80 mmol). The solution was allowed to gradually warm to room temperature and stirred for a total of 6 h. The reaction was quenched by pouring the mixture into an excess of sat. NaHCO3 solution. The aqueous was then extracted several times with 5% EtOH/EtOAc. The organic was combined and dried (Na2SO4) and then concentrated in vacuo to a foam. The crude product was chromatographed (1-6% CH3 OH/CHCl3) to provide 325 mg (49%) of 2-(4-hydroxyphenyl)-3-[N-[4-[2-(1-piperidinyl)ethoxy]phenyl]amino]-6-hydroxybenzo[b]thiophene as an oil. This material was converted to the hydrochloride salt by treatment with Et2O.-HCl in EtOAc, and isolated as a white solid by filtration. Data for 2-(4-Hydroxyphenyl)-3-[N-[4-[2-(1-piperidinyl)ethoxy]phenyl]amino]-6-hydroxybenzo[b]thiophene Hydrochloride: mp 140°-150° C. 1H NMR (DMSO-d6) δ6 9.57 (s, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.19 (d, J=10.1 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 6.75 (dd, J=10.1, 2.0 Hz, 1H), 6.70 (d, J=8.6 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 6.46 (d, J=8.8 Hz, 2H), 4.21 (m, 2H), 3.50-3.30 (m, 4H), 3.01-2.95 (m, 2H), 1.81-1.63 (m, 5H), 1.38 (m, 1H). FD mass spec: 461. Anal. Calcd. for C27H28 N2O3S.1.5 HCl: C, 62.94; H, 5.77; N, 5.44. Found: C, 62.99; H, 5.88; N, 5.27.
Reaction SMILES: [H-].[Na+].C[C:4](OS(C1C=CC(C)=CC=1)(=O)=O)([CH2:21][CH2:22][CH3:23])[CH2:5][C:6]1[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[OH:20].O.[CH2:36]1COCC1>C(OCC)(=O)C>[CH3:36][C:22]1([CH3:23])[CH2:21][CH2:4][CH2:5][C:6]2[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[O:20]1
Reactant: C1CCOC1
Reactant: CCCC(C)(Cc1c(NC(C)=O)ccc(C(=O)OC)c1O)OS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(C)=O)c2c1OC(C)(C)CCC2

Procedure:
To a mixture of 2.2 g sodium hydride (60%) and 20 ml THF is added dropwise at 0° C. a solution of 15 g of methyl 3-(2'-methyl-2'-tosyloxypentyl)-4-acetylaminosalicylate in 10 ml THF. This is allowed to come to room temperature over several hours, then chilled and 2 ml H2O added slowly. This is then diluted with ethyl acetate, the salts filtered off, washed with water and brine, dried and concentrated to dryness to obtain methyl 2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate which is used directly in the next step.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][CH:12]1[CH2:11][CH:10]([CH2:9][OH:8])[CH2:15][CH2:14][N:13]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1CCC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N1CCC(CO)CC1CCC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
Methyl 4-((tert-butyldimethylsilyloxy)methyl)-2-(3,3-dimethylbutyl)piperidine-1-carboxylate (3.606 g, 9.7 mmol) was dissolved in THF (50 mL) and TBAF (1M in THF) (13 mL, 13 mmol) added. Stirred at room temperature for 3.5 h. The solvent was evaporated. Redissolved in DCM and washed with satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield an oil. The residue was purified via Biotage (eluent 30-70% EtOAc in heptane) to yield methyl 2-(3,3-dimethylbutyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.45 g, 98%) as a colourless oil. MS m/z 258 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:26])=O>ClC(Cl)C>[Cl:26][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 80 °C

Procedure:
To a solution of 6-nitroquinazolin-4-ol (4.40 g, 23.01 mmol) and N-ethyl-N-isopropylpropan-2-amine (11.89 g, 92.04 mmol) in dichloroethane (50 mL) was added phosphoryl trichloride (7.06 g, 46.02 mmol). After heating to 80° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was concentrated again with toluene (2×100 mL) to provide the product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: C1COCCN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cnc2c(C(=O)N3CCOCC3)cnn2c1NCc1ccccc1)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-Benzylamino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.18 mmol) obtained in Example 1, step 5 was dissolved in DMF (1 mL), morpholine (0.02 mL, 0.21 mmol), 3-[(3-dimethylamino)propyl]-1-ethylcarbodiimide hydrochloride (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, and the mixture was stirred at room temperature for 5 hr. 10% Aqueous citric acid solution (1 mL) and water (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with water (20 mL), and purified by silica gel column chromatography (chloroform/methanol=90/10) to give compound a-11 (0.02 g, 18%).
Reaction SMILES: COC([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])=[CH:8][CH:7]=1)=O.N>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])=[CH:21][CH:22]=1
Reactant: CCCCCCCCOC(=O)c1ccc(OC(=O)OC)cc1
Agent: N
Solvent: CCO
Product: CCCCCCCCOC(=O)c1ccc(O)cc1

Procedure:
Quantities: compound 21 (13.76 g, 0.045 mol), ethanol (150 ml), aqueous ammonia (35% w/v, 150 ml).
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].[Na].CS([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])=O>C(O)C>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCNc2[nH]ccc2[N+](=O)[O-])cs1

Procedure:
A solution of 2-(2-guanidino-4-thiazolylmethylthio)-ethylamine dihydrochloride (4 g, 0.013 mole) in ethanol (25 ml) was basified with a solution of sodium (0.65 g, 0.028 mole) in ethanol (20 ml). The mixture was filtered and the filtrate added to 2-methylsulphinyl-3-nitropyrrole (1.5 g, 0.0086 mole). The mixture was refluxed for 5 days, then the solvent was removed in vacuo and the residue chromatographed on a silica-gel column. The product was eluted with ethyl acetate/propan-2-ol (8:2) and recrystallised from methanol/acetone (6:4). Yield: 0.65 g, 22%. M.P. 195.5°-200° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[Cl:23][C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved in dichlorormethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added to the mixture, followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 1 hour at room temperature and the solvents evaporated to give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 g) as a pale yellow solid.
Reaction SMILES: I[CH3:2].[I-].[Na+].C[O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1>CC#N>[CH3:2][N:12]1[CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:6]
Reactant: COc1ccc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Reactant: CI
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)ccc1=O
Temperature: 45 °C

Procedure:
Iodomethane (0.063 mL, 1.007 mmol) and sodium iodide (151 mg, 1.007 mmol) were added to a solution of N-[3-(6-methoxypyridin-3-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (109 mg, 0.315 mmol) in MeCN (3.1 mL) at room temperature under nitrogen. The mixture was heated to 45° C. for 72 hours, then cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 1-methyl-5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2(1H)-one as an off-white solid. MS APC calc'd for C17H14F3N4O [M+H]+ 347. found 347. Check LCMS data. 1H NMR (400 MHz, Acetone-d6): δ 9.31 (s, 1H); 8.83 (d, J=4.9 Hz, 1H); 8.72 (s, 1H); 7.96 (d, J=8.2 Hz, 1H); 7.84 (d, J=7.8 Hz, 1H); 7.79 (t, J=7.8 Hz, 1H); 7.54 (d, J=7.4 Hz, 1H); 7.48 (t, J=7.9 Hz, 1H); 7.24 (d, J=4.9 Hz, 1H); 6.76 (d, J=8.2 Hz, 1H); 4.04 (s, 3H). APCI: [M+H]+ m/z 347.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[Pd].C(O)C>[NH2:11][C:9]1[CH:8]=[C:7]([F:14])[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1c(F)cc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(C(=O)O)c(F)c1
Yield: 91 %

Procedure:
A mixture of 2,6-difluoro-4-nitrobenzoic acid (2.5 g, 12 mmol) and 10% palladium-on-charcoal catalyst (500 mg) in ethanol (I50 ml) was stirred under 1 atmosphere of hydrogen at ambient temperature for 3 hours. The catalyst was removed by filtration through diatomaceous earth, the filter pad washed with ethanol and the solvent removed by evaporation to give 4-amino-2,6-difluorobenzoic acid (3-8 g, 91%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])=[CH2:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)C1CCC(C)=C1CCC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC1=C(C)CCC1C(C)C
Yield: 99 %

Procedure:
4 g of 3-isopropenyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene were hydrogenated in 50 ml of ethyl acetate in the presence of 400 mg of palladium on calcium carbonate (5%). After the uptake of one equivalent of hydrogen, the solution was filtered over Celite, concentrated and distilled under a high vacuum. There were obtained 4 g of 3-isopropyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene; boiling point 0.005 about 70°C; nD20 = 1.4709; IRfilm : μmax = 1725, 1390/70 and 1170 cm-1. The compound has a woody, floral note.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:11])[CH:3]=1.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([O:20][N:21]=[CH:6][C:5]1[C:4]([CH3:11])=[CH:3][C:2]([NH2:1])=[C:9]([CH3:10])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: Cc1cc(C=O)c(C)cc1N
Agent: Cl
Solvent: CO
Product: Cc1cc(C=NOCc2ccccc2)c(C)cc1N
Yield: 47.7 %

Procedure:
0.50 g (2.51 mmol) of 4-amino-2,5-dimethylbenzaldehyde is initially charged in 10 ml of methanol, 0.40 g (3.27 mmol) of O-benzyl hydroxylamine hydrochloride is added at room temperature and the reaction mixture is heated under reflux for 18 h. The mixture is then concentrated using a rotary evaporator and the residue is taken up in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under reduced pressure. This gives 0.3.8 g of product (purity 82.0%, yield 47.7%, log P (pH 2.3)=4.22).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[Br:26][C:11]1[C:10](=[O:27])[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:35](=[O:36])[O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)[C:14]([CH3:15])=[CH:13][C:12]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CN)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.08 g, 2.48 mmol) was suspended in dichloromethane (7.5 mL). Pyridine was added (0.222 mL, 2.74 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (5.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded a yellow solid (0.85 g, 57%).
Reaction SMILES: [F:1][CH:2]([F:11])[CH:3](C(F)F)[C:4]([F:7])([F:6])[F:5].ClC(Cl)(Cl)C(=[O:18])C(Cl)Cl>>[F:5][C:4]([F:7])([F:6])[C:3](=[O:18])[CH:2]([F:11])[F:1]
Reactant: FC(F)C(C(F)F)C(F)(F)F
Reactant: O=C(C(Cl)Cl)C(Cl)(Cl)Cl
Product: O=C(C(F)F)C(F)(F)F

Procedure:
The 2-difluoromethyl-1,1,1,3,3-pentafluoropropane may be prepared by fluorinating commercially available 1,1,1,3,3-pentachloro-2-propanone to form 1,1,1,3,3-pentafluoro-2-propanone which may then be reacted with CF2 carbene to form 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene. The 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene may then be hydrogenated to form 2-difluoromethyl-1,1,1,3,3-pentafluoropropane.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:13][C:9]1[CH:8]=[C:7]([C:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)N2CCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C(=O)N2CCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of tert-butyl (3-(azetidine-1-carbonyl)phenyl)carbamate (600 mg, 2.171 mmol) in DCM (5.0 ml) was added trifluoroacetic acid (0.167 ml, 2.171 mmol) at 0° C. under nitrogen atmosphere. Reaction was stirred at room temperature for 1 hr. Solvent evaporated up to dryness and the residual solid was dissolved in DCM (20 ml) and washed with saturated solution of NaHCO3. DCM layer was dried over sodium sulphate and evaporated under vacuum. Resulting solid was washed with pentane and ether to give the titled compound (310 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=O)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1cccnc1)C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC(=NO)c1cccnc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 91.8 %

Procedure:
tert-Butyl N-allyl-N-[2-oxo-2-(3-pyridyl)ethyl]carbamate (31.34 g 113.41 mmol) is dissolved in ethanol (110 mL) with stirring under nitrogen. Hydroxylamine hydrochloride (18.31 g, 260.85 mmol) and pyridine (12.84 mL, 158.78 mmol) are added. The resulting solution is heated at 80° C. under nitrogen for 2 hours and then is cooled to room temperature. The solvents are partially evaporated and the resulting residue is then partitioned between 2 M sodium hydroxide (150 ml) and dichloromethane (500 mL). The phases are separated and the aqueous phase is re-extracted with dichloromethane (2×250 mL). The organic extracts are combined and evaporated under reduced pressure. The crude product is purified by silica gel column chromatography using a gradient of 0-10% 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (30.34 g, 91.82%) as a mixture of E/Z isomers. ES/MS (m/e) M+1=292.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:21]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate (3 g, 10.47 mmol) in THF (20 mL) was added to a freshly prepared solution of LDA (prepared from n-butyllithium (26.2 mmol) in hexane and diisopropylamine (3.73 mL, 26.2 mmol) in 7 mL of THF) at −78° C. the reaction was stirred for 1 h, warmed to 0° C. for 5 min, cooled again to −78° C. followed by addition of methyl iodide (2.292 mL, 36.7 mmol). The reaction mixture was allowed to warm to room temperature overnight, quenched with aqueous ammonium chloride, and concentrated under vacuum to remove volatile solvents. The residual aqueous mixture was extracted with ether, and the ether solution was dried and concentrated under vacuum to give the crude product as an oil which was further purified via normal phase chromatography on silica gel (Biotage SP1, 40+S column) to give product (2.7 g; MS: (M+H)+=301.3) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36]C)=[O:35])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31](=[O:38])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:28])=[O:29])=[CH:25][CH:26]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 2.1 %

Procedure:
A solution of methyl 4-[({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]phenyl}sulfonyl)amino]-4-oxobutanoate (0.1 g 0.1 8 mmol) in methanol (20 ml) was heated under reflux with 2M sodium hydroxide (0.45 ml 0.9 mmol) for 24 hr. The solvent was removed and the resulting solid was dissolved in water (20 ml) and the pH was adjusted to 2 with 2M hydrochloric acid. The liberated solid was extracted into ethyl acetate (3×20 ml) and the combined extracts were washed with water (20 ml) and brine (20 ml). Drying (MgSO4) and removal of solvent gave the title compound as a white solid (0.09 g 92%). MH+: 536
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([F:37])=[C:20]([CH:36]=2)[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[CH3:35])=[O:22])[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:37][C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][OH:8])[CH2:11]2)=[CH:36][C:20]=1[C:21]([NH:23][C:24]1[C:33]([CH3:34])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[CH3:35])=[O:22]
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2F)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2F)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
To a solution of methyl 4-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]-2-fluoro-benzoyl]amino]-3,5-dimethyl-benzoate (0.30 g, 0.54 mmol) in THF (8 ml) is added Bu4NF 1.0 M in THF (0.35 g, 1.60 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 4 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using ethyl acetate in hexanes as eluent to afford the title compound as a white solid (0.10 g, 55%). Mass spectrum (m/z): 414.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:14]=3)[CH:9]=2)[CH:4]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH:9]=2)[CH:4]=1
Reactant: [H][H]
Reactant: CCCC1CC=C(c2ccc3cc(OC)ccc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](c2ccc3cc(OC)ccc3c2)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
44.8 g of 2-methoxy-6-(4-propylcyclohexa-1-ene-1-yl)naphthalene was dissolved in 800 ml of ethyl acetate. To the solution was then added 10 g of 5% palladium carbon. The reaction mixture was then stirred at a hydrogen pressure of 4 kg/cm2 for 6 hours. The catalyst was then removed by filtration. The solvent was then distilled off. The residue was then dissolved in 180 ml of N,N-dimethylformamide. To the solution was then added 18 g of potassium t-butoxide. The reaction mixture was then heated to a temperature of 120° C. with stirring for 1 hour. The reaction solution was then allowed to cool to room temperature. To the reaction solution was then added 70 ml of a 10% hydrochloric acid to causes crystallization. The crystal thus precipitated was filtered off, washed with water, and then dried under reduced pressure. The crystal was then recrystallized from ethanol to obtain 28.0 g of 2-methoxy-6-(trans-4-propylcyclohexyl)naphthalene.