Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][SH:37])[CH3:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>C(COC)OC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][S:37][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1)[CH3:33]
Reactant: CCN(CC)CCS
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCSc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 25 mg, 0.057 mmol) was dissolved in dimethoxyethane (0.5 mL), added with 2-diethylaminoethanethiol hydrochloric acid salt (19.6 mg, 2 eq.), Pd2(dba)3 (2.6 mg, 0.05 eq.), Xantphos (3.3 mg, 0.1 eq.) and DIPEA (0.06 mg, 6 eq.), and the mixture was stirred at 160° C. for 30 min. The reaction solution was added to water, extracted with ethyl acetate, and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (white amorphous, 22.4 mg, 93%).
Reaction SMILES: [F:1][C:2]([S:5]([O:8]S(C(F)(F)F)(=O)=O)(=[O:7])=[O:6])([F:4])[F:3].[CH3:16][C:17]1([CH3:24])[O:21][CH:20]([CH2:22]O)[CH2:19][O:18]1.N1C(C)=CC=CC=1C>C(Cl)Cl.O>[F:1][C:2]([F:4])([F:3])[S:5]([O:8][CH2:22][CH:20]1[CH2:19][O:18][C:17]([CH3:24])([CH3:16])[O:21]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OCC(CO)O1
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC1(C)OCC(COS(=O)(=O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethylsulfonic anhydride (7.03 ml, 41.6 mmol) was added dropwise over 15 mins to a solution of solketal (4.70 ml, 37.8 mmol) and 2,6-lutidine (5.73 ml, 49.2 mmol) in DCM (126 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. The mixture was diluted with DCM (100 mL) and water (100 mL), the phases were separated and the aqueous phase extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to afford the title compound as a crude material which was used directly.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][C:9]1[C:10]([C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][C@H:5]([CH3:40])[N:4]2[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccccc3F)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccccc3F)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-tert-butyl 4-(4-(1-acetyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (370 mg, 0.67 mmol), dichloromethane (10 mL) and trifluoroacetic acid (4 mL). The resulting solution stirred for 2 h at room temperature. The pH value of the solution was adjusted to 8 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford (S)-1-(5-(2-fluorophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (141 mg, 47%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.15 (d, J=6.60 Hz, 3H), 1.25-1.45 (m, 1H), 1.75-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.15-2.35 (m, 5H), 2.65-2.89 (m, 3H), 3.09-3.20 (m, 2H), 4.15-4.29 (m, 1H), 4.65-4.85 (m, 1H), 6.35-6.48 (m, 1H), 6.85-6.98 (m, 2H), 7.13-7.22 (m, 1H), 7.27-7.42 (m, 1H), 7.61 (d, J=8.40 Hz, 1H), 7.81 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 449 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH:10]2[CH2:12][CH2:11]2)=O)=[CH:6][N:5]=[C:4]([CH:13]([F:15])[F:14])[N:3]=1.C([OH:18])C>CC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:10]2([OH:18])[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH:13]([F:15])[F:14])[N:3]=1
Reactant: CCO
Reactant: O=C(c1cnc(C(F)F)nc1Cl)C1CC1
Solvent: CC(C)=O
Product: OC1(Cc2cnc(C(F)F)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 g of 4-chlorodifluoromethyl-5-cyclopropylcarbonylpyrimidine was added to 100 ml of ethanol, then, 15 g of a t-butylamine borane complex was further added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. After addition of 30 ml of acetone, the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. 100 ml of water was added to the residue, and extraction with ethyl acetate was carried out. The extract layer was washed with water, and the solvent was distilled off under reduced pressure. The residue was dried in vacuum to obtain 45 g of the desired product. nD20.5 1.5020
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:37])=[CH:22][C:23]([CH3:36])([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[CH3:24])(=O)C>O1CCCC1>[F:37][C:21](=[CH:22][C:23]([CH3:36])([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=1)[CH3:24])[CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: CC(=O)OCC(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C=C(F)Cc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Yield: 41.7 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.3 g), tetrahydrofuran (2 ml) and magnesium (22 mg), and 2-fluoro4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enyl acetate (Example 15) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to give the title compound (56 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH3:16][N:17]([CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[Na+]>[Cl-].[Na+]>[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[NH2:24][C:20]1=[CH:19][C:18](=[N+:17]([CH3:25])[CH3:16])[CH:23]=[CH:22]/[C:21]/1=[N:1]\[C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CN(C)c1cccc(N)c1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Cc1c(/N=C2\C=CC(=[N+](C)C)C=C2N)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
60 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one and 60 mmol of N,N-dimethylbenzene-1,3-diamine was dissolved in 300 ml of ice-water. This solution was admixed with 60 mmol of ferric chloride and 300 ml of saturated aqueous sodium chloride. Sodium perchlorate was added to saturation, and the mixture was left to stand for 30 minutes at zero degrees.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[CH2:13])[NH:6]1)=[O:4].[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][CH:27]=[CH2:28])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].CC(COC1N(C(OCC(C)C)=O)C2C(=CC=CC=2)C=C1)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[CH2:13])[N:6]1[C:23](=[O:24])[CH:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH:27]=[CH2:28])=[O:4]
Reactant: C=CCC1CCCC(C(=O)OC)N1
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)N1c2ccccc2C=CC1OCC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCCC1C(=O)OC

Procedure:
A solution of 6-allyl-piperidine-2-carboxylic acid methyl ester, 39, (2.1 g, 11.5 mmol), 2-tert-butoxycarbonylamino-pent-4-enoic acid (9.9 g, 46 mmol), and IIDQ (13.9 g, 46 mmol) in THF (50 mL) is stirred at rt for 24 h. The reaction is diluted with EtOAc and washed with 1N HCl, saturated NaHCO3, and brine. The solution is then dried (MgSO4), concentrated, and purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 1.1 g of the desired product. 1H NMR (CDCl3) δ 5.76 (m, 2H), 5.60–4.20 (series of m, 8H), 3.71 (s, 3H), 2.60–1.50 (series of m, 10H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)CI>CN(C=O)C>[F:5][CH:4]([F:7])[CH2:2][N:25]1[CH2:26][CH2:27][C:21]2[C:22](=[N:23][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([O:11][C:10]4[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:9]=4[F:8])[CH2:13][CH2:14]3)=[C:19]([NH:28][CH:29]([CH3:31])[CH3:30])[N:20]=2)[CH2:24]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(CC(F)F)CC2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (50 mg, 0.080 mmol) and Cs2CO3 (92 mg, 0.281 mmol) in DMF (0.5 mL) was added 1,1-difluoro-2-iodoethane (0.071 mL, 0.804 mmol) at 23° C. The reaction mixture was stirred at 80° C. for 18 h. The resulting crude material was filtered, rinsed with DMSO (2×0.5 mL), and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (6.1 mg, 13%) as a yellow film. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.4 Hz, 6H), 1.82-1.93 (m, 2H), 2.03-2.10 (m, 2H), 2.79-2.98 (m, 4H), 3.24-3.32 (m, 2H), 3.33-3.75 (m, 4H), 4.05-4.18 (m, 3H), 4.52-4.55 (m, 1H), 5.76-5.82 (m, 1H), 6.39-6.72 (m, 1H), 7.00-7.04 (m, 1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]+ 468.3.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].Cl.[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O.C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[NH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c[nH]c1C(C)C
Yield: 51.3 %

Procedure:
A mixture of 6.85 g (43.3 mmol) of ethyl isobutyrylacetate, 10.69 g (56.3 mmol) of 2-amino-4'-fluoracetophenone hydrochloride, 16.3 ml of acetic acid, 6.04 g of sodium acetate, and 10.8 ml of water is refluxed for 4 hours. After cooling, the reaction mixture is adjusted to pH 8 with saturated NaHCO3 and extracted with ether. The extract, 8.36 g, is subjected to column chromatography with silica gel, eluting with methylene chloride to give 6.12 g (Yield:51.3%) of the compound 1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[methyl(2-pyridinylmethyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 35) (527 mg, 1.12 mmol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was azeotroped from toluene. The residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate (3 ml) and the pH was adjusted to pH 4 with aqueous citric acid solution (10% w/v). The aqueous phase was extracted with ethyl acetate (×2) and the combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a yellow oil (456 mg)
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][S:8]([O:11]C)(=[O:10])=[O:9]>CS([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N:4]([CH2:3][CH2:2][O:11][S:8]([CH3:7])(=[O:10])=[O:9])=[C:5]=[O:6]
Reactant: COS(C)(=O)=O
Reactant: O=C=NCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)[O-]
Product: CS(=O)(=O)OCCN=C=O
Temperature: 120 °C

Procedure:
20.0 g (0.06 mol) of tetrabutylammonium methanesulfonate are added to a solution of 36.0 g (0.34 mol) of 2-chloroisocyanatoethane and 93.3 g (0.85 mol) of methyl methanesulfonate and the mixture is heated at 120° C for 6 hours. It is distilled in a thin layer evaporator at 180° C. under a pressure of 0.04 mbar and the crude product is purified by distillation. 18.0 g (0.17 mol) of 2chloroisocyanatoethane and 71.0 g (0.65 mol) of methyl methanesulfonate are recovered in this way.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:35])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C:9]([CH3:35])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1N

Procedure:
{5-[4′-(1-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid tert-butyl ester (0.25 g, 0.49 mmol)) in CH2Cl2 (2 mL) and TFA (2 mL) was stirred overnight then poured into EtOAc/NaHCO3 (aq). The organic layer was concentrated to yield the title compound that was used directly in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[C:29]1([C:35]([NH2:38])([CH3:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:38][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:37])[CH3:36])=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(N)c1ccccc1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC(C)(C)c3ccccc3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 2-phenylpropan-2-amine via General Procedure E to give 7.4 mg of 303 following reverse phase purification. MS (Q1) 497.2 (M)+
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([C:12]([O:21][Si](CC)(CC)CC)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(CC)CC.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[NH4+].[Cl-]>CCOCC.ClCCCl.C1COCC1>[CH:1]1([CH2:4][N:5]([C@H:6]2[CH2:11][CH2:10][C@H:9]([C:12]([OH:21])([C:13]([F:15])([F:14])[F:16])[C:17]([F:20])([F:19])[F:18])[CH2:8][CH2:7]2)[C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCC2CC2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCCl
Product: O=C(c1ccccc1)N(CC1CC1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 50 mg (0.12 mmol) of trans cyclopropylmethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine in 3 mL of a 1:2-mixture of THF and 1,2-dichloroethane was treated with 0.03 mL (0.23 mmol) of NEt3 and 0.02 mL (0.14 mmol) of benzoylchloride. The mixture was stirred at RT for 2 hrs and distributed between a saturated aqueous solution of NH4Cl and Et2O. After drying of the combined organic phases over Na2SO4 and evaporation of the solvent the residue was redissolved in 2 mL of THF, treated with an excess of TBAF and distributed between a saturated aqueous solution of NH4Cl and Et2O. Drying of the combined organic phases over Na2SO4 and column chromatography on silica gel with heptane/EtOAc 2:1 gave 35 mg (72%) of trans N-cyclopropylmethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzamide as a white solid, MS: 424, (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 37 %

Procedure:
The product of Example 29, step B and sodium 4-chlorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 85:15 hexane/ethyl acetate) provided tert-butyl 8-(4-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (118 mg, 37%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.06 (s, 1H), 7.92-7.85 (m, 2H), 7.80 (dd, J=8.7, 1.8 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.49-7.43 (m, 2H), 4.57 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 2.92-2.81 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1I
Reactant: Sc1ccccc1
Product: COc1ccccc1Sc1ccccc1

Procedure:
The general procedure was used to convert 2-iodoanisole and thiophenol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (412 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.41–7.25 (m, 6H; Hc, He, He′, Hf, Hf′, Hg), 7.12 (dd, J=6.03, 1H; Ha), 6.96–6.89 (m, 2H; Hb, Hd), 3.90 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 157.21 (C6), 134.39 (C8), 131.50 (C2), 131.35 (C9, C13), 129.07 (C10, C12), 128.27 (C4), 126.99 (C11), 123.96 (C1), 121.16 (C3), 110.76 (C5), 55.78 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.23; H, 5.70; S, 14.67.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cnn(C)c1
Product: Cc1ccc(Nc2cnn(C)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 6-Methyl-3-(1-methyl-1H-pyrazol-4-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-fluoropyridine in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]([CH2:24][OH:25])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18]([CH2:24][OH:25])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(CO)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CO)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoate (121 mg, 0.29 mmol) was dissolved in MeOH (10 mL) and treated with 1 M NaOH (10 mL). After stirring overnight, the MeOH was removed in vacuo, the residue acidified with conc HCl to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 115 mg (98%) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoic acid. MS found: (M+H)+=405.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1OC(=O)[S:31][N:30]=1>ClC1C=CC=C(Cl)C=1>[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:11]=[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[S:31][N:30]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2-c2nsc(=O)o2)c1Cl
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: Clc1cccc(Cl)c1
Product: Cc1ccc(S(=O)(=O)c2nc(-c3ccccc3Nc3c(Cl)ccc(C)c3Cl)ns2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 155° C. solution of p-toluenesulfonyl cyanide (420 mg, 2.32 mmols) in 5 mL of m-dichlorobenzene is added 5-[2 [(2,6-dichloro-3-methylphenyl]amino]phenyl]-1,3,4-oxathiazol-2-one (442 mg, 1.25 mmols) in three portions. Heating is continued for 1.5 hours. The solution is cooled to room temperature and directly purified by flash chromatography, eluting with 10:1 hexane:diethyl ether providing 446 mg (73%) of 2,6-dichloro-3-methyl-N-[2-[5-[(4-methylphenyl)sulfonyl]-1,2,4-thiadiazol-3-yl]phenyl]benzenamide as a bright yellow solid; mp 130.5°-135° C.