Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[NH2:29]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[C:26]([Cl:25])[CH:27]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (802 mg) in 1-methyl-2-pyrrolidone (8.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (745 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with a mixed solvent (50 mL×3) of ethyl acetate/tetrahydrofuran (3/1). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (1141 mg) as a yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:7][CH2:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:33]1[C:34]([CH3:62])([CH3:61])[C@H:35]2[C@:48]([CH3:51])([CH2:49][CH:50]=1)[C@@H:47]1[C@:38]([CH3:60])([C@@:39]3([CH3:59])[C@H:44]([CH2:45][CH2:46]1)[C@H:43]1[C@H:52]([C:55]([CH3:57])=[CH2:56])[CH2:53][CH2:54][C@:42]1([NH2:58])[CH2:41][CH2:40]3)[CH2:37][CH2:36]2)(=O)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:58][C@:42]12[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:43]1[C@@H:44]1[C@@:39]([CH3:59])([CH2:40][CH2:41]2)[C@@:38]2([CH3:60])[C@@H:47]([C@:48]3([CH3:51])[C@@H:35]([CH2:36][CH2:37]2)[C:34]([CH3:61])([CH3:62])[C:33]([C:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:3][CH:4]=2)=[CH:50][CH2:49]3)[CH2:46][CH2:45]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(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)OB(C2=CCC(O)(C(=O)OCc3ccccc3)CC2)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: C1COCCO1
Solvent: O
Product: 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=CCC(O)(C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 56.5 %

Procedure:
A flask containing benzyl 1-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (0.113 g, 0.221 mmol) and (1R,3aS,5aR,5bR,7aR,11aR,11bR,13 aR,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 trifluoromethanesulfonate (0.082 g, 0.147 mmol) was diluted with 1,4-dioxane (1 mL) and water (0.25 mL). To the mixture was added sodium carbonate hydrate (0.075 g, 0.605 mmol) and the mixture was degassed with nitrogen for five minutes. To the mixture was added palladium tetrakis (5.10 mg, 4.41 mmol) then the flask was purged then refilled with nitrogen three times. The mixture was heated to 85° C. for 4 h then was cooled to rt and was purified by flash chromatography using a 20-80% ethyl acetate in hexanes gradient and a 25 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to give benzyl 4-((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)-1-hydroxycyclohex-3-enecarboxylate (0.053 g, 0.083 mmol, 56.3% yield) as an off-white foam. LCMS: m/e 640.6 (M+H)+, 1.91 min (method 1).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[Br:14][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](CBr)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (100 mg, 571 μmol) and carbon tetrabromide (303 mg, 913 μmol) was cooled on an ice bath. Triphenylphosphine (299 mg, 1141 μmol) was added and the reaction was stirred for 10 min. The reaction was then allowed to warm to r.t. and stirred for 18 hours. After this time, a TLC suggested that the reaction was complete (silica, 50% EtOAc/Hexanes, Ninhydrin stain). The solvent was removed and the product purified by column chromatography (0,5,10,15,20% EtOAc/Hexanes) to yield (R)-tert-butyl 1-bromopropan-2-ylcarbamate (67.1 mg, 0.28 mmol, 49.3%) as a colorless oil that turned solid upon standing. LCMS 238.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 1.23 (d, J=6.57 Hz, 3 H), 1.46 (s, 9 H), 3.44 (dd, J=5.56, 1.77 Hz, 2 H), 3.71-3.92 (m, 1 H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:18])=[O:17])=[C:9]([O:29][CH2:30][O:31][CH3:32])[CH:8]=1)(=O)=O.[CH3:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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.C1(C)C=CC=CC=1>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36][CH3:35])=[CH:8][C:9]=2[O:29][CH2:30][O:31][CH3:32])(=[O:17])=[O:18])[CH:24]=1)#[N:26]
Reactant: CSc1ccccc1B(O)O
Reactant: COCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCOc1cc(-c2ccccc2SC)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 85 °C
Yield: 83.9 %

Procedure:
A mixture of 24.75 g of 4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluoromethanesulfonate, 8.32 g of 2-(methylthio)phenylboronic acid, 2.73 g of tetrakis(triphenylphosphine)palladium(0), 728 mg of tetra-n-butylammonium bromide, 10.00 g of sodium carbonate, 48 mL of water and 285 mL of toluene was heated under an argon atmosphere at 85° C. for 15 hours. The precipitate was collected by filtration, washed successively with ethyl acetate and water to give 19.74 g of 5-cyano-2-methoxy-N-[2-(3-methoxymethoxy-2′-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide as an yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7](C)=[C:6](O)[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH3:34])=[N:26][C:27]=2[O:32][CH3:33].C[C:36](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:36]=[O:37])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH3:34])=[N:26][C:27]=2[O:32][CH3:33]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)c(C)c1O
Solvent: ClCCl
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-hydroxy-methylphenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (11 mg) in methylene chloride (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (19 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2−1/3) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-formylphenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (9 mg). To this material were added tert-butanol (1 mL), water (0.5 mL), tetrahydrofuran (1 mL), sodium dihydrogen phosphate (4 mg), 2-methyl-2-butene (0.006 mL) and sodium chlorite (6 mg) successively, and the mixture was stirred at 30° C. for 3 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual crystals were suspended in a mixed solvent (n-hexane/ethyl acetate=3/1), and collected by filtration. The collected crystals were dried under reduced pressure to give the title compound (4 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:20][C:21](OC)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:20][CH2:21][OH:22])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a slurry of lithium aluminum hydride (580 mg in 65 mL dry diethyl ether) at 0° C. was added dropwise a solution of (S)-2-(methoxycarbonylmethyl)piperidine-1-carboxylic acid tert-butyl ester (5.47 g in 40 mL dry diethyl ether) over a period of 30 minutes. The reaction was allowed to continue at 0° C. for an additional hour, at which time it was quenched by the careful addition of 0.58 mL water followed by 0.58 mL 2N sodium hydroxide and 1.8 mL water. The resulting suspension was stirred vigorously for 30 minutes then filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound (4.61 g).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH:10]3[CH2:12][CH2:11]3)=[CH:8][C:7]([CH2:13][OH:14])=[C:6]([O:15][CH2:16][CH3:17])[CH:5]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH:10]3[CH2:12][CH2:11]3)=[CH:8][C:7]([CH:13]=[O:14])=[C:6]([O:15][CH2:16][CH3:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOc1cc(C2CC2)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOc1cc(C2CC2)c(C2CC2)cc1C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Manganese dioxide (8.50 g) was added at room temperature to a toluene (50 mL) solution of (4,5-dicyclopropyl-2-ethoxyphenyl)methanol (2.84 g) in a nitrogen atmosphere, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered through celite, and then, the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.68 g).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH:25]([CH3:27])[CH3:26])[N:20]=[C:19]([Cl:28])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C>CO.Cl.O1CCOCC1>[Cl:28][C:19]1[N:20]=[C:21]([NH:24][CH:25]([CH3:27])[CH3:26])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CC(C)Nc1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Nc1nc(Cl)nc(NN)c1F

Procedure:
A solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (597 mg, 1.15 mmol) in MeOH (5 mL) and 4.0M HCl in dioxane (5 mL) was stirred at room temperature overnight. After filtering away the precipitate, the solvent was removed in vacuo, providing the crude 2-chloro-5-fluoro-6-hydrazino-N-(1-methylethyl)-4-pyrimidinamine, presumably as the tri-HCl salt. LCMS: (M+H)+: 219.9.
Reaction SMILES: [CH:1]([NH-:4])([CH3:3])[CH3:2].[OH:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:16]([O-:18])=[O:17])[C:12]2=[O:15])=[CH:8][CH:7]=1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1C=CC=CC=1>[CH:1]([NH-:4])([CH3:3])[CH3:2].[N:28]1([CH2:27][CH2:26][O:5][C:6]2[CH:14]=[C:13]3[C:9]([C:10]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:11]([C:16]([O-:18])=[O:17])[C:12]3=[O:15])=[CH:8][CH:7]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: OCCN1CCOCC1
Reactant: O=C([O-])C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC(C)[NH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C([O-])C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylate isopropyl amide (7.0 g, 22.78 mmol) was dissolved in tetrahydrofuran:benzene (150 ml:50 ml). Then, hydroxyethylmorpholine (3.59 g, 27.33 mmol) and triphenyl phosphine (7.17 g, 27.33 mmol) were added thereto. When the temperature was adjusted to 0° C., diisopropyl azodicarboxylate (5.53 g, 27.33 mmol) was added dropwise to the mixture followed by stirring for 2 hours at room temperature. The mixture was washed with brine and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 6-(2-morpholine-4-yl ethoxy)-1-oxo-3-phenyl-1H-indene-2-carboxylate isopropyl amide (9.5 g, yield 99%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[NH2:25])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c(N)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
The crude material from step 1 (170 g) was dissolved in 3 litres of methanol in a pressure vessel, 20 g of moist 5% Pd/C catalyst was added and stirred under an atmosphere of hydrogen at 3 bar and 50° C. for one hour. The reaction was cooled, filtered and evaporated to give 133 g N-(1-benzylpiperidin-4-yl)-2-amino-4-methylsulphonylaniline as a brown solid.
Reaction SMILES: FC1C=CC2C(C3CCNCC3)=NOC=2C=1.C([O-])([O-])=O.[K+].[K+].BrCCCO[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1.[F:37][C:38]1[CH:65]=[CH:64][C:41]2[C:42]([CH:45]3[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][O:54]C4C=CC(C(=O)C)=CC=4)[CH2:47][CH2:46]3)=[N:43][O:44][C:40]=2[CH:39]=1>C(#N)C>[F:37][C:38]1[CH:65]=[CH:64][C:41]2[C:42]([CH:45]3[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][C:53]([C:28]4[CH:29]=[CH:30][C:31]([C:34](=[O:36])[CH3:35])=[CH:32][CH:33]=4)=[O:54])[CH2:47][CH2:46]3)=[N:43][O:44][C:40]=2[CH:39]=1
Reactant: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(C(=O)CCN2CCC(c3noc4cc(F)ccc34)CC2)cc1

Procedure:
A mixture of 6fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 & 14.8 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5 mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. The solvent was removed. The residue was dissolved in dichloromethane (300 ml) and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography (SiO2, 60 g; eluted with 1% methanol in dichloromethane, 1 liter). The purest fractions were combined and gave 2.8 g, 48%, of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone, m.p.=111-112° C.
Reaction SMILES: C[S-].[Na+].[ClH:4].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([CH3:32])([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH3:20])=[N:15][N:14]=2)=[C:9]([C:33]([F:36])([F:35])[F:34])[CH:8]=1.O>CN(C=O)C>[ClH:4].[CH3:18][N:17]1[C:16]([C:19]([CH3:32])([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)[CH3:20])=[N:15][N:14]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][C:9]=1[C:33]([F:34])([F:36])[F:35]
Reactant: COc1ccc(-c2nnc(C(C)(C)Oc3ccc(C(F)(F)F)cc3)n2C)c(C(F)(F)F)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 42.6 %

Procedure:
Sodium thiomethoxide (30 mg) was added to a solution of 3-[4-methoxy-2-(trifluoromethyl)phenyl]-4-methyl-5-{1-methyl-1-[4-(trifluoromethyl)phenoxy]ethyl}-4H-1,2,4-triazole monohydrochloride (87 mg) in DMF (3 ml) under a nitrogen atmosphere, followed by stirring at 100° C. for 17 hours. The reaction solution was stood to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine in this order and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate). The resulting residue was powdered with diisopropylether, the resulting solid was dissolved in ethyl acetate (1 ml), and 4M hydrogen chloride-ethyl acetate was added thereto. The precipitated solid was collected by filtration and dried under reduced pressure to obtain, as a colorless solid, 4-(4-methyl-5-{1-methyl-1-[4-(trifluoromethyl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)phenol monohydrochloride (36 mg).
Reaction SMILES: [N:1]1C=CC=CC=1N(CCCOC1C(CC(O)=O)CC2C=CC=CC=2CN1)C(OC(C)(C)C)=O.[O:34]=[C:35]1[CH:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:40][C:39]2[CH:46]=[CH:47][C:48]([O:50][CH2:51][CH2:52][CH2:53][N:54]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)C(OC(C)(C)C)=O)=[CH:49][C:38]=2[CH2:37][N:36]1[CH2:68][C:69]1[CH:74]=[CH:73][C:72](C(F)(F)F)=[CH:71][CH:70]=1.C(C(O)=O)(F)(F)F>O>[NH2:1][C:72]1[CH:73]=[CH:74][C:69]([CH2:68][N:36]2[C:35](=[O:34])[CH:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:40][C:39]3[CH:46]=[CH:47][C:48]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=4)=[CH:49][C:38]=3[CH2:37]2)=[CH:70][CH:71]=1
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Reactant: CC(C)(C)OC(=O)N(CCCOC1NCc2ccccc2CC1CC(=O)O)c1ccccn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2Cc3cc(OCCCNc4ccccn4)ccc3CC(CC(=O)O)C2=O)cc1
Yield: 44 %

Procedure:
According to the procedure of Example 25(a) except substituting (±)-2-(4-aminobenzyl)-3-oxo-[3-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid for the (±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-triflouromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, the title compound (0.029 g, 44%) was prepared: MS (ES) m/e 475.4 (M+H)+. Anal. Calcd for C27H30N4O4.2 CF3CO2H.1.5 H2O: C, 51.03; H, 4.83; N, 7.68. Found: C, 50.92; H, 4.78; N, 7.64.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([F:38])[F:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Cl.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C:45](Cl)=[O:46]>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([F:38])[F:37])(=[O:34])=[O:35])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:45]([C@@H:41]4[CH2:42][CH2:43][CH2:44][NH:40]4)=[O:46])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)[C@@H]1CCCN1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(F)F)n2)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(F)F)n2)c(OC(C)C)cc1C1CCN(C(=O)[C@@H]2CCCN2)CC1

Procedure:
Prepared according to the method of Example 1 by replacing N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine with 5-chloro-N4-(2-(difluoromethylsulfonyl)phenyl)-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine and replacing2-(dimethylamino)acetyl chloride hydrochloride with (S)-pyrrolidine-2-carbonyl chloride hydrochloride, product was obtained. MS (ES+): 663.23 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:39]=[CH:38][C:37]([N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:43][CH:42]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(-n3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-yl)aniline (Maybridge, 108 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[C:25]([Cl:34])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12].ClCCl>O>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:32])=[C:25]([Cl:34])[CH:24]=1)[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1c(Cl)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Boron trifluoride dimethyl sulfide (1.0 mL) was added at room temperature to a stirred solution of methyl-N-[3,5-dichloro-4-(3-chloro-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine (90 mg) and dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 24 hours, poured out in water and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (4×20 mL), concentrated and the resulting residue purified on column (silica gel, chloroform/methanol/acetic acid 94:6:0.65). This gave 53 mg (63%) of N-[3,5-dichloro-4-(3-chloro-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine. LC-MS (ES+1): m/z 434.