Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[S:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:44])C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[S:18](=[O:44])[CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CS(=O)c2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h

Procedure:
A solution of 1 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 1 in 100 ml of methylene chloride is added 0.51 g of m-chloroperbenzoic acid. After stirring for 30 minutes, 0.15 g of m-chloroperbenzoic acid is added, and stirring is continued for further 30 minutes. Fifty ml of 1N aqueous sodium hydroxide is added to the mixture, and the methylene chloride layer is separated, washed with water and concentrated under reduced pressure to yield tert-butyl 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate 1-oxide as a mixture of two stereoisomers. Separation by silica gel column chromatography yields 0.3 g of one isomer and 0.5 g of another isomer. Both are obtained as colorless oil. Mass spectrum of each isomer shows the peak due to molecular ion at 514.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[Cl:21][C:22]1[C:27]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1>>[Cl:21][C:22]1[N:23]=[C:24]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=3[F:20])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:25]=[CH:26][C:27]=1[C:28]([OH:31])([CH3:29])[CH3:30]
Reactant: CC(C)(O)c1ccc(Cl)nc1Cl
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)c(Cl)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (300 mg, 1.02 mmol) and 2-(2,6-dichloropyridin-3-yl)propan-2-ol (210 mg, 1.02 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:20][C:17]1[CH:18]=[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[CH:14]=[CH:15][C:16]=1[OH:19]
Reactant: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.3 %

Procedure:
To a solution prepared by dissolving the resulting 2.88 g of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol in 300 ml of chloroform, 4.80 g of tetra-n-butylammonium tribromide was slowly added with stirring under room temperature. After 12 hours, the reaction solution was concentrated, and the residue was extracted twice with 100 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.53 g of 2-bromo-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (yield, 69%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:27][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCC3)nc3ccc(Cl)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2c(C(=O)O)c(N3CCCC3)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 78 step E from 6-chloro-4-(3-isopropyl-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol) and 4N HCl in dioxane. White solid (16 mg, 37%). LC-MS (ESI): 395 (M+H)+.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:16][C:17]1[C:21](OCC)=[N:20][S:19](=[O:26])(=[O:25])[N:18]=1)[CH3:15]>C(O)C>[CH2:8]([N:7]([C:21]1[C:17]([O:16][CH2:14][CH3:15])=[N:18][S:19](=[O:26])(=[O:25])[N:20]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCNCCCCCC
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Solvent: CCO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Dihexylamine (90 mg, 0.48 mmol) was added to a solution of 3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (100 mg, 0.48 mmol) in ethanol (5 mL) and the reaction stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue absorbed onto silica gel, and purified by flash column chromatography (silica, hexane:EtOAc 3:1) to yield the title intermediate (120 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:23][CH:24]([F:35])[C:25]1[CH:26]=[C:27]([CH3:34])[C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[C:27]([CH3:34])=[CH:26][C:25]([CH:24]([F:23])[F:35])=[CH:30][N:29]=3)[CH:3]=[C:4]([CH3:22])[C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Reactant: Cc1cc(C(F)F)cnc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Product: Cc1cc(C(F)F)cnc1C(=O)Nc1cc(C)c(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
To a solution of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.075 g, 0.232 mmol) and 5-(difluoromethyl)-3-methylpicolinic acid (0.048 g, 0.255 mmol) in DMF (2 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (0.177 ml, 0.278 mmol) and the resulting mixture was stirred at 0° C. for 2 h, the ice bath was removed and stirred at rt for 1 h. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, and chromatographed on silica gel using 0-4% MeOH/DCM to afford a white solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-5-methylphenyl)-5-(difluoromethyl)-3-methylpicolinamide (0.0145 g, 0.029 mmol, 12.69% yield). MS m/z=492.9 [M+H]+. Calculated for C21H19F7N4O2: 492.14.
Reaction SMILES: B.C1COCC1.[CH2:7]([C:12]1[CH:13]=[C:14]([C:24]([NH2:26])=O)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[C:8]([CH3:11])([CH3:10])[CH3:9]>>[CH2:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:14]([CH2:24][NH2:26])[CH:13]=1)[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)Cc1ccc(-c2ccccc2)c(C(N)=O)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc(-c2ccccc2)c(CN)c1
Yield: 105.2 %

Procedure:
To borane-THF (1M, 1.7 mL, 1.7 mmol) was added 4-neopentyl-1,1′-biphenyl-2-carboxamide (200 mg, 0.75 mmol), and the reaction stirred at reflux 16 h. The solution was cooled and quenched with 1N HCl. The solution was basified with saturated sodium bicarbonate, and the product was extracted into ethyl acetate. The organics were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated in vacuo to give the title compound as an oil (200 mg). ESI MS m/z 254.22 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C>[Pd].CO>[CH2:22]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][C:2]=1[OH:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCc1ccc(C(=O)CCCCC)c(O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(O)c1
Reaction time: 24 h
Yield: 93.4 %

Procedure:
A mixture of 16.99 g of 1-(2-hydroxy-4-tetradecylphenyl)-1-hexanone, 4 g of 5% palladium on carbon catalyst, 100 ml of glacial acetic acid and 50 ml of methanol was hydrogenated in a Parr apparatus for 24 hours. The mixture was filtered, the solvents removed and the residue dissolved in ether, washed with water and dried. This crude material was chromatographed on silica gel, eluting with hexane:ethyl acetate (10:1), giving 15.3 g of the desired product, mp 43°-45° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:19][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCCC1
Reactant: Nc1nc2cccc(Cl)n2n1
Product: Nc1nc2cccc(NC3CCCCCC3)n2n1
Temperature: 180 °C
Yield: 59 %

Procedure:
The title compound was prepared following procedure described for intermediate A9, but starting from 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 2.88 g; 17.1 mmol; 1.0 eq.) and cycloheptylamine (14 mL) and heated at 180° C. for 1 h under microwave radiation to give the title compound as a beige oil (2.48 g; 59%). HPLC, Rt: 2.90 min. (purity 97.2%). LC/MS, M+(ESI): 292.9.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].Cl.Cl.[NH2:16][O:17][CH2:18][CH2:19][NH2:20].C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:20][CH2:19][CH2:18][O:17][N:16]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NCCON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5.5 g.) in ethanol (100 ml.) was added a solution of 2-(aminooxy)ethylamine.dihydrochloride (4.1 g.) in water (50 ml). The resulting mixture was adjusted to pH 4 with an aqueous solution of sodium bicarbonate and stirred for 3 hours at room temperature. The reaction mixture was evaporated to a volume of 100 ml. and cooled. The resulting precipitates were collected by filtration, washed successively with cold-water and ethanol to give the title compound (6.5 g.), mp 213° to 214° C. (dec.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([NH2:20])=[C:18]([C:21](=[O:24])[CH2:22]Cl)[N:17]=[CH:16]2)[C@@H:6]1[Cl:25])(=[O:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([NH2:20])=[C:18]([C:21](=[O:24])[CH2:22][N:26]=[N+:27]=[N-:28])[N:17]=[CH:16]2)[C@@H:6]1[Cl:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N)[C@H](Cl)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N)[C@H](Cl)[C@@H]1OC(C)=O
Yield: 92 %

Procedure:
Compound (39) obtained in step (5) above (170 mg) was dissolved in N,N-dimethylformamide (3.4 ml), to which was added sodium azide (45 mg). The resultant mixture was stirred at room temperature for 1 hour to conduct the reaction intended. The reaction solution obtained was concentrated and the residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to leave a yellow syrup. The syrup was purified by silica gel column chromatography (developer solvent: toluene-ethyl acetate, 1:2) to afford the titled compound (40) as a colorless solid (159 mg). Yield: 92%.
Reaction SMILES: [CH2:1]1[CH2:30][O:29][C:20]2([O:25][CH2:26][CH2:27][O:28][C:3]2([CH:4]=[CH:5][C@@H:6]2[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8][CH2:7]2)[O:2]1)[CH2:21][CH2:22][CH2:23][CH3:24].[N+](=[CH2:33])=[N-]>>[CH3:33][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C@@H:6]([CH:5]=[CH:4][C:3]23[O:28][CH2:27][CH2:26][O:25][C:20]2([O:29][CH2:30][CH2:1][O:2]3)[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9]1
Reactant: C=[N+]=[N-]
Reactant: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)O)OCCO2
Product: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)OC)OCCO2

Procedure:
Into 0.2 g of 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid, ethereal diazomethane solution is dropped until a pale yellow color just remains. The organic solution is washed several times with aqueous sodium acetate solution. The organic phase is dried over MgSO4 and the solvent distilled. As the residue, 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid methyl ester is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:18][NH:19][CH3:20].CCN(CC)CC>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:18][N:19]([CH3:20])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CNCc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cc(Cl)cc(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a stirred solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.96 g, 5 mmol) in CH2Cl2 (20 mL) was added a solution of 3,5-dichlorobenzyl-methylamine hydrochloride (1.133 g, 5 mmol) and Et3N (2 mL) in CH2Cl2 (25 mL). The addition flask was rinsed with CH2Cl2 (5 mL) and added to the reaction mixture. After 2 h, the reaction mixture was concentrated and the resulting residue was triturated with ether (100 mL), filtered and concentrated to give the desired product as a viscous brown oil (1.70 g, 100% yield). 1HNMR (300 MHz, CDCl3) δ: 7.30–7.27 (1H, m), 7.16 (1.5H, br s), 7.06 (0.5H, s), 6.17 (0.66H, s), 6.07 (0.34H, s), 4.59 (1.33H, s), 4.53 (0.67H, s), 3.03 (2H, s), 2.97 (1H, s), 1.74 (4H, s), 1.70 (2H,s).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[N:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].BrC1N=CC(N2CCN([CH:46]3[CH2:49][O:48][CH2:47]3)CC2)=CC=1>>[O:48]1[CH2:49][CH:46]([N:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH:10]=[N:11][C:6]([Sn:5]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)[CH2:17][CH2:16]2)[CH2:47]1
Reactant: Brc1ccc(N2CCN(C3COC3)CC2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C3COC3)CC2)cn1

Procedure:
Following the procedure described for intermediate 7.14, starting from 1-(6-bromopyridin-3-yl)-4-(oxetan-3-yl)piperazine (1.78 g, 5.97 mmol), 1.78 g of 1-(oxetan-3-yl)-4-(6-(tributylstannyl)pyridin-3-yl)piperazine 7.16 was obtained. LCMS [M+H]+: 510.07.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH3:20][O:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: COCc1cccc(B(O)O)c1
Product: COCc1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
2-(3′-Methoxymethyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 3-methoxymethylphenylboronic acid (available from Digital Specialty Chemicals, Inc., Dublin, N.H.). Mass spectrum MH+=356.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]3[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-morpholin-4-yl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M170) (336 mg, 0.575 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (155 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)=[O:30])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=C(Cl)c1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccs1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline and 2 ml of dimethylformamide at 0° C. is added 0.23 g (1.55 mmol) of 2-thiophencarbonylchloride. The reaction mixture solution is allowed to stir overnight while slowly reaching room temperature. The reaction mixture is then diluted with water producing a tan precipitate which is collected by filtration, washed with water and dried to yield 0.282 (50%) of the title compound as a tan solid: m.p.>250° C.; IR (KBr) 3420, 1640, 1440 cm-1 ; NMR (DMSO-d6) δ14.1 (s, 1H), 9.6 (s, 1H), 8.6 (d, 1H), 8.3 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.2 (d, 1H), 5.0 (s, 2H), 4.0 (t, 2H), 3.1 (m, 2H); m/e 368 (M+H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3](O)(O)[CH:4]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[N:16]=[CH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH2:33][OH:34]>N1C=CC=CC=1>[F:1][C:2]([F:31])([F:30])[C:3](=[N:33][OH:34])[CH:4]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[N:16]=[CH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(O)(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol (147c) 1.22 g, 2.8 mmol) and hydroxylamine hydrochloride (3.32 g, 48 mmol) was mixed in pyridine (85 mL, dried over 4 Å MS). The mixture was stirred at 115° C. for 30 min, after which time HPLC analysis showed complete reaction. Solvent was evaporated and the residue partitioned between ethyl acetate and water. The phases were separated and the organic phase washed twice with water, followed by brine and then evaporated. The residue was subjected to chromatography (SiO2, gradient of 10-60% Ethyl acetate in Heptane) to afford somewhat impure 1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-one oxime as a 3:7 mixture of diastereomers (0.99 g, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:26]2[CH2:27][NH:28][CH2:29][C:25]=2[CH:24]=[N:23][CH:22]=1>>[N:21]1[C:26]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:29][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ncc2c(n1)CNC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4cncnc4C3)n2)c1

Procedure:
B50 was prepared following the general procedure reported for B10 using A1 and 6,7-dihydro-5H-pyrrolo[3,4-d]pyrim idine hydrochloride; yield: 205.4 mg (53%), colorless amorphous solid. MS (ES) C16H16N8O2S requires: 384. found: 385 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]>>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)C[C@H](C)N1

Procedure:
The title compound is obtained in a similar manner as described in Example 18b starting with cis-2,6-dimethylpiperazine (Aldrich, Buchs, Switzerland) and 2-fluoro-5-nitrobenzotrifluoride (Aldrich, Buchs, Switzerland). Title compound: ES-MS: 304 (M+H)+; analytical HPLC: tret=2.89 minutes (Grad 1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 0.11 g (0.24 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182), 0.17 mL (0.96 mmole) of ethyldiisopropyl amine, 0.030 g (0.26 mmole) of 4-amino-1-methyl-piperidine and 3.0 mL of dimethylformamide was added 0.11 g (0.26 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(1-methyl-piperidin-4-yl)-benzamide (I-183) as a white solid.