Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:13][C@H:14]([C:18]([OH:20])=[O:19])[CH2:15][CH2:16]O.P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2].[Cl-].[Ca+2].[Cl-]>>[NH2:13][C@H:14]([C:18]([OH:20])=[O:19])[C@H:15]([CH2:2][CH3:3])[CH3:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](CCO)C(=O)O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Product: CC[C@H](C)[C@H](N)C(=O)O
Reaction time: 120 h

Procedure:
selecting a microorganism belonging to Escherichia coli which forms colonies more than 0.6 mm in diameter when cultured in 3 to 7 days at 30° to 35° C. when grown on minimum agar medium containing 0.5 wt. % glucose, 0.02 wt. % L-homoserine, 0.3 wt. % potassium dihydrogen phosphate, 0.6 wt. % disodium hydrogen phosphate, 0.01 wt. % magnesium sulfate, 20 mg/liter calcium chloride, and 2 wt. % agar (pH 7.2) supplemented with 20 mg/liter auxotrophic material and produces L-isoleucine in a nutrient medium;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[H-].[Na+].[CH3:15]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (102 mg, 0.62 mmol) in THF (5 ml) was added NaH (49 mg of a 60% dispersion in mineral oil, 1.23 mmol) giving a thick white precipitate. After 30 minutes, methyl iodide (76 μl, 1.23 mmol) was added and the reaction was heated at 50° C. for 1 hour. Complete conversion was observed by TLC and the reaction was concentrated, diluted with dichloromethane (30 ml), washed with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC (using a gradient of eluents 1:1 Hexane/EtOAc to EtOAc) to provide the title compound as colourless oil (106 mg, 96%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:50][CH:49]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:47]4[CH2:50][CH:49]([N:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[CH2:48]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCN(C2CNC2)C1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CC(N3CCCC3)C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 1-azetidin-3-ylpyrrolidine (VWR) to give the title product. LC-MS (ES+) 773 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:5]2[N:4]=[C:3]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3CCCN(C(C)=O)C3)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (55 mg, 0.166 mmol) (for synthesis, see example 34, Step 7) in DCM (3 mL) in ice bath was added DIEA (0.116 mL, 0.666 mmol) followed by acetyl chloride (0.012 mL, 0.166 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded to next step without purification (50 mg, 81%). LCMS (m/z): 373.3 (MH+), 0.666 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:34][CH2:33][CH2:31][OH:32])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) was dissolved in THF (4 ml) and a solution of ethanolamine (115 mg, 1.87 mmol) in THF (1 mL) was added. The mixture was stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a light-yellow amorphous solid. mp 120-124°, LC MS m/z=409 (MH+) Retention time=1.84 min.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
According to the procedure described for the synthesis of example 4, step c, the title compound has been synthesized from 2-chloro-5-methanesulfonyl-benzoic acid and isopropanol. MS (m/e): 257.0 (M−H, 100%)
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=2)[N:18]([CH2:29][CH2:30][OH:31])[C:17](=[O:32])[CH:16]=1>O.C(N(CC)CC)C>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=2)[N:18]([CH2:29][CH:30]=[O:31])[C:17](=[O:32])[CH:16]=1
Reactant: O=c1cc(Cl)c2ccc(C(F)(F)F)cc2n1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCn1c(=O)cc(Cl)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2 mL of a dichloromethane solution containing 10 μL of oxalyl chloride, 20 μL of dimethylsulfoxide was added dropwise under nitrogen atmosphere at −60° C., and stirred for 10 min. 3 mL of a dichloromethane solution containing 31 mg of 4-chloro-1-(2-hydroxyethyl)-7-trifluoromethylquinolin-2(1H)-one was added dropwise at the same temperature, and stirred for 10 min. 60 μL of triethylamine was added at the same temperature, the mixture was stirred for 1 hour while slowly raising the reaction mixture to room temperature, and water was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (4-chloro-7-trifluoromethyl-2-oxoquinolin-1(2H)-yl)acetaldehyde as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13](C(OCC)=O)[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[CH:13][S:12][N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)ns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2ncsn2)cc1
Temperature: 85 °C

Procedure:
Ethyl cianoformate was added to a dodecane suspension of 5-(4-nitrophenyl)-1,3,4-oxathiazol-2-on, and the mixture was refluxed under heating for 3 hours. After cooling the reaction mixture to room temperature, the precipitation was separated by filtration and washed with hexane. The crude product obtained was purified by silica gel column chromatography to obtain ethyl 3-(4-nitrophenyl)-1,2,4-thiadiazole-5-carboxylate (pale yellow solid). The ethanol suspension of this product was added with water and sodium hydroxide and heated at 85° C. for 40 minutes while stirring. After cooling to room temperature, the mixture was added with 1M hydrochloric acid to make it acidic. The resulting mixture was heated for one hour while stirring on an oil bath at 95° C. The mixture was then cooled to room temperature and added with chloroform and an aqueous sodium hydrogencarbonate to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure to obtain 3-(4-nitrophenyl)-1,2,4-thiadiazol (pale yellow solid). The ethanol suspension of this product was added with water and 1M hydrochloric acid, heated to 80° C. and added with reduced iron. The reaction mixture was further heated at 80° C. for 50 minutes while stirring and then filtered through Celite. After evaporation of the ethanol in the resulting filtrate under reduced pressure, chloroform and an aqueous sodium hydrogencarbonate were added to the residue to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure to obtain 4-(1,2,4-thiadiazol-3-yl)aniline (pale yellow solid). Electron Impact-MS (M)+: 177.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](OCC)=[O:17].O.[OH-].[Na+]>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH2:16][OH:17]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccccc2[nH]1
Reaction time: 3 h
Yield: 83 %

Procedure:
To a suspension of lithium aluminum hydride (10.6 g, 264 mmol) in THF (200 mL) is added dropwise a solution of ethyl indole-2-carboxylate (50.0 g, 256 mmol) in THF (250 mL) over 25 minutes. After 3 h, water (10.6 mL) is carefully added, followed by 15% NaOH (10.6 mL), followed by additional portion of water (31.8 mL). The resulting suspension is dried (Na2SO4) and filtered through celite. After concentration under reduced pressure, the white solid (34.0 g) is crystallized from EtOAc/hexanes to give white needles for 1H-indol-2-ylmethanol. Yield 83%. HRMS (FAB) calcd for C9H9NO+H 148.0762, found 148.0771.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[O:22][C:23]([CH2:26]Cl)=[CH:24][CH:25]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:23]2[O:22][C:21]([C:19]([OH:20])=[O:18])=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)o1

Procedure:
5-(2′-Nitro-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 82 mg. Mass spectrum (ES) MH+=340.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:33][C:17]3=[N:18][CH:19]=[C:20](Br)[C:21]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][N:27]=[CH:26]5)=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:35](#[N:37])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:33][C:17]3=[N:18][CH:19]=[C:20]([C:35]#[N:37])[C:21]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][N:27]=[CH:26]5)=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)c(Br)cnc3[nH]2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)c(C#N)cnc3[nH]2)CC1

Procedure:
To a mixture of 4-[5-bromo-4-(1H-indazol-5-ylamino)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8 mg, 0.015 mmol), DPPF (4.1 mg, 0.007 mmol), water (0.03 mL) and zinc cyanide (3.7 mg, 0.031 mmol) in acetonitrile (3 mL) was added Pd2 dba3 (3.6 mg, 0.004 mmol) and the mixture was heated to reflux under N2 overnight. The reaction mixture was evaporated and the crude product was purified by preparative TLC using 10% methanol in DCM as eluent to afford 4-[5-cyano-4-(1H-indazol-5-ylamino)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as light gray solid. 1H NMR (400 MHz, CD3OD): δ=8.05 (s, 1H), 7.96 (s, 1H), 7.62 (dd, J=1.8, 0.5 Hz, 1H), 7.50 (s, 1H), 7.27 (dd, J=8.8, 1.9 Hz, 1H), 6.05 (bs, 1H), 5.35 (bs, 1H), 3.93-3.97 (m, 2H), 3.40 (t, J=6.2 Hz, 2H), 2.02-2.07 (m, 2H), 1.37 (s, 9H); MS (ES+): m/z 455.99 (100) [MH+]; HPLC: tR=2.97 min (ZQ2000, polar—5 min).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile (0.33 mg, 1.64 mmol) and triphenylphosphine (0.86 g, 3.28 mmol) were combined in methylene chloride (6 mL) and cooled to 0° C. N-Bromosuccinimide (0.61 mg, 3.43 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with methylene chloride, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.36 g (83%). 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 2H), 7.84 (s, 1H), 4.50 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:28][C:27]([O:26][CH3:25])=[O:30])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(O)cc3)c2cc1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (15 mg) was added to the solution, and the mixture was stirred at 0° C. for 10 min. Methylbromoacetate (0.037 ml) was added thereto, and the mixture was further stirred at 0° C. for 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Diethyl ether was added to the residue, and the precipitated crystal was collected by filtration and was washed to give the title compound (88 mg, yield 71%).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:31]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CCOC(C)=O.O=[Pt]=O>[NH2:36][C:34]1[CH:33]=[CH:32][C:31]([O:39][CH3:40])=[C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:28])([F:29])[F:27])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:41])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:4]=3)[O:17][C:16]2=[O:18])[CH:35]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.75 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (example 122) (48.2 mg, 0.077 mmol) in EtOAc (4 mL) was added PtO2 (12 mg) and the reaction was placed under an atmosphere of hydrogen (balloon) and stirred vigorously. After 45 minutes, the catalyst was removed by filtration through a plug of silica gel with 100% EtOAc. The filtrate was concentrated to afford (4S,5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.20 (40% EtOAc/hexanes). LCMS=593.2 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.85 (s, 1H), 7.60-7.70 (m, 4H), 7.36 (d, J=7.8 Hz, 1H), 6.74-6.84 (m, 2H), 6.56 (s, 1H), 5.45-5.54 (m, 1H), 4.82-4.87 (m, 1H), 3.64-4.17 (m, 2H), 3.70 (s, 3H), 0.43-0.53 (m, 3H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:7]=2[CH:21]=1>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH2:1])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:7]=2[CH:21]=1
Reactant: N
Reactant: Fc1ccccc1C1=NCC(=S)Nc2ccc(Cl)cc21
Solvent: C1CCOC1
Product: NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Yield: 87 %

Procedure:
800 ml of aqueous ammonia solution (25%) were added to a solution of 27.6 g of 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester jr., A. D. Rudzik and B. V. Bharat, J.Med. Chem., 1971, 14, 1078-1081) in 900 ml of tetrahydrofuran and the mixture was stirred intensively at room temperature for 72 h. The separated organic phase was concentrated in a vacuum to about 50 ml and the crystals which thereby separated were filtered off. Drying was carried out in a vacuum at 50° C., firstly over calcium chloride, then over phosphorus pentoxide. There were obtained 22.8 g (87%) of 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamine as a pale yellow crystalline powder of m.p. 248-249° C. (dec.) which was used without further purification for the steps described below.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(N(CC)CC)C>ClCCl>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:7](=[O:8])[C:6]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])=[CH:31][C:32]=1[C:38]([F:39])([F:40])[F:41])#[N:35]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Propoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-n-propoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH:1]1[C:9]2[C@H:10]3[O:15][CH2:14][CH2:13][NH:12][C@@H:11]3[CH2:16][C:7]3[C:8]=2[C:4]([NH:5][CH:6]=3)=[CH:3][CH:2]=1>[Pd].C(O)C>[CH2:9]([N:12]1[C@@H:11]2[CH2:16][C:7]3[C:8]4[C:4]([NH:5][CH:6]=3)=[CH:3][CH:2]=[CH:1][C:9]=4[C@H:10]2[O:15][CH2:14][CH2:13]1)[CH2:1][CH2:2][CH3:3]
Reactant: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCO[C@H]21
Agent: [Pd]
Solvent: CCO
Product: CCCCN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 56.6 %

Procedure:
A suspension of trans-4,6,6a,8,9,10a-hexahydro-7H-indolo-[3,4 gh]-[1,4]-benzoxazine (700 mg; 0.0032 m), Pd/c (10%, 700 mg) and butrylaldehyde (500 mg, 0.006 m) in abs. ethanol (75 ml) is hydrogenated at room temperature for 8 hours. The catalyst is filtered, and the solvent is removed under reduced pressure (20 mm). The resulting oil is chromatographed (silica, chloroform, saturated with aqueous ammonia). The solid is recrystallized from hexane to yield 250 mg of trans-4,6,6a,8,9,10a-hexahydro-7-n-butyl-7H-indolo-[3,4 gh]-[1,4]-benzoxazine; m.p. softens 29°-130°, m.p. 134°-140°.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C(N(CC)CC)C>>[CH3:5][N:6]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:1]([Cl:4])=[O:2]
Reactant: CNC1CCOCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)Cl)C1CCOCC1

Procedure:
248 g (2.5 mol) of phosgene, 96 g (0.83 mol) of N-methyl-N-(tetrahydro-2H-pyran-4-yl)amine and 84 g (0.83 mol) of triethylamine were reacted by the method of the process described in Intermediate 1.2. Yield 108 g. 1H NMR (250 MHz, in CDCl3): δ=1.60-1.95 (m, 4H), 2.94 and 3.01 (2 s, together 3H), 3.35-3.55 (rm, 2H), 3.95-4.10 (m, 2H), 4.27-4.46 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]([CH3:9])[CH3:8])=[N:4][NH:5][CH:6]=1.[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[Br:1][C:2]1[C:3]([CH:7]([CH3:9])[CH3:8])=[N:4][N:5]([CH2:10][OH:11])[CH:6]=1
Reactant: C=O
Reactant: CC(C)c1n[nH]cc1Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)c1nn(CO)cc1Br
Temperature: 130 °C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
The mixture of 1.88 g of 4-bromo-3-i-propyl-1H-pyrazole, 0.60 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.29 g of 4-bromo-3-i-propyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C:6]([O-:8])=[O:7])([CH3:4])[CH3:3].O.[Zr:10].O(Cl)Cl.[Zr].ClO.[Al:17]>>[Zr:10].[Al:17].[CH3:1][N+:2]([CH2:5][C:6]([OH:8])=[O:7])([CH3:4])[CH3:3]
Reactant: C[N+](C)(C)CC(=O)[O-]
Agent: [Zr]
Agent: ClOCl
Agent: OCl
Solvent: O
Product: C[N+](C)(C)CC(=O)O

Procedure:
Betaine monohydrate powder (287 g) is added to a zirconium compound (1000 g of a 31% solution of zirconium oxychloride (ZrOCl2)) with stirring. Aluminum chlorohydrate (“ACH”) (2800 g of a 20% ACH solution made from a powder (REACH 101, from Reheis, Berkeley Height, N.J.) is then added with additional stirring. The final solution is then quickly spray dried to remove water. The Zirconium/Aluminum/Betaine (“ZAB”) powder obtained has a Betaine/zirconium molar ratio of 1.42:1; an aluminum:zirconium molar ratio of 3.56:1; and a metal:chloride ratio of 1.05:1.