Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:17][CH2:16][N:15]([CH2:32][C:33]([OH:35])=[O:34])[CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1N(CCO)CCN(C[CH2:46][S:47](O)(=O)=O)C1.C(Cl)(Cl)=S.C(Cl)(Cl)Cl>Cl>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:13][CH2:14][N:15]([CH2:32][C:33]([OH:35])=[O:34])[CH2:16][CH2:17][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)=[C:46]=[S:47]
Reactant: Nc1ccc(C(C(=O)O)N2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: Cl
Agent: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1CCN(CC(=O)O)CCN(C(C(=O)O)c2ccc(N=C=S)cc2)CCN(CC(=O)O)CC1

Procedure:
To a solution of α-(4-aminophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, samarium-153 complex prepared from 220 μl of 153Sm solution in 0.1N HCl were added 2 μl of HEPES buffer (0.5M, pH 8.9), 2 μl of thiophosgen and 200 μl of chloroform. It was vortexed vigorously 2 or 3 times for a few seconds each time. The chloroform layer was discarded and the aqueous layer which contained mainly the desired product was saved and further purified. The yield of α-(4-isothiocyanatophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, samarium-153 complex, as analyzed by HPLC on GF-250 column based on the 153Sm activity using the HPLC System I was usually over 90%. To purify, the aqueous layer was passed through a Sep-Pak™ C-18 cartridge and eluted with 90 percent acetonitrile in water. The first 300 μl of effluent was discarded, and the desired product came off in the next 1200 μl, with 86-93% recovery. The bulk of the solvent was then evaporated off in a Speed Vac™ concentrator over a period of about 2 hours.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][C:29]=5[CH3:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:38].[ClH:40].CCOCC>>[ClH:38].[ClH:40].[ClH:38].[CH3:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:28]=1[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: Cc1cccc2cc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)ncc12
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Cc1cccc2cc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[6-amino-5-(8-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (11.0 mg, 0.0227 mmol) in DCM (0.40 mL, 6.2 mmol) was added 1.0 M of HCl in Et2O (0.60 mL, 0.60 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately an off-white solid precipitated. The solvents were evaporated, and the residue was suspended in Et2O, filtered off, and dried in vacuo overnight, yielding the title compound as yellow solid. It appeared to be hygroscopic during the filtration; however, after the washing and initial drying it appeared to be non-hygroscopic. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.60 (s, 1H), 9.18-9.07 (brm, 1H), 9.05-8.92 (brm, 1H), 8.88 (d, J=2.0 Hz, 1H, 8.86 (brs, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.81 (dd, J=8.4, 6.8 Hz, 1H), 7.61 (d, J=6.8 Hz, 1H), 4.58-4.49 (m, 1H), 3.40 (brd, J=12.4 Hz, 2H), 3.12 (brq, J=12.2 Hz, 2H), 2.83 (s, 3H), 2.30-2.12 (m, 4H). MS(ES+): m/z=385.21 (43) [MH+], 302.15 (100) [MH+-piperidine]. HPLC: tR=1.80 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH:23]=[O:24])=[C:17]([CH:22]=1)[C:18]([O:20]C)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].C1COCC1>[Br:12][C:13]1[CH:22]=[C:17]2[C:16]([CH:23]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:24][C:18]2=[O:20])=[CH:15][CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1cc(Br)ccc1C=O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: C1=CCCC=CCC1
Product: COc1ccccc1C1OC(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
(2-Methoxyphenyl)boronic acid (4.69 g, 30.9 mmol), methyl 5-bromo-2-formylbenzoate (5.00 g, 20.6 mmol; GLSyntech, LLC), tripotassium phosphate (17.5 g, 82.0 mmol) and THF (103 mL) were added to a pressure tube. The tube was purged with argon. Then chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.507 g, 1.03 mmol) was added. The tube was sealed and stirred at rt. After 30 min, LCMS showed lactone product. TLC confirmed a complete conversion of methyl 5-bromo-2-formylbenzoate to a lower spot. The reaction was filtered with the aid of EtOAc. The filtrate was concentrated and the crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexanes, to provide 6-bromo-3-(2-methoxyphenyl)isobenzofuran-1(3H)-one (5.15 g, 78% yield). m/z (ESI) 319.0 (M+H)+, 321.0 (M+3H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][CH2:34][C:35]3=[O:40])O1>CN(C)C=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>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][CH2:34][C:35]3=[O:40])=[C:3]([O:13][CH2:14][O:15][CH3:16])[C:4]=1[O:11][CH3:12])[CH3:10]
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Reactant: CCOc1ccc(Br)c(OCOC)c1OC
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: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCOC)c1OC
Temperature: 85 °C
Yield: 56.7 %

Procedure:
A stirring solution of 1-bromo-4-ethoxy-3-methoxy-2-(methoxymethoxy)benzene (300 mg, 1.030 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h, to this cesium carbonate (1 g, 3.092 mmol), Pd(PPh3)4 (59 mg, 0.051 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (265 mg, 1.030 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded 4-(4-Ethoxy-3-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (200 mg, 56%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=O.[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:20][C:4]1[C:3](/[CH:1]=[C:24](/[N+:21]([O-:23])=[O:22])\[CH3:25])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: C/C(=C\c1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
A solution of benzyl 3-formyl-2-methylphenylcarbamate (5.1667 g, 19.19 mmol), nitroethane (6.89 ml, 96 mmol) and ammonium acetate (7.39 g, 96 mmol) in acetic acid (Volume: 64.0 ml) under nitrogen was heated at 95° C. After 3 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 mL) and CH2Cl2 (75 mL), and basified with Na2CO3 (s). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×75 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 330 g column eluting with 50-100% hexane/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give (E)-benzyl 2-methyl-3-(2-nitroprop-1-enyl)phenylcarbamate (2.4714 g, 39.5% yield) as a yellow solid, LC/MS (M+H)=327.16. 0.6875 g of desired product (75% pure by HPLC) was also collected.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].CO.O.[NH2:16][NH2:17]>ClCCl.C(O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH:16][NH2:17])=[O:5]
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: NNC(=O)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To 2,3,6-trifluorobenzoyl chloride, (29 g, 0.15 mol) in dichloromethane (200 ml) was added methanol (30 ml) dropwise at 5° C. The solution was allowed to warm to room temperature and was stirred under nitrogen for 2 h. The solvent was removed in uacuo and the residual oil was stirred with hydrazine monohydrate (19 ml, 0.40 mol) in ethanol (120 ml) at reflux for 3 h. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane (400 ml) and water (200 ml). The biphasic mixture was filtered to remove insoluble material, then the aqueous layer was washed with dichloromethane (2×300 ml). The combined organic layers were dried over magnesium sulfate, and were concentrated in vacuo to yield 2,3,6-trifluorobenzoic hydrazide as a white solid (6.0 g). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 4.18 (2H, br s), 6.93 (1H, m), 7.25 (2H, m); MS (ES+) m/e 191 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:12]3=[N:24][N:25]=[C:26]([CH3:27])[N:11]3[C:10]3[CH:28]=[CH:29][CH:30]=[CH:31][C:9]2=3)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[C:12]3=[N:24][N:25]=[C:26]([CH3:27])[N:11]3[C:10]3[CH:28]=[CH:29][CH:30]=[CH:31][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetate (90 mg, 0.21 mmol) in 5 mL of DCM, was added TFA (1 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with DCM:MeOH=20:1 to give 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetic acid as a yellow solid (68 mg, 87%). LRMS (M+H)+: 382 m/z.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25](O)=[O:26])[N:16]=1>>[CH3:1][O:2][C:3](=[O:14])[C@@H:4]([NH:13][C:25]([C:17]1[N:16]=[CH:15][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1cc2ccccc2cn1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cc2ccccc2cn1
Yield: 100.1 %

Procedure:
3-(4-Hydroxyphenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (807 mg, 90%) was prepared from (2S)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (500 mg, 3.0 mmol) and isoquinoline-3-carboxylic acid (530 mg, 2.3 mmol) according to general procedure A.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].N1C=CN=C1.FC(F)(F)S(O[Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])(=O)=O>C(Cl)Cl.CCCCCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.25 g, 4.1 mmol) in MeCl2 (17 ml) containing imidazole (2.55 g, 48.7 mmol) was cooled to 0° C. and treated with triisopropylsilyl trifluoromethanesulfonate (7.41 g, 24.2 mmol). The reaction mixture was allowed to warm to RT and stirred for 16 hrs. The reaction mixture was diluted with MeCl2 (20 ml) and n-hexane (40 ml). The resultant suspension was filtered and the filtrate was passed over SiO2. Elution with n-hexane/ethyl acetate (3:1) yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.35 g, 86.3%). Mass Spec: C49H83NO12Si(906.29) FAB:928(M+Na), 756, 678, 511, 266.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#CC)[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][CH2:21][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CC#CCC(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(CCNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 3-chloroaniline (4.33 mL, 40.9 mmol), the product from Step F (ca. 41 mmol), and crushed 4 Å molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen was added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction was stirred for one hour, then warmed to room temperature. After 3 hours, the solution was poured into EtOAc and washed with water, sat. NaHCO3 soln. and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[CH:5][CH:4]=1.[N+](C1C=CC=C(COC2C=CC=C(Br)C=2)C=1)([O-])=O>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: O=[N+]([O-])c1cccc(COc2cccc(Br)c2)c1
Product: COc1ccc(Oc2ccc(C)cc2N)cc1

Procedure:
The product from Example 116A was reduced according to the procedure of Example 104B substituting the product from Example 116A for the product from Example 104A to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH2:6][N:7]2[C@@H:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][O:9][C:8]2=[O:15])C[CH2:2]1.C(Cl)(=[O:22])C(C)(C)C.C(O)(=O)CCC=C.CN1CCOCC1.C([Li])CCC.CCCCCC.CC([C@H]1COC(=O)N1)C.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][CH:12]([C@H:11]1[CH2:10][O:9][C:8](=[O:15])[N:7]1[C:6](=[O:22])[CH2:5][CH2:4][CH:1]=[CH2:2])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1CC(=O)CC1CC1
Agent: C=CCCC(=O)O
Agent: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN1CCOCC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Cyclopropyl-2-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone: A solution of mixed anhydride was prepared by adding under a N2 atmosphere pivaloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min. Meanwhile, a second solution was prepared by adding dropwise under a N2 atmosphere a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone [12.9 g, 100 mmol, described by L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989)] in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78°, the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone].
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30]C)([CH3:22])[CH3:21])[N:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:37]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])([CH3:21])[CH3:22])[N:7]=1)=[O:5])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Reaction time: 20 h
Yield: 27.5 %

Procedure:
210 mg (0.39 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylic acid diethylamide is mixed with 7.8 ml (7.8 mmol) of a 1 M boron tribromide solution in dichloromethane. After 20 hours at room temperature, the reaction is halted by adding water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution, and it is dried on sodium sulfate. After the solvent is removed and after purification on silica gel with hexane-ethyl acetate (0-100%), 56 mg (28%) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:19][CH2:16][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(OCc2ccccc2)ccc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a solution of {2-chloro-4-[(phenylmethyl)oxy]phenyl}methanol (2.08 g, 8.36 mmol) in DCM (20 ml) under nitrogen in an ice-water bath was added a solution of phosphorus tribromide (0.83 ml, 8.80 mmol, Aldrich) in DCM (10 ml). The solution was allowed to warm to ambient temperature and stirred for 1.5 h. The reaction mixture was poured onto ice-water (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The mixture was diluted with DCM (50 ml), and the phases separated. The aqueous extract was washed with dichloromethane (20 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give 1-(bromomethyl)-2-chloro-4-[(phenylmethyl)oxy]benzene as white solid (2.48 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][SH:12])=[CH:4][CH:3]=1.[C:13](=O)(OC1C=CC=CC=1)[O:14]C1C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][S:12][C:13]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc(CNCCS)cc1
Product: Cc1ccc(CN2CCSC2=O)cc1
Yield: 29.8 %

Procedure:
The procedure of Example 2 is followed, 4.0 g (0.022 mol) of N-(4-methylphenylmethyl)cysteamine are reacted with 4.71 g (0.022 mol) of diphenyl carbonate then the reaction mixture is worked up to give 1.36 g (29.8%) of the title compound, m.p.: 49°-50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][N:9]1C(=O)C2=CC=CC=C2C1=O)([O-:3])=[O:2].NN>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Product: NCCc1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
In ethanol (150 ml) was suspended N-(3-nitrophenethyl)phthalimide obtained in Preparation Example 26. To the mixture was added hydrazine (5.7 ml), followed by heating under reflux for 1 hour. Though the reaction mixture was once completely dissolved, crystals again precipitated. The crystals were filtered off and washed with cooled ethanol. Then, the solvent was evaporated, to give the title compound (5.559 g, 99%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cnc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
In a falsk, 4.0 g of 2,3-dichloro-5-trifluoromethyl pyridine, 10 ml of dimethyl sulfoxide, 5.1 g of anhydrous potassium carbonate and 2.9 g of p-chlorophenol were charged. The flask was heated in an oil bath at 110° C. to react them with stirring for 2 hours. The completion of the reaction was confirmed by a gas chromatography. The reaction mixture was cooled and poured into suitable amount of water. The reaction product was extracted with methylene chloride and the extracted phase was washed with a diluted sodium hydroxide aqueous solution and then, with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure and the oily residue was distilled to obtain 4.4 g of the object compound having a boiling point of 124°-127° C./2.5 mmHg.