Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>C1C=CC=CC=1>[C:22]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)(=[O:24])[CH3:23]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)N1c2ccccc2C=Cc2ccccc21
Reaction time: 3.5 h

Procedure:
In a 500 ml round bottom flask fitted with a stirrer, dropping funnel and calcium chloride drying tube was placed recrystallized dibenz[b,f]azepine (33.5 g, 0.173 moles), 200 ml of anhydrous benzene and pyridine (13.6 g, 0.173 moles). Acetyl chloride (~12.3 ml) was then added dropwise to the mixture. A white precipitate formed with disappearance of orange color. After 3 to 4 hours of stirring, the reaction mixture was extracted with three 100 ml portions of 10% hydrochloric acid or until the extract remained acidic. The organic phase was washed with 5% Na2CO3 in water, dried over anhydrous magnesium sulfate, filtered and concentrated. Crystallization from a hexane-chloroform mixture afforded 49 g of 5-acetyl-5H-dibenz[b,f]azepine, m.p. ~121°.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2cncs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(F)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:8][O:17]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C2CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: C(OC(=O)C)(=O)C.[S:8](=[O:11])(=[O:10])=[O:9].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)=O
Reactant: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(O)c1ccccc1
Temperature: 40 °C
Yield: 98 %

Procedure:
Mono-sulfonation of benzene was carried out in the apparatus of FIG. 1. Dry benzene (390 g., 5 gram molecules) was placed in the three-necked reaction flask (1 litre capacity) together with acetic anhydride (1 g) which was added to suppress sulfone formation. The reaction flask was heated to 40°C and the pressure gradually reduced until the benzene refluxed vigorously at 400 mm Hg. The sulfur trioxide generator was charged with liquid, stabilized sulfur trioxide (200 g, 2.5 gram molecules) and the two flasks were connected to allow the sulfur trioxide to be aspirated into the reaction flask. External heating of the reaction flask was discontinued but the trioxide generator was gently warmed to maintain an internal temperature of 30°C to aid evaporation. The reaction was completed when all the sulfur trioxide had been evaporated from the generator and had passed into the reaction vessel. At this point reflux ceased. Anhydrous benzene sulfonic acid was isolated by distilling off the excess benzene in vacuo, leaving a light amber coloured oil which crystallized slowly when kept in a desiccator over concentrated sulfuric acid. The sulfonic acid was contaminated by 0.2% sulfuric acid and 1.5% diphenyl sulfone. The yield was 98% calculated with respect to the amount of sulfur trioxide employed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1([CH3:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C:15]([CH3:25])([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1(C)Cc2ccccc2CN1
Product: CC1(C)Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[C:2]1([NH:8][NH:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:11]=2[F:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a stirred mixture, under nitrogen, of 72.3 g of phenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 97.1 g of 2,4-difluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for about 16 hours. Dilution of the mixture with water formed a precipitate which was collected, dried, and recrystallized from ethyl acetate to yield 98 g (79%) of 2,4-difluorobenzoic acid, 2-phenylhydrazide. Subsequent recrystallization from ethyl acetate afforded the analytical sample, m.p. 171°-173° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)C(=O)c1ccccc1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 261.0 [M+H]+) was prepared from 6-chloro-pyridin-3-ylamine and benzoylformic acid chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]2[CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1.[H-].[Na+].O>CN1CCCC1=O>[N:41]1([S:38]([C:35]2[CH:36]=[CH:37][C:32]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:44][CH2:43][CH2:42]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 57.5 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60.0 mg, 0.139 mmol) synthesized in Example (38d) and 1-[(4-fluorophenyl)sulfonyl]azetidine (60.0 mg, 0.279 mmol) synthesized in Example (55a) were dissolved in N-methylpyrrolidone (5.0 mL), and sodium hydride (60%, 24 mg, 0.60 mmol) was added, followed by stirring at 100° C. for 6 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-35%) to afford the desired compound (42 mg, yield 57%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[NH2:12].[I:14]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:14])[C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[NH2:12]
Reactant: CCc1ccc(C(=O)OC)c(N)c1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCc1cc(N)c(C(=O)OC)cc1I
Yield: 72.8 %

Procedure:
To a solution of 2-amino-4-ethyl-benzoic acid methyl ester (500 mg, 2.79 mmol) in EtOH (2 mL) were added Ag2SO4 (868.15 mg, 2.79 mmol) and I2 (708.1 mg, 2.79 mmol) and the resultant mixture was stirred at r.t. for 3 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 1M Na2S2O3 and sat. aq NaHCO3. The solvent was removed in vacuo and the orange oil was purified by flash chromatography (silica gel, hexanes→4:1 hexanes:EtOAc) to provide the title compound (620 mg, 73%) as an orange solid. ESI-MS: m/z 306.2 [M+H]+, rt 6.03 min
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: FC(F)(F)c1ccc(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 2-(chloromethyl)-5-(trifluoromethyl)thiophene (171 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (138 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[C:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccccc1CCN
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1ccccc1CCNC(=O)C(C)(C)C

Procedure:
1-Amino-2-(2-methylphenyl)ethane and pivaloyl chloride were reacted in the same way as in step (a) of Example 1 to afford 1-pivaloylamino-2-(2-methylphenyl)-ethane. The product was successively reacted in the same way as in steps (b), (c), (d) and (e) of Example 1 to afford 1-tert-butylsioquinoline-5-acetonitrile.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH2:3]1
Reactant: NC1CCCCNC1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A solution of 3-aminohomopiperidine (1.71 g, 15 mmol) in CH3CN (45 mL) was treated with p-chlorobenzyl chloride (463 mg, 2.9 mmol) and K2CO3 (828 g, 6 mmol) and heated to 70° C. for 9 h. The reaction mixture was cooled to 25° C. and concentrated to afford a yellow solid. The residue was partitioned between H2O (5 mL) and EtOAc (50 mL), and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated. The resulting yellow oil was purified by chromatography (SiO2, 5-20% CH3OH—CH2Cl2 gradient elution) to afford the desired product as a yellow oil (639 mg, 93%).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>CCCCCC>[F:28][C:25]1[CH:26]=[CH:27][C:21]2[S:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH:24]=1
Reactant: Fc1ccc2sc(-c3ccc(CBr)cc3)nc2c1
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Product: CCOP(=O)(Cc1ccc(-c2nc3cc(F)ccc3s2)cc1)OCC
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Triethyl phosphite (50.0 g) was added to 31.0 g of 2-(4-bromomethylphenyl)-5-fluorobenzothiazole, and the mixture was reacted at 150° to 160° C. for 15 minutes under a stream of nitrogen. The reaction mixture was allowed to cool to room temperature, and 100 ml of n-hexane was added. The precipitated crystals were collected by filtration and dried to give 39.0 g of crude crystals. Recrystallization from a mixture of ethyl acetate and cyclohexane gave 30.0 g of the captioned compound as colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:4].C(=O)(O)[O-].[Na+].[CH2:21]([O:28][CH2:29][C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:30](=[O:31])[CH2:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)COC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10 grams, 47.84 mmol) and sodium bicarbonate (8 grams, 95.23 mmol) in ethyl acetate (50 mL) at 0° C. is added benzyloxy acetyl chloride (12 grams, 65.04 mmol) drop wise. The reaction mixture is stirred at room temperature for 10 hours. The solids are filtered off, and the ethyl acetate layer is washed with 5% sodium bicarbonate solution (2×25 mL), water (2×25 mL), dried over sodium sulfate, and distilled to give crude 7, which can be purified via crystallized with a suitable solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33]>>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Fc1cccc(CBr)c1F
Product: COc1ccc(CN(Cc2cccc(F)c2F)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and 1-(bromomethyl)-2,3-difluorobenzene. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.30 (s, 3H), 4.29 (s, 2H), 4.32 (s, 2H), 6.87 (d, 2H, J=8 Hz), 7.02-7.20 (m, 5H), 7.95 (d, 2H, J=8 Hz). 8.05 (d, 2H, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:26])=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Yield: 44 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethyl ester (prepared as described in E above), 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (7.06 g, 31.5 mmol) and Cs2CO3 (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between EtOAc (250 mL) and H2O (250 mL), and the aqueous phase extracted with EtOAc (2×100 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, hexanes to 10% EtOAc/hexanes) to provide 2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (6.81 g, 44%) as a off-white solid: Rf=0.48 in 35% EtOAc/hexanes; mp 78-79° C.; 1H NMR (300 MHz, CDCl3) δ 7.85-7.82 (m, 2H), 7.57-7.53 (m, 2H), 6.83-6.75 (m, 4H), 4.22 (q, J=7.0 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=7.0 Hz, 3H) and by-product 2-(4-Bromophenyl)-5-methyl-4-vinyloxazole (1.81 g, 22%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.92-7.87 (m, 2H), 7.58-7.55 (m, 2H), 6.54 (dd, J=17.3, 10.8 Hz, 1H), 5.94 (dd, J=17.0, 1.8 Hz, 1H), 5.30 (dd, J=10.8, 1.8 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][NH:35][NH2:36])=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:35]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:36]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)cc1
Reaction time: 17 h
Yield: 91.4 %

Procedure:
Triethylamine (83.68 ml) was added to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one (61.23 g), (4-methoxybenzyl)-hydrazine hydrochloride (41.50 g) produced by the method described in U.S. Patent No. US2003/18197, and dichloromethane (600 ml) over 30 minutes under cooling in an ice bath. Thereafter, while the temperature of the reaction solution was gradually raised, it was stirred for 17 hours. Thereafter, a 10% citric acid aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. A 5% citric acid aqueous solution was added to the resulting residue, and the precipitate was then collected by filtration. The resultant was washed with water, so as to obtain the title compound (73.84 g) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[S:29][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:31][CH:32]=2)=[CH:22][N:21]=1)([O-])=O>>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[S:29][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=2)=[CH:22][N:21]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CN(C)Cc1cccc(OCCCNc2ncc(Cc3ccc(CN(C)C)s3)c(=O)[nH]2)c1

Procedure:
Reaction of 3-(3-dimethylaminomethylphenoxy)propylamine with 2-nitroamino-5-(5-dimethylaminomethyl-2-thienyl methyl)-4-pyrimidone gives 2-[3-(3-dimethylaminomethylphenoxy)propylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[C:11]([CH2:13][O:14]C3C=CC(C)=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:32]O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[C:11]([C:13](=[O:14])[CH3:32])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1ccc(OCc2cn(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(Cl)cc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1

Procedure:
A suspension of ethyl [2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl] carboxylate (Example 159) (929 mg, 2.29 mmol) in 16 ml of methanol and 16 ml of 1N aqueous sodium hydroxide was stirred at reflux for one hour. After cooling, the mixture was concentrated, water was added, and the resulting mixture was acidified with acetic acid. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Acetic acid was removed by azeotropic distillation with toluene to give the title compound, 520 mg, as a white crystalline solid: mp (DSC) 121° C. Anal. Calc'd. for C17H13ClN2O4S.H2O (MW 394.83): C, 51.71; H, 3.32; N, 7.10. Found: C, 51.89; H, 3.29; N, 6.97.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@H:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][C@@H:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@H]2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: C[C@@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (R)-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.38 g, 1.04 mmol), cyclohexene (0.27 mL, 2.61 mmol), and 1.0 M boron tribromide in dichloromethane (6.27 mL, 6.27 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane, to yield 4-{[(R)-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.26 g, 0.74 mmol, 71%) as a white, solid, single enantiomer, m.p. 181-183° C.;