Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=O.[ClH:22].C(O)(=O)C>O1CCCC1.B>[ClH:22].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:4]([NH:3][CH3:1])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1
Reactant: O=CNC(Cc1ccccc1[N+](=O)[O-])c1ccc(F)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(Cc1ccccc1[N+](=O)[O-])c1ccc(F)cc1

Procedure:
To a cooled mixture of 31.1 g of N-formyl-α-(4-fluorophenyl)-2-nitrophenethylamine in 500 ml of tetrahydrofuran, 441 ml of 0.98 M borane in tetrahydrofuran is added dropwise. The mixture is allowed to stand over the weekend. The mixture is cooled and 100 ml of 5% hydrochloric acid and 20 ml of glacial acetic acid are added cautiously. The solvent is evaporated in vacuum and the residue treated with 10% sodium hydroxide solution. The free amine is extracted with ether and dried over anhydrous sodium sulfate and filtered. Ethereal hydrogen chloride is added dropwise to the filtrate and the product precipitates as the hydrochloride salt. Recrystallization from ethanol gives crystals, mp 241°-243° C. of α-(4-flurophenyl)-N-methyl-2-nitrophenethylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:6])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CO.CN(C)C=O.CCCCCC>[CH3:3][C:2]([CH3:17])([O:4][C:5]([NH:7][NH:8][C@H:9]([C:14]([O:16][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)NN[C@@H](CC(N)=O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN[C@@H](CC(N)=O)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 48.8 %

Procedure:
The compound was prepared according to Bioorg. Med. Chem., 6(1998)1185-1208. N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine (20.7 g, 89.1 mmol, 1 eq.), of Step 1, was dissolved in methanol (500 ml) and cesium carbonate (15.97 g, 49 mmol, 0.55 eq.) was added. The solvent was evaporated to give a white solid that was dissolved in N,N-dimethylformamide (200 ml). To the suspension, benzyl bromide (11.6 ml, 98 mmol, 1.1 eq.) was added dropwise and the mixture was stirred overnight. The solvent was reduced under reduced pressure, water (300 ml) was added and the mixture extracted with ethyl acetate (200 ml), washed with brine (50 ml) and the solvent removed under reduced pressure to give a crude that was suspended in n-hexane (160 ml), filtered and dried under vacuum to give 14.68 g of white solid. Yield 51%.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([N:15]=[N:16][C:17]1([N:23]=[C:24]=[S:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].[N-]=C=S>CO>[C:11]([N:15]=[N:16][C:17]1([NH:23][C:24](=[S:25])[NH:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [N-]=C=S
Solvent: CO
Product: CC(C)(C)N=NC1(NC(=S)NNC(=O)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4.02 grams (0.0295 moles) of benzoylhydrazine in 25 ml of methanol in a 50 ml erlenmeyer flask was added 6.82 grams (0.0295 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane and the reaction mixture stirred for 6 days at room temperature. The methanol was evaporated under reduced pressure leaving a pale yellow solid weighing 9.0 grams (75% crude yield). The product melted with decomposition at 190°-193° C. The infrared spectrum of the product had amide bands at 1640 and 1690 cm-1, a strong band at 1550 cm-1 [-N(H)CS] and weak NH bands from 3100-3300 cm-1. The isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:17][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 25 mL round-bottomed flask, 5-bromo-6-chloropicolinic acid (433 mg, 1.83 mmol) and powdered potassium hydroxide (411 mg, 7.32 mmol) were combined with DMSO (1.9 ml) to give a colorless solution which was stirred at room temperature for 15 min. 2,2,2-trifluoroethanol (275 mg, 198 μl, 2.75 mmol, Eq: 1.5) was added. The reaction mixture was stirred for 24 h at ambient temperature. Since the reaction was complete, 0.75 extra equivalents of 2,2,2-trifluoroethanol was added and the reaction was stirred 48 h at ambient temperature. The reaction mixture was poured onto 1 M HCl/ice water (1×20 mL), extracted with iPrOAc (2×25 mL). The organic layers were dried over Na2SO4 and filtered, removed under reduced pressure to give the title compound as a white solid after recrystallization from CH2Cl2 and heptane (409 mg, 1.36 mmol, 74.4% yield), MS (EI): m/e=299.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
0.31 g (2 mmol) of 5-hydroxy-nicotinic acid methyl ester and 3.1 g (4 mmol) of polymer-supported triphenylphosphine were combined in a flask charged with 45 mL of THF and 0.31 mL (3 mmol) of benzyl alcohol, and shaken at r.t. until the starting materials dissolved. The reaction mixture was then cooled to 0° C. with a water/brine bath, 0.58 mL (3 mmol) of DIAD was added and the reaction slurry then stirred overnight at r.t. The reaction mixture was filtered and the resin was washed 3 times with DCM/MeOH=1:1. The organic layer was then evaporated and flashed (EtOAc/hexanes=1:2) to give the desired 5-benzyloxy-nicotinic acid methyl ester, which was subsequently hydrolyzed according to general procedure B to give 5-benzyloxy-nicotinic acid which was used in the next step without further purification. LCMS: 230 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3]2[O:4][C:5]3=[N:13][CH:12]=[CH:11][CH:10]=[C:6]3[C:7](=[O:9])[C:14]=2[CH:15]=[C:16]([C:18]2[NH:19][N:20]=[N:21][N:22]=2)[CH:17]=1
Reactant: Cc1cc(-c2nnn[nH]2)ccc1Oc1ncccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2nnn[nH]2)cc2c(=O)c3cccnc3oc12
Temperature: 180 °C
Yield: 53.2 %

Procedure:
A mixture of 1 g of 2-[2-methyl-4-(5-1H-tetrazolyl)phenoxy]nicotinic acid and 10 ml of concentrated sulfuric acid is heated at 180° C for 2.5 hours, and then poured into ice water. The crystalline precipitate is filtered off, washed with water and with methanol and recrystallized from dimethylformamide to give 0.5 g of 9-methyl-7-(5-1H-tetrazolyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 290° C to 291° C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (47 mg, 35%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8](OOC(=O)C1C=CC=CC=1)(=O)[C:9]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:4]([O:6][CH2:1][CH:8]=[CH2:9])[CH:3]=[CH2:2].[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: C=CCOCC=C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Into a glass reaction vessel provided with a thermometer, a stirrer, a dropping funnel, a nitrogen introduction tube and a reflux condenser are charged 336 parts of methoxy-6-ethylene glycol allyl ether (made by NOF Corporation), 98.0 parts of maleic anhydride, 6.0 parts of benzoyl peroxide and 566.0 parts of toluene. After an inside of the vessel is substituted with nitrogen with stirring, it is heated to 80° C. and this temperature is kept for 4 hours to progress the reaction. After toluene is distilled off at 110° C. under a reduced pressure of 10 mmHg, the inside is turned to a normal temperature and a normal pressure to obtain allyl ether-maleic anhydride copolymer having a weight average molecular weight of 27,000 (polyethylene glycol conversion).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](O)[CH3:13].[ClH:15]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([Cl:15])[CH3:13]
Reactant: Cl
Reactant: CC(O)c1ccccc1Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Cl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Thionyl chloride (1.49 g, 12.6 mmol) was added to 1-(2-chlorophenyl)ethanol (1.0 g, 6.3 mmol) in toluene (50 mL) and the mixture was allowed to stir at room temperature for 2 h. To the reaction mixture was added 10% aq. HCl solution (20 mL). The organic phase was separated and washed with another portion of 10% aq. HCl solution, brine (20 mL) and then separated, dried and evaporated to provide 1-chloro-2-(1-chloroethyl)benzene in 72% yield.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=CC(B(O)O)=CC=1>>[Cl:21][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1NCCc2c(-c3ccc(Cl)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-chlorophenylboronic acid (195 mg, 1.24 mmol) were coupled to yield 2-(4-chloro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 223 mg (66%) as an off-white solid: m.p. 250-252° C.; 1H NMR (300 MHz, d6-DMSO) δ3.04 (m, 2H), 3.39 (m, 2H), 7.23 (app t, J=7.5 Hz, 1H), 7.58 (m, 3H), 7.68 (m, 3H), 8.10 (br t, 1H), 11.66 (br s, 1H). MS (FAB, MH+) 297. Anal. (C17H13ClN2O.0.8 H2O) C, H, N.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH3:16])[C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[C:6]([CH3:16])[C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:18][C:17]1=[O:19]
Reactant: CNc1scc(C)c1C(=O)c1ccccc1
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1csc2c1c(-c1ccccc1)nc(=O)n2C
Temperature: 200 °C

Procedure:
A mixture of 2.0 g of 2-methylamino-3-benzoyl-4-methylthiophene, 2.3 g of ethyl carbamate and 0.18 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is recrystallized from chloroform-ethanol to give 1-methyl-4-phenyl-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 275° - 280°C.
Reaction SMILES: [N:1]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[N:16]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[CH2:25][N:26]([S:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:19][CH:18]=2)[N:16]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)S(=O)(=O)N3CCOCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 37 h
Yield: 38 %

Procedure:
4-Morpholinesulfonyl chloride (213 mg, 1.15 mmol) was added (5 min) to an ice-cold solution of N-{4-(2-amino-4-thiazolyl)phenyl}-2-{(phenylmethyl)-amino}acetamide.2HCl (450 mg, 1.09 mmol), the corresponding free base has been described in example 2) and Et3N (443 mg, 4.38 mmol) in CH2Cl2 (10.9 mL). The reaction mixture was allowed to warm to room temperature and DMAP (14.0 mg, 0.11 mmol) was added. After standing for 37 h at room temperature, the mixture was dissolved in EtOAc (125 mL). The solution was washed successively with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (SiO2, EtOAc) gave the title compound (200 mg, 38% yield) as a white solid: M.p. 193-194°; 1H NMR (400 MHz, DMSO-d6) δ10.02 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.30-7.41 (m, 5H), 7.01 (s, 2H), 6.89 (s, 1H), 4.59 (s, 2H), 3.91 (s, 2H), 3.58 (t, J=4.6 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H); MS (FAB) m/z 488 (MH)+; Anal. Calcd for C22H25N5O4S2: C, 54.19; H, 5.17; N, 14.36. Found: C, 53.63; H, 5.07; N, 14.34.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH3:15][O:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([CH:17]([O:16][CH3:15])[CH3:18])=[CH:20][CH:21]=1
Reactant: COC(C)c1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(C)c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), 4-(1-methoxyethyl)phenylboronic acid (27.4 mg, 0.152 mmol) and 2N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 7.0 min, HOLD at 0% H2O/100% MeCN to 8.5 min. Flow: 25 mL/min) to afford the title compound (4.9 mg, 11% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.71 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.CC(O)C>ClCCl>[CH2:1]([S:8]([C:9]1[N:10]=[CH:11][C:12]([Br:15])=[CH:13][N:14]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(SCc2ccccc2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=S(Cc1ccccc1)c1ncc(Br)cn1
Yield: 91 %

Procedure:
The oxidation of 2-benzylthio-5-bromopyrimidine was carried out using one molar equivalent of 85% m-chloroperbenzoic acid in dichloromethane, initially at -10° C. and then at 0° C., as described in Example 40 above; yield 91%, m.p. 101° C. (iPrOH). 1H NMR (CDCl3); δ4.26 and 4.31 (CH2), 7.16 (Ph), 8.80 (H-4, H-6).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[F:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc(F)cc2)cc1
Yield: 85.3 %

Procedure:
A mixture of 4- [[2-(4-fluorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.65 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction with dichloromethane-diethyl ether provided solids which were crystallized from dichloromethane-hexane to give 0.53 g of colorless 4-[[2-(4-fluorophenoxy) ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 97°-98° C.
Reaction SMILES: Cl.C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[Cl:50][C:47]1[CH:48]=[CH:49][C:43]2[O:42][C:41]([C:38]3[CH:39]=[CH:40][C:35]([CH2:34][O:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH2:26][CH2:25][NH:9][CH:10]4[CH2:19][CH2:18][CH2:17][C:16]5[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]4=5)=[CH:36][CH:37]=3)=[N:45][C:44]=2[CH:46]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 ml of a 4 N solution of hydrogen chloride in dioxane were added to 247 mg (0.36 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 59A), and the mixture was stirred at room temperature for 4 h. The reaction solution was then concentrated to dryness and the residue was dried under high vacuum overnight. This gave 210 mg of the title compound as the hydrochloride in the form of a solid. This solid was taken up in 5 ml of THF, 0.13 ml of triethylamine was added and the mixture was stirred at room temperature for one hour. Water and ethyl acetate were then added to the mixture, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were then dried over magnesium sulphate, filtered and then concentrated to dryness. This gave 149 mg (0.26 mmol, 72% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (128.4 mg, 0.341 mmol) in tetrahydrofuran (4.0 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.17 mL, 0.512 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (122.5 mg, 0.301 mmol, 88%).
Reaction SMILES: [Bi:1].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([OH:7])=[O:6])[CH3:3].[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([O-:17])=[O:16])[CH3:13].[NH4+]>CO>[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3].[Bi+3:1].[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([O-:17])=[O:16])[CH3:13].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3]
Reactant: [Bi]
Reactant: CCCCC(CC)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: [Bi+3]

Procedure:
The electrolyzer of FIG. 1 was used to assist the reaction. The anolyte contained a solution formed from 10 ml of 2-ethylhexanoic acid, 1.6 g of ammonium 2-ethylhexanoate, and 90 ml of methanol. The anode was a bismuth plate having a surface area of 10 cm2. The catholyte solution contained 3 ml of 2-ethylhexanoic acid, 0.5 g of ammonium 2-ethylhexanoate, and 27 ml of methanol. A graphite cathode having a surface area of 10 cm2 was utilized. Electrolysis was conducted using a current of 0.100 amps for 20 hours. A 2 ml quantity of 2-ethylhexanoic acid was added to the catholyte solution every 3 hours. The anolyte solution was removed from the electrolyzer and filtered. The mother liquor was cooled to a temperature ranging from about 0-2° C. to precipitate crystals. The crystals were isolated by filtration, washed with methyl alcohol, and dried in a vacuum heater at a temperature ranging from about 50-60° C. for a duration of 7-8 hours. The product included 14.3 g of a viscous transparent liquid, namely, Bi(C7H15COO)3. Table 2 presents the analytical data for the product.