Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([C:33]3[S:37][C:36]([CH3:38])=[N:35][CH:34]=3)[NH:13]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:6]=2[CH:39]=1.CC(O)C.Cl>C(Cl)(Cl)Cl.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([C:33]3[S:37][C:36]([CH3:38])=[N:35][CH:34]=3)[NH2:13])[C:6]=2[CH:39]=1
Reactant: Cc1ncc(C(COc2noc3ccc(Cl)cc23)NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ncc(C(N)COc2noc3ccc(Cl)cc23)s1

Procedure:
To a solution of 1.7 g of 5-chloro-3-[2-(2-methyl-1,3-thiazol-5-yl)-2-tritylaminoethoxy]-1,2-benzoisoxazole in 17 ml of chloroform and 17 ml of methanol is added 2.05 ml of a 2-propanol solution (7.5N) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for two hours, after which the solvent is removed by distillation under reduced pressure. To the residue obtained is added 2-propanol, and after stirring, the crystals precipitated are collected by filtration, to obtain 0.90 g of colorless, crystalline 5-chloro-3-[2-(2-methyl-1,3-thiazol-5-yl)-2-aminoethoxy]-1,2-benzoisoxazole hydrochloride having a melting point of 212° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCCC1
Product: C[C@@H]1C(=O)N(c2cccnc2)c2cnc(Cl)nc2N1C1CCCCC1

Procedure:
(7R)-2-chloro-8-cyclohexyl-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one was prepared from (7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one and pyridin-3-ylboronic acid, according to procedures similar to step d for the preparation of Example 18. Examples 304 was prepared according to procedures similar to the preparation of Example 303, using corresponding starting materials and intermediates.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: COc1ccc(C#CBr)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1F
Temperature: 80 °C

Procedure:
9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol), CuSO4.5H2O (21 mg, 0.085 mmol), 1,10-Phenanthroline (30 mg, 0.17 mmol) and K3PO4 (180 mg, 0.85 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (131 mg, 0.46 mmol) in toluene (5 mL) were charged and flushed with nitrogen. The reaction mixture was heated at 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get 9-chloro-6-((3-fluoro-4-methoxyphenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole which was further purified by prep TLC to get 24 mg of product. 1HNMR (CDCl3, freebase) δ (ppm): 7.40 (d, 2H), 7.30 (m, 2H), 7.20 (d, 1H), 6.95 (t, 1H), 3.90 (s, 3H), 3.10 (m, 2H), 2.90 (m, 6H), 2.50 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:26]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Cl-].[NH4+].Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:26])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2oc(-c3ccc(Br)cc3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc2oc(-c3ccc(Br)cc3)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 3.9 %

Procedure:
2-(4-bromophenyl)benzo[d]oxazole-4-carboxylic acid (0.075 g, 0.24 mmol) in dimethyl formamide (10 mL) was added HOBT (0.0425 g, 0.28 mmol), EDCI (0.0575 g, 0.3 mmol), DIPEA (0.097 g, 0.75 mmol) and ammonium chloride (0.0133 g, 0.25 mmol). The reaction mixture was stirred at room temperature for 20 hr, cooled and poured into water (10 mL). The solution was acidified to pH=3 with 1N aqueous hydrochloric acid. Then the solution was extracted with dichloromethane (70 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, condensed in vacuum and separated by silica gel chromatography (ethyl acetate:methanol=1:0 to 10:1) to afford 2-(4-bromophenyl)benzo[d]oxazole-4-carboxamide as a solid (0.003 g, yield 4.15%). LC-MS (ESI) m/z 319 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](NC2C=CC(S(CC)(=O)=O)=C(C#N)C=2)=[O:12])=[C:4](C)[CH:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([S:37]([C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:39])=[O:38])=[C:33]([CH:36]=1)[C:34]#[N:35].BrC1C=CC(CCCC(Cl)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([S:37]([C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:39])=[O:38])=[C:33]([C:34]#[N:35])[CH:36]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)(=O)c1ccc(N)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2C)cc1C#N
Agent: O=C(Cl)CCCc1ccc(Br)cc1
Product: CC(C)(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Yield: 100 %

Procedure:
Using a procedure analogous to that used to prepare 8B, 10B (250 mg, 1.05 mmol) was reacted with 4-(4-bromophenyl)butyric acid chloride to give 10C (493 mg, 100%). MS (ESI) m/z 461.2, 463.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:12][CH2:13][C@@H:14]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]#[N:24])=[O:17])[NH2:15])([CH3:11])([CH3:10])[CH3:9].[CH2:25]([O:27][C:28](Cl)=[O:29])[CH3:26].C(N(CC)CC)C>ClCCl>[C:8]([S:12][CH2:13][C@@H:14]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]#[N:24])=[O:17])[NH:15][C:28]([O:27][CH2:25][CH3:26])=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)SC[C@H](N)C(=O)N1CCC[C@H]1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H](CSC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Yield: 34.1 %

Procedure:
A solution of (2S)-1-(S′-tert-butylcysteinyl)pyrrolidine-2-carbonitrile trifluoroacetate (1000 mg, 0.27 mmol; prepared according to Jenkins et al., WO95/15309), ethylchloroformate (35 mg, 0.32 mmol) and triethylamine (50 mg, 0.50 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60–80° C.; 8:2) yielding a white solid identified as the title compound (30 mg, 0.092 mmol, 35%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]2[C:13]3([CH3:17])[C:14]([CH3:16])([CH3:15])[CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]([O:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25].CC([O-])(C)C.[K+].C(OCC)C>C1COCC1.CC(O)(C)C.O>[OH:25][CH2:24][C:23]([O:28][CH3:29])([O:22][CH3:21])[CH2:26][O:27][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]2[C:13]3([CH3:17])[C:14]([CH3:16])([CH3:15])[CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: COC(CO)(CO)OC
Reactant: CC12CCC(C(=O)C1=Cc1ccc(CBr)cc1)C2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: COC(CO)(COCc1ccc(C=C2C(=O)C3CCC2(C)C3(C)C)cc1)OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-bromomethylbenzylidene)-4,7,7-trimethylbicyclo[2.2.1]-heptan-2-one (C. Bouillon, C. Vayssie, in Ger. Offen., (Oreal S. A., Fr.). Appl: DE 19780314. 78-2811041, 1978, p. 71. C. Bouillon, C. Vayssie, in Fr. Demande, (Oreal S. A., Fr.), Fr, Number 2421878, 1979, p. 31. C. Bouillon, C. Vayssie, (Oreal S. A., Fr.). Ca, Number 1113480, 1981, p. 61) (10.0 g, 30 mmol) in THF (30 ml) is slowly added dropwise at 40° C. with stirring to a solution of 2,2-dimethoxy-1,3-propanediol (M. W. Chun, D. H. Shin, H. R. Moon, J. Lee, H. Park, L. S. Jeong, Bioorg. Med. Chem. Lett 1997, 7, 1475. E. Cesarotti, P. Antognazza, M. Pallavicini, L. Villa, Helv. Chim. Acta 1993, 76, 2344. E. L. Ferroni, V. DiTella, N. Ghanayem, R. Jeske, C. Jodlowski, et al., J. Org. Chem. 1999, 64, 4943) (8.17 g, 60 mmol) and t-BuOK (4.50 g, 40 mmol) in t-BuOH (150 ml). E is stirred at 40° C. for 30 min and subsequently at the reflux temperature for 1 h. After the reaction mixture has been cooled, diethyl ether (30 ml) and water (100 ml) are added. The organic phase is separated off, and the aqueous phase is extracted with diethyl ether (3×50 ml). The combined organic phases are washed with saturated sodium chloride solution (3×70 ml) and dried over magnesium sulfate; the solvent is removed. Work-up by column chromatography using ethyl acetate:cyclohexane 1:1 gives
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([OH:18])[C:9]=2[C:10](=[O:12])[CH:11]=1)([O:3]CC)=[O:2].O>C(O)(=O)C>[C:1]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([OH:18])[C:9]=2[C:10](=[O:12])[CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cc(=O)c2c(O)c(Cl)ccc2o1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(=O)c2c(O)c(Cl)ccc2o1

Procedure:
2-carboethoxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran is dissolved in glacial acetic acid and water (5:1) and the solution refluxed for 4 hours. This is cooled and the resulting solid collected and washed with water to give 2-carboxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[F:57][C:58]([F:73])([F:72])[C:59]1[CH:71]=[CH:70][CH:69]=[CH:68][C:60]=1[O:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[O:27]=[C:25]([N:65]1[CH2:64][CH2:63][CH:62]([O:61][C:60]2[CH:68]=[CH:69][CH:70]=[CH:71][C:59]=2[C:58]([F:57])([F:72])[F:73])[CH2:67][CH2:66]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 58.7 %

Procedure:
DIPEA (154 mg, 1.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (100 mg, 0.4 mmol) in DMF (2.0 mL) followed by HOBt (60 mg, 0.49 mmol) and EDCI.HCl (93 mg, 0.49 mmol). After 2 minutes of stirring, 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoroacetate (167 mg, 0.49 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine and concentrated to afford 111 mg (57.81% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 473.17, 97.38%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.1 (bs, 1H), 7.9-7.3 (m, 8H), 7.2-7.0 (m, 2H), 4.9 (bs, 1H), 4.2 (m, 2H), 3.8-2.9 (m, 4H), 2.0-1.7 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:46])[C:3]([C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][CH:45]=1)[O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N+:23]([O-])=O)=[C:11]([O:26][C:27]2[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:10]=1)=[O:4].Cl>[Zn].C1COCC1>[CH3:1][N:2]([CH3:46])[C:3]([C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][CH:45]=1)[O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([NH2:23])=[C:11]([O:26][C:27]2[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=2[O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:10]=1)=[O:4]
Reactant: CN(C)C(=O)c1cccc(Oc2nc(NCc3ccccc3)c([N+](=O)[O-])c(Oc3cc(C#N)ccc3OCc3ccccc3)n2)c1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(Oc2nc(NCc3ccccc3)c(N)c(Oc3cc(C#N)ccc3OCc3ccccc3)n2)c1
Temperature: 80 °C

Procedure:
2-(3-Dimethylaminocarbonylphenoxy)-4-benzylamino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (H) (0.29 g, 0.47 mmol) and 0.1 g granular zinc were mixed with 10 mL THF and 1.0 mL 10% aqueous HCl. The reaction was heated at 80° C. for 90 minutes. The volatiles were evaporated. Saturated aqueous NaHCO3 was added and the solution extracted with ethyl acetate (300 ml). The organic layer was dried (Na2SO4) and evaporated to afford 0.27 g of 2-(3-dimethylaminocarbonylphenoxy)-4-benzylamino-5-amino-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (J).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.180 g, 0.226 mmol) in 4 mL of DCM at 0° C. was added TFA (1 mL). The mixture was stirred for 1 hour at 0° C. for 3 hours then concentrated in vacuo. The residue was partitioned between EtOAc (20 mL) and saturated NaHCO3 solution (20 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo to afford the desired product as a yellow gum, 0.157 g, 100%.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:12][CH:8]([CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH:10]=[CH2:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C=CCC(O)COc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-(4-fluorophenoxy)-1-penten-4-ol (9.81 g., 0.05 mole) in dry dimethylformamide (15 ml.) is added dropwise to a stirred suspension of hexane (2 × 10 ml.)--prewashed sodium hydride (50% dispersion in mineral oil, 2.64 g., 0.055 mole) in dry dimethylformamide (45 ml.) at 25° C. Upon cessation of gas evolution, the reaction mixture is cooled to 0°-5° C. and treated with a solution of benzyl bromide (10.3 g., 0.06 mole) in dry dimethylformamide (10 ml.). The resulting mixture is stirred at 25° C. for 16 hours, then heated at 100° C. for 1 hour. After cooling to 25° C., the reaction mixture is diluted with ice water (50 ml.) and extracted with ether four times. The combined organic extract is washed with 2 N hydrochloric acid and saturated aqueous brine, dried over magnesium sulfate and filtered. In vacuo evaporation of the filtrate leaves an oily residue which affords the title compound upon distillation as a colorless oil (13.1 g., 92%), bp0.025 112°-116° C.; pmr (CCl4) δ2.37 (2H, t), 3.5-4.0 (3H, m), 4.57 (2H, s), 4.8-5.05 (H, m), 5.05-5.25 (H, m), 5.4-6.2 (H, m), 6.6-7.1 (4H, m) and 7.19 (5H, s).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=[O:10].[OH-:28].[Na+]>>[CH:9]([NH:8][C:7]1[C:6](=[O:11])[C:5]2[CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:4]=2[O:3][C:2]=1[OH:28])=[O:10]
Reactant: [OH-]
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Agent: [Na+]
Product: CS(=O)(=O)Nc1cc2oc(O)c(NC=O)c(=O)c2cc1Oc1ccccc1

Procedure:
2-Bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with 1N aqueous sodium hydroxide solution to obtain 3-formylamino-2-hydroxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.Br[CH2:30][C:31](Br)=[O:32]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11]3=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]3[C:31](=[O:32])[CH2:30]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Br)CBr
Reactant: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)c2nc3ccccc3n21
Temperature: 25 °C
Yield: 8.4 %

Procedure:
A mixture of N-(4-nitrophenyl)-1H-benzimidazol-2-amine (947 mg) and N,N-diisopropylethylamine (1.45 g) in THF (10 mL) at −78° C. was treated dropwise with a solution of bromoacetyl bromide (826 mg) in THF (2.0 mL) then the resulting mixture was allowed to warm to ambient temperature overnight. After this time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were washed with brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 2:3 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-1,2-dihydro-3H-imidazo[1,2-a]benzimidazol-3-one (92 mg) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:36]([C:35]1[C:31]([O:30][CH2:2][C:3]2[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]4)[S:12][C:13]=3[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=2)=[N:32][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=1)=[O:37]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(CCl)cc3OC)c(C)s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)s2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A mixture of ethyl 1-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (0.40 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.18 g), anhydrous potassium carbonate (0.13 g), and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-(4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (0.37 g, yield 69%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]2[C:10]([Cl:16])=[C:11]([Cl:15])[C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC.CCOCC.O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:14][C:12]1[C:11]([Cl:15])=[C:10]([Cl:16])[C:8]2[S:9][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][C:7]=2[CH:13]=1)[CH3:23]
Reactant: CCCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc2cc(OCC(=O)OCC)c(Cl)c(Cl)c2s1

Procedure:
A mixture of 2-n-butyl-6,7-dichloro-5-hydroxybenzo[b]thiophene, 3.6 g of ethyl bromoacetate, 3.2 g of potassium carbonate and 4 ml dimethylformamide in 50 ml of 2-butanone is refluxed for 20 hrs. The cooled mixture is poured into 100 ml water and 100 ml ether. The layers are separated and the aqueous layer is extracted with two 100-ml portions of ether. The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization from ether-hexane gives 4.1 g of ethyl[(2-n-butyl-6,7-dichlorobenzo[b]thien-5-yl)oxy]acetate, mp 72°-73°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[CH:6]=[C:5]2[S:14]([CH3:16])=O.C(=O)(O)[O-].[Na+].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:6]1[N:7]([CH2:11][C:12]#[N:13])[C:8]2[C:4]([C:5]=1[S:14][CH3:16])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O=S(Cl)Cl
Reactant: CS(=O)c1cn(CC#N)c2ccc(Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1c(Cl)n(CC#N)c2ccc(Cl)cc12
Yield: 71.7 %

Procedure:
Following a procedure similar to that reported by Greenhouse et al., J. Org. Chem. 53 (1988) 2634, a solution of (5-chloro-3-methanesulfinyl-indol-1-yl)-acetonitrile (0.851 g, 3.38 mmole) in methylene chloride (85 ml) was cooled to 0° C. and solid sodium bicarbonate (3.66 g) was added. Thionyl chloride (0.422 g, 3.55 mmole) was dissolved in methylene chloride and added dropwise over a 45 minute period. Upon termination of addition, the reaction mixture was stirred an additional 15 m. Tlc analysis revealed the presence of a small amount of starting material. Additional thionyl chloride was added, one drop at a time until tlc analysis revealed the total consumption of starting material. When no more starting material was present, the entire reaction mixture was poured onto a short silica gel column and the product was eluted with methylene chloride and isolated by evaporation of the solvent to afford 0.657 g (72%) pure (2,5-dichloro-3-methylsulfanyl-indol-1-yl)-acetonitrile.