Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:24]=CC=C[CH:20]=1.[PH4+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCCCCC.C1(C)C=CC=CC=1>[CH2:19]([CH:24]=[CH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2ccccc12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC=Cc1cccc2ccccc12
Yield: 63 %

Procedure:
1-(ethyl)-2-(naphthyl)ethylene (IXd) was prepared from 1.00 g (2.7 mmol) of (ethyl)triphenylphosphonium bromide (Vd), 0.42 g (2.7 mmol) of naphthaldehyde and 0.79 g (5.5 mmol) of anhydrous K2CO3 by ball-milling for 26 hours. The formed powder was analyzed by the solid state 31P MAS NMR spectroscopy. The solid state 31P MAS NMR spectrum of the ball-milled powder contained two signals: a major signal corresponding to triphenylphosphine oxide at δ31P=25 ppm and a minor signal corresponding to the starting phosphonium salt at δ31P=30 ppm, the estimated ratio ˜8:1. The powder (2.0 g) was loaded on the top of a silica-gel filled chromatographic column, and the mixture of (E)- and (Z)-isomers was isolated by eluation with a hexane-toluene mixture (E:Z ratio ca. 1:1 by 1H NMR in CDCl3) in the 63% yield, (0.26 g). Triphenylphosphine oxide was further obtained from the same column in 80% yield (0.61 g) using a hexane-acetone mixture as an eluant. Assignment of the signals in the 13C and 1H NMR spectra of the reaction products was performed according to the literature (see, e.g., Kulasegarm, et al., J. Org. Chem. 62, 6547 (1997); Kulasegarm et al., Tetrahedron 54, 1361(1998)).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][C:11]1=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O:20]CC)C.O>O1CCCC1>[C:3]([O:7][C:8]([NH:10][C:13]1([CH2:12][C:11]([OH:17])=[O:20])[CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC12CCC2
Reactant: CCOCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Reaction time: 2 h

Procedure:
An 1 N aqueous solution of lithium hydroxide (227 ml, 227 mmol) was added to a solution of 2-oxo-1-azaspiro[3.3]heptane-1-carboxylic acid tert-butylester (48 g, 0.227 mmol) in tetrahydrofuran (200 ml). The reaction mixture was stirred for 2 h. Diethyl ether (200 ml) and water (200 ml) were added. The mixture was stirred for 16 h. The organic layer was isolated. The aqueous phase was extracted with diethyl ether (200 ml). The aqueous phase was acidified with a 10% aqueous solution of sodium hydrogen sulfate until pH 3. The formed precipitation was filtered off, washed with water, and dried in vacuo, to give 38.84 g of (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=N)[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=1)([CH3:16])[CH2:9][CH2:8]2)(=O)C.Cl.C[O:35]CCO>>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:35])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=1)([CH3:16])[CH2:9][CH2:8]2
Reactant: COCCO
Reactant: CC(=O)Oc1cc2c(cc1C)OC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)CC2
Agent: Cl
Product: Cc1cc2c(cc1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
170 mg of 5-[4-(6-acetoxy-2,7-dimethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one (prepared as described in Example 5) were added to a mixture of 0.2 ml of 2N hydrochloric acid and 2 ml of ethylene glycol monomethyl ether, and the mixture was reacted at 95°-97° C. for 6 hours. It was then processed and purified as described in Example 1(a), except that the crude product, in the form of an oil, was subjected to column chromatography through silica gel, eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:13][O-].[Na+]>>[CH2:11]([O:10][C:1](=[O:9])[C:2]1[CH:8]=[C:7]([Cl:13])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH3:12]
Reactant: CCOC(=O)c1ccccc1N
Reactant: [O-]Cl
Agent: [Na+]
Product: CCOC(=O)c1cc(Cl)ccc1N

Procedure:
Prepared from ethyl anthranilate and sodium hypochlorite (according to M. Okabe and R-C Sun, Tetrahedron, 1995, 51, 1861) to give an off-white solid, mp 80° C., m/z 199.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](OCC3CC3)=[O:13])=[C:8]([CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[C:8]([CH3:19])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(OCC2CC2)ncc1C(=O)OCC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC2CC2)ncc1CO
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of cyclopropylmethyl 6-fluoro-4-methylpyridine-3-carboxylate (3.85 g, 18.4 mmol) obtained in Reference Example 319 and cyclopropylmethanol (1.75 mL, 22.1 mmol) in DMF (30 mL) was added 60% sodium hydride (883 mg, 22.1 mmol) under ice-cooling. After stirring for 30 min, the mixture was stirred at room temperature for 10 min. The reaction was quenched with ice, and the mixture was extracted with ethyl acetate, washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give cyclopropylmethyl 6-(cyclopropylmethoxy)-4-methylpyridine-3-carboxylate (4.54 g, 94%) as an oil. To a solution of the obtained cyclopropylmethyl 6-(cyclopropylmethoxy)-4-methylpyridine-3-carboxylate (4.54 g, 17.4 mmol) in THF (100 mL) was added lithium aluminum hydride (989 mg, 26.1 mmol) under ice-cooling, and the mixture was stirred for 30 min. To the reaction mixture was slowly added sodium sulfate decahydrate, and the mixture was filtered through celite. The filtrate was concentrated, the residue was dissolved in ethyl acetate, and the solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to give the title compound (2.87 g, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][OH:10])[O:8][C:4]=2[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15].O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([C:9]([OH:15])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuran (10.4 gm.) in acetone (200 ml.) cooled to 20° C. is added an oxidizing solution prepared from chromium trioxide (6.0 g.), concentrated sulfuric acid (5.3 ml.) and water (43 ml.) over a one-half hour period. The reaction mixture is stirred at 25° C. for 18 hours. The acetone layer is separated from the precipitated chromium salts, added to water (600 ml.) and extracted with ether (2×150 ml.). The ether extract is washed with water then extracted with aqueous sodium bicarbonate. Acidification of the basic solution gives 3.4 g. of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid which is purified by reprecipitation from aqueous sodium hydroxide with aqueous hydrochloric acid.
Reaction SMILES: CCCC[N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11]O)=[S:7].Cl>[OH-].[Na+]>[CH2:18]([C:16]1[CH:15]=[CH:14][C:13]([N:5]=[C:6]2[NH:8][CH2:9][CH2:10][CH2:11][S:7]2)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN(C(=S)NCCCO)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ccc(N=C2NCCCS2)cc1
Yield: 174.1 %

Procedure:
A mixture of 18.0 g (0.068 mol) of N-4-n-butylphenyl-N'-3-hydroxypropylthiourea and 20 ml of 12N HCl is heated under reflux for 1 hour. After cooling, the mixture is basified with 100 ml of 4N NaOH and extracted with chloroform. The extract is dried and concentrated; and the resulting residue is recrystallized from hexane to give 14.7 g (yield: 88%) of 2-[(4-n-butylphenyl)imino]-3,4,5,6-tetrahydro-2H-1,3-thiazine, m.p. 77°~78.5° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:13])=[C:7]([Cl:23])[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[C:25]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)#[N:26]>>[Cl:23][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([C:25]#[N:26])[CH2:28][CH2:29]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13]
Reactant: O=C(NCCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: N#CC1CCNCC1
Agent: Cl
Product: N#CC1CCN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 28.3 %

Procedure:
Prepared according to the method of example 51, using 2,6-dichloro-N-(cyclohexylethyl)-5-quinolinecarboxamide (Example 94 (d)) (0.35 g), and 4-cyanopiperidine hydrochloride (0.25 g) to afford the title compound (0.12 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8](C)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](I)C>>[CH3:19][N:2]([CH3:1])[C:3]([C:4]1([N:5]2[CH:9]=[CH:8][C:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:6]2)[CH2:17][CH2:20]1)=[O:18]
Reactant: CCI
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Product: CN(C)C(=O)C1(n2ccc(-c3ccccc3)n2)CC1

Procedure:
Following the procedure of Example 95, but substituting α-(2-chloroethyl)-N,N-dimethyl-3-phenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and without addition of ethyl iodide there was obtained N,N-dimethyl-1-(3-phenylpyrazol-1-yl)cyclopropanecarboxamide having a melting point of 96°-99° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31](OS(C(F)(F)F)(=O)=O)[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]2)[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Yield: 6 %

Procedure:
Using 3-(tert-butoxycarbonylamino)piperidine (301 mg, 1.50 mmol) and methyl 3-benzyloxy-5-(trifluoromethanesulfonyloxy)benzoate (595 mg, 1.52 mmol), the same procedure was followed as in Example 58 to give 39.7 mg (6.0%) of the desired compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:24][CH:21]2[CH2:23][CH2:22]2)=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: NC1CC1
Product: COc1ccc(C(=O)NC2CC2)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and cyclopropylamine in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=O)[C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C12CCOCC2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)NCC21CCOCC1
Temperature: 80 °C

Procedure:
A heterogeneous mixture of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one (3.5 g, 12.4 mmol) in toluene (25 mL) was stirred at 80° C. To the heated mixture was added a solution of Red-Al (65% in toluene, 11.6 mL, 37.2 mmol) and the mixture was stirred at 80° C. for 50 min. After this time the mixture was cooled to 0° C. and quenched with a 2 N solution of aqueous NaOH (31 mL, 62 mmol). The mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (3×100 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The resulting residue was purified by column chromatography (0 to 100% gradient of DCM-MeOH—NH4OH (89:9:1) in DCM) to give 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] as a yellow solid. Mass Spectrum (ESI) m/e 268 [(M+1) (79Br)] and 270 [(M+1) (81Br)].
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].O.C(Cl)[Cl:23]>>[Cl:23][C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([CH2:5][OH:4])[CH:7]=2)[O:12][CH:13]=1
Reactant: ClCCl
Reactant: CC(=O)OCc1cc2ccoc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1cc2c(Cl)coc2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethyl acetate (956 mg, 5 mmol) is dissolved in CH2Cl2 (40 mL) and cooled to 0° C. Chlorine gas is bubbled through the solution for 15 min, the cooling bath is immediately removed and the mixture stirred for 2 h. The mixture is re-cooled to 0° C., saturated with chlorine gas, the cooling bath removed and the solution warmed to rt. The solution is layered with saturated NaHCO3 (20 mL), stirred gently for 2 h then stirred vigorously for 15 min. The mixture is diluted with saturated NaHCO3 (50 mL), extracted with CH2Cl2 (1×40 mL then 1×20 mL), dried over K2CO3 and concentrated to a volume of 20 mL under a stream of nitrogen. The solution is diluted with EtOH (35 mL), treated with K2CO3 (4.09 g, 29.6 mmol) and stirred for 18 h at rt. Water (7 mL) is added and the mixture stirred for 2 days. The mixture is concentrated to dryness, partitioned between 50% saturated NaCl (50 mL) and CH2Cl2 (4×50 mL), dried over K2CO3 and concentrated in vacuo to a brown solid (833 mg). The crude material is chromatographed over a standard 40 g Biotage column, eluting with 50% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 624 mg (68%) of (3-chlorofuro[2,3-c]pyridin-5-yl)methanol as a yellow oil. 1H NMR (DMSO-d6): δ 4.69, 5.56, 7.69, 8.55, 8.93 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](P(=O)(OCC)OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution containing 164 mg of 5-(3,5-dichloro-phenylsulphanyl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 103 mg of diethyl benzylphosphonate and 27 mg of sodium hydride (60% in mineral oil) in 5 ml of anhydrous tetrahydrofuran was stirred under nitrogen at rt for 16 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°–60° C. (1:10) for the elution to give 162 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole as a pale yellow solid. Mass spectrum (EI) m/z 436 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[Si]([O:21][CH2:22][C@@H:23](/[N:28]=[CH:29]/[C:30]([F:33])([F:32])[F:31])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C)C>CCOCC>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C@H:29]([NH:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:21])[C:30]([F:32])([F:31])[F:33])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloropyridine (2.5 g, 13 mmol) in ether (30 mL) at −78° C. was added n-butyllithium (13 mmol, 2.5 M in hexane). The mixture was stirred at −78° C. for 1 h. (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (3.64 g, 11.7 mmol, see Step 2, Example 8) was added. The mixture was stirred at −78° C. for 2 h. Saturated aqueous NH4C1 was added to the reaction mixture and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil (5.3 g). The crude oil (2.0 g) was then treated with (Bu)4NF (6 mL, 1M in THF). The mixture was stirred at rt for 1 h, saturated aqueous NH4C1 was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil. Chromatography (20% EtOAc/hexane) afforded the title compound.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(CC)CC)C.[Cl-].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.Cl>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:22]([O:33][CH3:34])=[O:32])=[CH:24][CH:25]=1)=[O:28])#[N:10]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: Br
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reaction time: 3 h

Procedure:
1.50 g (6.2 mmol) of 3-(2-aminoethoxy)benzonitrile hydrobromide and 3 ml of triethylamine were stirred in 15 ml of dimethylformamide under cooling with ice. 1.23 g (6.2 mmol) of monomethyl terephthalate chloride was slowly added thereto, and they were stirred for 3 hours. The temperature was elevated to the room temperature, and the reaction liquid was diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)(=[O:16])=[O:15])[C:5]([Cl:29])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][C:11]2[CH:26]=[CH:27][CH:28]=[C:9]([NH:8][C:6]3[C:5]([Cl:29])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 90 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzenesulfonamide (50.0 mg, 0.11 mmol) in water (0.08 mL), methanol (0.42 mL) and acetic acid (0.17 mL) was added iron (15 mg, 0.28 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 3 h and the reaction was complete. The mixture was filtered and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a light brown powder (42 mg, 90%). LCMS for C17H15Cl2N5O2S (M+H)+: m/z=424.0, 426.0, 428.0. 1H NMR (400 MHz, CD3OD): δ 8.22 (t, J=2.0 Hz, 1H), 8.52 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.48 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (m, 1H), 7.20 (t, J=8.0 Hz, 1H), 7.08 (ddd, J=8.4, 2.0, 1.2, 1H), 6.84 (ddd, J=8.0, 1.6, 1.2, 1H), 4.21 (s, 2H).
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:31]1([CH2:30][CH2:29][CH2:28][NH:27][C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:2])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCCN1CCCCC1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)NCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 125.7 %

Procedure:
To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially 1-amino-3-(piperidin-1-yl)propane (500 mg, 1.1 eq), 1-hydroxybenzotriazole (475 mg, 1.1 eq), and dicyclohexylcarbodiimide (726 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 2.00 grams of a semi-solid material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](O)=[O:11]>C1COCC1>[OH:11][CH2:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of indole-2-carboxylic acid (485 mg, 3.01 mmol) in THF (20 mL), cooled to 0° C. under nitrogen, was added a suspension of LiA1H4 (248 mg, 6.2 mmol) in THF (6 mL). The resultant green suspension was stirred at room temperature for 4 hours. The reaction was quenched by slow addition of an 80% aqueous MeOH solution (1.0 mL) and the solvent was evaporated under reduced pressure. The residue was suspended in MeOH and filtered through Celite, rinsing with MeOH. Concentration of the filtrate under reduced pressure gave a yellow oil. Purification by flash column chromatography on silica (MeOH/CH2Cl2, 19:1 then 9:1) gave the alcohol as a beige solid (357 mg, 2.43 mmol, 81%). 1H NMR (CDCl3) δ 1.85 (t, 1H, J=6.0 Hz), 4.83 (d, 2H, J=6.0 Hz), 6.42 (d, 1H, J=1.5 Hz), 7.11 (td, 1H, J=6.9, 1.5 Hz), 7.20(td, 1H, J=6.9, 1.5 Hz), 7.35 (dd, 1H, J=6.9, 1.5 Hz), 7.59(d, 1H, J=6.9 Hz), 8.33 (br s., 1H).