Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:5][C:6](=O)[C:7]=1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To a suspension of methyl 2-(4-methyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (5.97 g; 19.42 mmol) in dry toluene (40 mL) under nitrogen atmosphere were carefully added phosphorus oxychloride (18.05 mL; 194 mmol) and dimethylaniline (1.961 mL, 15.54 mmol). The reaction was heated to reflux for 3 h and after cooling at room temperature, the volatiles were removed under reduced pressure and the remaining residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The product was extracted twice with ethyl acetate and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 2.45g (39%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH2:37]([NH2:41])[CH2:38][CH2:39][CH3:40]>>[CH2:37]([NH:41][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:38][CH2:39][CH3:40]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CCCCN
Product: CCCCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with n-butylamine.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][N:29]1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[N:32]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:31][CH2:30]1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@@H:22]4[CH2:23][C:24](=[O:27])[NH:25][CH2:26]4)[CH3:21])=[CH:10][C:11]([C:13]4[CH:18]=[C:17]5[C:16]([N:29]([CH3:28])[CH2:30][CH2:31][N:32]5[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: C[C@@H](Oc1cc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCN3C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 45.6 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-phenyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead tert-butyl 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (92.0 mg, 0.24 mmol) as a starting material to afford 40.0 mg (45.6%) of tert-butyl 7-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-4-methyl-3,4 dihydroquinoxaline-1(2H)-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H37N5O4:531.28; found 532.23.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.[ClH:33]>N1C=CC=CC=1.C(O)C>[ClH:33].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:28](=[O:29])[CH:23]5[CH:22]([CH2:27][CH2:26][CH2:25][CH2:24]5)[C:31]4=[O:30])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1C2CCCCC2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229-231° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-butylaniline to yield 2-[(4-butylphenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[OH:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([NH:36][O:37][CH3:38])=[O:35])=[CH:32][C:31]=1[O:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>>[CH3:42][O:41][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:30]=1[O:29][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1)[C:34]([NH:36][O:37][CH3:38])=[O:35]
Reactant: CONC(=O)c1ccc(O)c(OC)c1
Reactant: NS(=O)(=O)c1cccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CONC(=O)c1ccc(Oc2nc(C(F)(F)F)nc(-c3ccc(F)cc3)c2-c2cccc(S(N)(=O)=O)c2)c(OC)c1

Procedure:
A suspension of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.15 g, 0.35 mmol), 4-hydroxy-N,3-dimethoxybenzamide (0.102 g, 0.52 mmol) and potassium carbonate (0.52 mmol) in acetonitrle (3 ml) were heated to relfux (65° C.) for 2 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with dichloromethane (50 ml) and washed with brine. Evaporation of the organic layer furnished a crude material, which was purified by column chromatography; elution with 2% MeOH in dichloromethane furnished the required compound. 1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.79 (s, 3H), 7.16-7.20 (m, 2H), 7.37 (d, 1H), 7.41-7.45 (m, 5H), 7.53 (s, 1H), 7.62-7.63 (d, 2H), 7.85 (d, 1H), 7.89 (s, 1H). 11.9 (s, 1H); MS m/z: 593 (M++1).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Br:16])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:17])=[O:5]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A cooled (0° C.) solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (1.00 g; 3.11 mmol) in DCM (22 mL) was treated with trifluoroacetic acid (2.38 mL; 31.1 mmol). The reaction mixture was stirred at room temperature for 5 hours, the solvents were removed under vacuum to give the title compound (825 mg, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O>[CH:22]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([CH3:24])[CH3:23]
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc3c(cnn3C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 2-iodopropane (0.090 mL, 0.15 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 1-isopropyl-5-(4-methoxy-phenoxy)-1H-indazole (90 miligrams) MS: 283.4 [M+H]+ and 2-isopropyl-5-(4-methoxy-phenoxy)-2H-indazole MS: 283.4 [M+H]+ (75 miligrams) as colorless syrup.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:12]([F:20])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N(Cl)C(OCC)=O>>[C:1]([C:5]1[O:6][C:7]2[C:13]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:12]([F:20])[CH:11]=[C:10]([Cl:21])[C:8]=2[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)Nc1c(F)ccc2nc(C(C)(C)C)oc12
Reactant: CCOC(=O)N(Cl)Cl
Product: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)C)oc12

Procedure:
The second starting material used to prepared those compounds in which the benzoxazole ring is formed first is a substituted-3-chloroaniline (STM2). The aniline (STM2) is reacted with the appropriate alkyl anhydride, for example trimethylacetic anhydride, under acidic conditions, yielding the corresponding N-(substituted-3-chlorophenyl)alkylamide (B-1). The aniline (STM2) can also be reacted with the appropriate propanoic acid (A-2), for example 2-methoxy-2-methylpropanoic acid, under basic conditions to form the appropriate N-(substituted-3-chlorophenyl)-substituted-alkylpropion-amide (B-2), for example N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methyl-propionamide. The amides (B-1 or B-2) are in turn treated with n-butyl-lithium and cyclized with solid carbon dioxide, affording the corresponding [2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carboxylic acid (C), for example, (2-t-butyl-6-fluorobenzoxazol-7-yl)carboxylic acid. The so-prepared carboxylic acid (C) is then reacted with ethyl chloroformate, 4-methylmorpholine, and sodium azide, yielding the corresponding [2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carbonyl azide (C-1), which is treated with ethanol to form the corresponding ethyl N-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carbamate (D). Additional substituents may optionally be added to the benzoxazole ring at this point. For example, ethyl N-(2-t-butyl-6-fluorobenzoxazol-7-yl)carbamate (D) is treated with N,N-dichlorourethane under acidic conditions, affording ethyl N-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)carbamate (E). The carbamates D and E are then reacted with ethyl 3-amino-4,4,4-trifluorocrotonate, sodium methoxide, and DBU to form the corresponding 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-6-trifluoromethyl-2,4-(1H,3H)-pyrimidine-dione (F). The pyrimidinedione (F) is further reacted under basic conditions with an alkyl halide, for example methyl iodide, or O-(2,4-dinitrophenyl)hydroxylamine, or 1-aminooxysulfonyl-2,4,6-trimethylbenzene, affording the targeted 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (I) or 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-1-amino-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (II). Examples 1, 2, 4, and 5 provide the detailed procedures for this route.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(O)(C)C.C(=O)=O.C([Li])CCC.[N:26]1([CH2:32][CH:33]2[CH2:36][C:35](=[O:37])[CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]C1>C1COCC1>[N:26]1([CH2:32][CH:33]2[CH2:36][C:35]([C:2]3[CH:13]=[CH:12][C:5]([CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=3)([OH:37])[CH2:34]2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Brc1ccc(CN2CCCC2)cc1
Reactant: O=C1CC(CN2CCCCC2)C1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OC1(c2ccc(CN3CCCC3)cc2)CC(CN2CCCC2)C1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a stirring solution of 1-(4-Bromo-benzyl)-pyrrolidine (Lednicer, Daniel; Lyster, Stanley C.; Duncan, Gordon W. Mammalian antifertility agents. IV. Basic 3,4-dihydronaphthalenes and 1,2,3,4-tetrahydro-1-naphthols. Journal of Medicinal Chemistry (1967), 10(1), 78–84, J. Org. Chem; EN; 46; 17; 1981; 3571–3574) (0.71 g, 2.96 mmol) in THF (13 mL) at −78° C. (isopropanol/CO2) was added a solution of n-butyl lithium (1.6 mL, 3.93 mmol, 2.5 M hexanes). After 15 minutes a pre-cooled (−78 □C) solution of 3-pyrrolidin-1-ylmethyl-cyclobutanone (Intermediate 6, General procedure B Step C) (0.2 g, 1.3 mmol, in 3 mL THF) was added down the side of the flask. After TLC analysis indicated complete consumption of starting material the reaction was quenched cold by the addition of a saturated solution of NH4Cl. The reaction was then warmed to room temperature and diluted with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were discarded. The aqueous layer was then extracted with 3:1 (CHCl3:isopropyl alcohol) and the combined organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. The material was purified by trituration using ether:hexanes to yield the title compound (0.24 mg, 58% yield) as a colorless solid and a mixture of cis:trans isomers.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (12) (234 mg, 0.52 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise. The reaction mixture was stirred at rt for 1 h before concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride (0.3% Et3N)) to give 6-amino-9-(3-aminophenyl)-7-(4-chlorophenyl)-7H-purin-8(9H)-one as a brown solid (13) (180 mg, 98.9%). LC-MS (ESI): m/z (M/M+2) 353/355.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:63]=[CH:62][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:54]=1)[CH2:37]2>O>[CH3:43][O:42][C:41]1[C:33](=[O:32])[C:34]2[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:63]=[CH:62][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:54]=3)[CH2:37][C:38]=2[C:39](=[O:46])[C:40]=1[O:44][CH3:45]
Reactant: CCOC(=O)c1ccc(OCCCCC2Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCCCCC2CC3=C(C2)C(=O)C(OC)=C(OC)C3=O)cc1
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
A water (1.0 ml) solution of CAN (299 mg, 0.545 mmols) was dropwise added to an acetonitrile (2.0 ml) solution of ethyl 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoate (100 mg, 0.218 mmols), with cooling with ice, and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 8:1) followed by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (45.0 mg) as crystals.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[OH:12][CH:13]([CH3:19])[C:14]([CH3:18])([CH3:17])[C:15]#[N:16]>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:12][CH:13]([CH3:19])[C:14]([CH3:18])([CH3:17])[C:15]#[N:16]
Reactant: CC(O)C(C)(C)C#N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CC(Oc1cc(F)ccc1N)C(C)(C)C#N

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and 3-hydroxy-2,2-dimethyl-butanenitrile.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.C1COCC1.[Pd]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Yield: 67.5 %

Procedure:
To a solution of 2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine (2.55 g) in ethanol (100 mL) and THF (25 mL) is added Pd/C (5%, 0.253 g), the mixture is stirred under 60 psi of hydrogen overnight. The catalyst is filtered off, concentration of the filtrate gave the title compound (1.25 g, 67.5%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([S:32][CH3:33])=[N:25][C:26]([CH3:31])=[CH:27][C:28]=2[S:29][CH3:30])=[O:21])[CH2:15][CH2:14]1.B1([O-])O[O:35]1.O.O.O.O.[Na+]>C(O)(=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([S:32][CH3:33])=[N:25][C:26]([CH3:31])=[CH:27][C:28]=2[S:29]([CH3:30])=[O:35])=[O:21])[CH2:17][CH2:18]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(C)cc(S(C)=O)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reaction time: 3 h
Yield: 7.1 %

Procedure:
To a solution of 2-[4-[2-(benzimidazol-2ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (1.00 g, 1.99 mmol) in acetic acid (20 ml) was dropped a solution of sodium perborate tetrahydrate (321 mg, 2.09 mmol) in acetic acid (30 ml), and the mixture was stirred for 3 hours. The reaction solution was concentrated in vacuo and the resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol 15:1) to provide 73 mg (yield 7%) of 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[4-methanesulfinyl-6-methyl-2-(methylthio)-3-pyridyl]acetamide as pale yellow oil. IR (KBr) cm−1: 3375, 2496, 1672, 1553, 1122. 1H-NMR (CD3OD) δ: 2.45 (3H, s), 2.51 (3H, s), 2.52-2.64 (8H,m), 2.70 (2H, t, J=6.8 Hz), 2.72 (3H, s), 3.04 (1H, d, J=16.1 Hz), 3.13 (1H, d, J=16.1 Hz), 3.30 (2H, t, J=6.8 Hz), 7.04-7.10 (2H, m), 7.32 (1H, s), 7.33-7.38 (2H, m), 7.78 (1H, s).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[C:1]([CH2:2][CH2:3][N:11]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: CCCCCCN
Reactant: C=CC#N
Product: CCCCCCN(CCC#N)CCC#N
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
20.1 g of acrylonitrile was added dropwise to an aqueous solution (150 ml) of 15.5 g of hexylamine at room temperature over 0.5 hours, and then the mixed solution was stirred at 70° C. for 3 hours. After standing to cool to room temperature, the mixed solution was extracted with 150 ml of ethyl acetate. The organic layer was separated from the solution, dried over anhydrous magnesium sulfate, and distilled off the solvent to obtain 31.4 g of a target compound as a colorless oily product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:26])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][N:18]=1)[CH:13]=[CH:12]2)(=O)=O.[CH3:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1.CN1C(=O)CCC1>O>[N:19]1[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[C:7]([N:32]4[CH2:33][CH2:34][CH2:35][CH:30]([CH3:29])[CH2:31]4)[C:8]([Br:26])=[CH:9][CH:10]=3)[N:15]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=12
Reactant: CC1CCCNC1
Reactant: O=S(=O)(Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1CCCN(c2c(Br)ccc3ccc(-c4nnc5ccccn45)nc23)C1
Temperature: 25 °C

Procedure:
The product from Step G (0.025 g, 0.0528 mmol) and 3-methylpiperidine (0.0186 mL, 0.158 mmol) were added to a small microwave reaction vial followed by NMP (0.250 mL). The vessel was placed inside the center of the microwave oven and then it was exposed to microwave irradiation (250 W) for 20 minutes at a temperature of 195° C. After the irradiation, the reaction mixture was cooled to ambient temperature, poured into 10 mL of water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with saturated brine and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by column chromatography on silica gel to give the product as a dark orange semisolid which was 80% pure. This material was purified via Preparative TLC using 50% Acetone/hexane as eluent to provide 0.005 g (22%) of the product as an orange film. MS ESI (+) m/z 422.3 (M) detected.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[O:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:50][N:51]=[C:52]=O)(=O)=O)=CC=1.O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:35][CH:52]=[N:51][CH:50]=3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2O)CCCCC1)c1cc2ccccc2o1
Yield: 100.9 %

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-ol (3 g, 6 mmol) obtained in Step 1 of Example 61, photassium carbonate (2 g, 20 mmol) and p-toluenesulfonylmethyl isocyanate (TosMIC; 1.8 g, 9 mmol) was refluxed in 500 ml of methanol for about 2 hours. 150 ml of water was added to the concentrated reaction mixture, which was then extracted with dichloromethane. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 3.2 g of the titled compound.