Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:38]=[CH:37][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:26]([F:36])=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[O:33]1[CH2:32][CH2:31][N:30]([C:27]2[C:26]([F:36])=[CH:25][N:24]=[C:23]([CH2:22][S:21]([C:19]3[NH:18][C:17]4[CH:37]=[CH:38][C:14]([O:13][CH3:12])=[CH:15][C:16]=4[N:20]=3)=[O:9])[C:28]=2[CH3:29])[CH2:35][CH2:34]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3ncc(F)c(N4CCOCC4)c3C)nc2c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(F)c(N4CCOCC4)c3C)nc2c1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
m-Chloroperbenzoic acid (0.48 g) in dichloromethane (10 ml) was added dropwise to a stirred solution of 5-methoxy-2-(4-morpholino-5-fluoro-3-methyl-2-pyridylmethylthio)-(1H)-benzimidazole (1.1 g) in dichloromethane (50 ml) at -30° to -35°. After 0.5 hour at -30° a further addition of m-chloroperbenzoic acid (0.048 g) in dichloromethane (2 ml) was made and the mixture stirred for a further 0.5 hour. After a further addition of m-chloroperbenzoic acid (0.048 g) in dichloromethane (2 ml) and after standing for a further 0.5 hour at -30°, ammonia gas was passed through the solution and the precipitated benzoate salts filtered off. The filtrate was evaporated to dryness and the residue crystallised from ethyl acetate to yield 2-(4-morpholino-5-fluoro-3-methyl -2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole (0.8 g) m.p. 158°-160°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32]C)[CH2:30]C.Cl.ClCl>ClCCl.CO>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:32]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1Cl

Procedure:
Prepared analogously to Example 3.7.c. from (4′-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-diethylaminoethoxy)phenylamine. Yield: 0.28 g (58% of theory); melting point: 226° C.-233° C.; C27H26Cl2N2O2 (M=481.41)*HCl; calc.: molecular ion peak (M+H)+: 481/3/5 (Cl2); found: molecular ion peak (M+H)+: 481/3/5 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[CH2:20][OH:21].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:22][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[CH:20]=[O:21]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(CO)c1CC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C=O)c1CC
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A mixture of 4.74 g (0.0145 mole) of the product of Example 96, 8.6 g (0.0336 mole) of pyridinium chlorochromate, and 70 ml of CH2Cl2 is held at room temperature for 18 hours. The CH2Cl2 solution is decanted and is chromatographed on silica gel using CH2Cl2 as eluent. The first 2 L eluate gives 3.93 g (83.4%) of the desired product as white solid, m.p. 63.5°-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][CH2:21][CH:22](P(OCC)(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:22]([CH2:21][CH3:20])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1OCCc1ccccc1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=Cc1ccc(OC)c(OCCc2ccccc2)c1)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-methoxy-3-(2-phenylethoxy)benzaldehyde (5.09 g), triethyl 2-phosphonobutyrate (10.76 g) and an aqueous solution of 6 M potassium carbonate (8.3 ml) was heated to 150° C. (oil bath temperature) and stirred vigorously for 8 hours. After the reaction mixture was cooled to room temperature, it was extracted with toluene. The toluene extract was washed with an aqueous solution of 0.5 N sodium hydroxide and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=25:1) to obtain 4.08 g of ethyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-ethylacrylate as a mixture of E- and Z-isomers (E-isomer:Z-isomer=5. 7:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2[S:13]CCC(OCC)=O)=[CH:4][CH:3]=1.[O-]CC.[K+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2[SH:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCSc1nnsc1-c1ccc(C)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(-c2snnc2S)cc1
Reaction time: 1.5 h
Yield: 123.4 %

Procedure:
A suspension of 13.8 g of 3-[[5-(4-methylphenyl)1,2,3-thiadiazol-4-yl]thio]propanoic acid, ethyl ester in 250 ml of dry ethanol was treated with 200 ml of 1M potassium ethoxide in ethanol. After standing 1.5 hours, the solvent was removed in vacuo to about 100 ml and 400 ml of anhydrous ether was added. The solid was collected, washed with ether, dissolved in methanol and filtered. The filtrate was concentrated to a small volume and then diluted with 400 ml of anhydrous ether. The solid was collected and dried in vacuo, giving 11.5 g of 5-(4-methylphenyl)1,2,3-thiadiazole-4-thiol, monopotassium salt as a yellow solid, mp>125° C. (dec.).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]=1[NH:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:3].[OH-].[K+].Cl>CO.O>[NH2:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[NH:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:3]
Reactant: CCOC(=O)c1ccc(C(N)=O)c(NC2CCCC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(C(=O)O)cc1NC1CCCC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A suspension of ethyl 4-(aminocarbonyl)-3-(cyclopentylamino)-benzoate (333 mg, 1.21 mmol) and potassium hydroxide (135 mg, 2.41 mmol) in methanol (6 mL) and water (2 mL) was stirred at 55° C. for 1 h. After cooling to room temperature, water was added and the pH adjusted to 4 with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to provide 4-(aminocarbonyl)-3-(cyclopentylamino) benzoic acid (260 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6): 13.02 (br s, 1H), 8.17 (d, 1H), 7.97 (br s, 1H), 7.66 (d, 1H), 7.34 (br s, 1H), 7.21 (d, 1H), 7.04 (dd, 1H), 3.81 (m, 1H), 1.99 (m, 2H), 1.64 (m, 4H), 1.42 (m, 2H). MS (EI) for C13H16N2O3: 249 (MH+).
Reaction SMILES: O[CH2:2][C@@H:3]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:47]=[C:45]1[C:44]2[C:43](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:42](=[O:52])[N:46]1[CH2:2][C@@H:3]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 1,1-dimethylethyl ((1S)-2-hydroxy-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate (4.2 g, 13.2 mmol), triphenylphosphine (4.5 g, 17.1 mmol) and phthalimide (1.9 g, 13.2 mmol) in THF (66 mL) at 25° C. was added diethyl azodicarboxylate (2.7 mL, 17.1 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue purified on silica gel (1% MeOH in DCM) affording the title compound (3.2 g, 54%) as a white solid: LCMS (ES) m/z 449 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH:7]([O:10][Si](C)(C)C)[C:8]#[N:9])([O-:3])=[O:2].CC[O:23]C(C)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH:7]([OH:10])[C:8]([NH2:9])=[O:23])([O-:3])=[O:2]
Reactant: C[Si](C)(C)OC(C#N)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Solvent: O
Product: NC(=O)C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
3,5-dinitro-O-trimethylsilylmandelonitrile (5.0 g, 16.9 mmol) and BF3-acetic acid complex (30 ml) were dissolved in H2O (5 ml) at room temperature. The reaction temperature was raised to 115° C. immediately and stirred for 10 minutes. The reaction solution was then cooled to 0° C. H2O (100 ml) and EtOAc (200 ml) were added. The organic phase was washed with sat NaHCO3 (100 ml) and brine (100 ml). Drying over MgSO4 was followed by removal of solvents at reduced pressure. The residue was crystallized from isopropylacetate. The crystalline residue was left for preparative HPLC, which gave 2.2 g (54%) of 3,5-dinitromandeloamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[CH:2]1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39](=[O:40])[N:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)([CH3:27])[CH3:28]
Reactant: CCCCCCCCc1ccc(NCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2c[nH]c3ccccc23)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 12.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(1H-indol-3-yl)methyl](4-octylphenyl)amine (0.61 g) and 2,6-diisopropylphenyl isocyanate (0.41 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(1H-indol-3-yl)methyl]-N-(4-octylphenyl)urea (0.12 g) was obtained.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>COCCOC>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:29]([C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:30])[CH:16]=1
Reactant: c1ccc2c(CCN=c3sc4ccccc4s3)c[nH]c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccc(Cl)cc1)n1cc(CCN=c2sc3ccccc3s2)c2ccccc21
Reaction time: 4 h

Procedure:
Sodium hydride (57% dispersion in mineral oil; 408 mg) is slurried in 10 ml of anhydrous 1,2-dimethoxyethane and treated dropwise with N-(1,3-benzodithiol-2-ylidene)-1H-indol-3-ethanamine (3g, prepared as described in Example 30) in 15 ml of anhydrous 1,2-dimethoxyethane. The reaction mixture is heated at reflux for 2 hours. A solution of p-chlorobenzoyl chloride (1.69g) in 10 ml of anhydrous 1,2-dimethoxyethane is added dropwise to the refluxing mixture. Refluxing is continued for an additional 4 hours. The reaction mixture is then poured into water (100 ml) and extracted with three 50 ml portions of dichloromethane. The combined dichloromethane extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (500 ml) eluting with dichloromethane/pentane (3:2). The fractions containing product with Rf =0.5 (silica gel; dichloromethane) are concentrated in vacuo. The solid thus obtained is recrystallized from hexane/dichloromethane to yield 2.1g of the title compound, melting point 135° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C@H:16]1[CH2:18][O:17]1.[Cl-].[NH4+]>O1CCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:15][C@@H:16]([OH:17])[CH3:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C[C@H]1CO1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](O)Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
4,4′-Dibromobiphenyl (0.62 g, 2.0 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tri-n-butylmagnesium lithium in tetrahydrofuran was added under a nitrogen atmosphere at 0° C., which was stirred at the same temperature for 1 hour, followed by addition of (2S)-2-methyloxirane (0.15 mL, 2.2 mmol). The temperature of the reaction solution was raised to room temperature, followed by stirring for 30 minutes, and subsequently a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.23 g, 0.79 mmol) as a white solid (yield 39%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][C:24]1([CH2:37][CH3:38])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][C:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)([CH2:37][CH3:38])[CH2:29][CH2:28]1)=[O:31])([CH3:34])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC1(NCc2cn(C(=O)OC(C)(C)C)c3nccc(C(=O)OC)c23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
1-tert-Butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (211 mg, 0.692 mmol) was dissolved in MeOH (10 mL) and tert-butyl 4-amino-4-ethylpiperidine-1-carboxylate (158 mg, 0.692 mmol) were added followed by 2 drops of acetic acid. The solution was allowed to stir at room temperature for 2 h. Then sodium cyanoborohydride (44 mg, 0.692 mmol) was added over the course of 6 h at room temperature. The solution was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/Hexanes) gave 127 mg of 1-tert-butyl 4-methyl 3-((1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate. [M+H] found 417.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8].N(OC(C)(C)C)=O.C(Br)(Br)[Br:28]>ClCCl>[Br:28][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrC(Br)Br
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(N)c2)c(C)c1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(Cl)c(Br)c2)c(C)c1
Temperature: 80 °C

Procedure:
Methyl 3′-amino-4′-chloro-2-methylbiphenyl-4-carboxylate (946 mg, 3.43 mmol) was dissolved in a mixture of CHBr3 (5 mL) and dichloromethane (5 mL). To the above stirred mixture was added t-butyl nitrite (680 μL, 530.6 mg, 5.145 mmol). The reaction mixture was heated to 80° C. for 30 minutes. Aliquot (LCMS) indicated complete consumption of starting material. Crude mixture was purified by flash chromatography (SiO2, Biotage 40+S cartridge) to afford methyl 3′-bromo-4′-chloro-2-methylbiphenyl-4-carboxylate. LCMS calc.=339.97; found=340.98 (M+1)+.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[NH:33][C:34]([SH:37])=[N:35][N:36]=2)[CH:27]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:34]3[NH:33][C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[N:36][N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1nnc(-c2cccnc2)[nH]1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4cccnc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione and 5-(3-pyridinyl)-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C=CC=CC=1.[CH:18]([C:20]([CH3:22])=[O:21])=[CH2:19]>C(N(CC)CC)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:19][CH2:18][C:20](=[O:21])[CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: C=CC(C)=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CCC(C)=O)CCCC1=O

Procedure:
(B.) A mixture of 102.0 g of ethyl 2-oxocyclopentanecarboxylate, 300 ml of benzene, 67 ml of methyl vinyl ketone and 20 ml of triethylamine was allowed to stir magnetically at reflux for 2.5 hours. Concentration followed by Claisen distillation gave 128 g of product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2C=CC(OC)=C(Cl)C=2)[C:5](C(OCC)=O)=CN=1.[CH2:24]([N:26](CC)CC)C>C(Cl)(Cl)Cl>[N:8]1[CH:9]=[CH:10][N:7]2[CH2:2][CH2:24][NH:26][CH2:5][C:6]=12
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1cn2c(n1)CNCC2

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (285 mg) obtained in the above (3), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (197 mg), triethylamine (0.22 ml) and chloroform (3 ml) is stirred at room temperature for 2.5 hours, and stirred at 60° C. for 2.5 hours. The reaction mixture is diluted with ethyl acetate, and washed with water. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel: 10 g, solvent; chloroform:methanol=50:1), and concentrated under reduced pressure. The resultant is triturated with isopropyl ether to give 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (290 mg) as colorless crystalline powder, m.p. 179-182° C., MS (m/z): 443 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:4][CH:3]=1.FC1C=C([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:31][C:26]1([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28][B:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]4[CH:16]=3)=[CH:4][CH:3]=2)[O:25]1
Reactant: Brc1ccc(-c2cn3ccccc3n2)cc1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: CC1(C)OB(c2ccc(-c3cn4ccccc4n3)cc2)OC1(C)C

Procedure:
2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyridine was prepared from 2-(4-bromophenyl)imidazo[1,2-a]pyridine (0.273 g, 1.00 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as a white solid (0.250 g, 78%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt=11.35 min, 87%; m/z 321 (MH+).
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19].C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cccc(-c3ccccc3C=O)c2OCC1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.03 g), 2-formylbenzeneboronic acid (0.49 g), tetrakis(triphenylphosphine)palladium(0) (0.35 g), and triethylamine (0.92 ml) in N,N-dimethylformamide (10.3 ml) was stirred at 100° C. under nitrogen atomsphere for 2.5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:30˜1:9) to give a solid of ethyl 2,3-dihydro-9-(2-formylphenyl)-1-benzoxepin-4-carboxylate (0.63 g).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[OH:28]O>>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:28])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-acetaminophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.