Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)[CH3:15].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:15][N:14]([CH2:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:24]=1)[CH3:13]
Reactant: C=Cc1ccc(CN(C)C)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cccnc1/C=C/c1ccc(CN(C)C)cc1
Temperature: 140 °C
Reaction time: 13 h
Yield: 33.9 %

Procedure:
6.7 g (39 mmol) of ethyl 2-chloronicotinate, 8.2 g (51 mmol) of 4-(N,N-dimethylaminomethyl)styrene, 9.9 g (98 mmol) of triethylamine, 0.36 g of palladium(II) acetate and 0.96 [lacuna] of tri(o-tolyl)phosphine were mixed in 150 ml of dimethylformamide and, after addition of 1 ml of water, stirred at 140° C. for 13 h. The reaction mixture was then concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated off, washed with water, dried and concentrated in vacuo. The residue was then crystallized as oxalate from isopropanol after addition of an equivalent amount of oxalic acid. 4.1 g (27%) of the product were obtained as monooxalate.
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].C(=O)(O)[O-].[K+].[C:11]1([CH:18]=[CH:17][CH:16]=[C:14]([OH:15])[CH:13]=1)[OH:12].C(=O)=O.Cl>O>[OH:12][C:11]1[CH:13]=[C:14]([OH:15])[CH:16]=[CH:17][C:18]=1[C:1]([OH:2])=[O:4]
Reactant: O=C([O-])O
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1O
Temperature: 12.5 °C
Yield: 88.8 %

Procedure:
A 35-1 solids mixer was charged with 10 kg of sodium bicarbonate, 5 kg of potassium bicarbonate and 3.3 kg of resorcinol and heated with mixing to 120° C. in a stream of carbon dioxide. After 3 hours the contents were cooled down with mixing, and 28 l of water were added. The hot suspension at 60° C. was then discharged and brought to pH 3 at room temperature with 20 kg of concentrated hydrochloric acid. The suspension was cooled to 10-15° C. and filtered on a filter press, and the filter residue was washed with water and dried, leaving 4.1 kg (81%) of 2,4-dihydroxybenzoic acid; purity (HPLC): 99.5%.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[CH:46]=[N:47][N:48]([CH2:51][CH2:52][CH2:53][OH:54])[C:49]=1[Cl:50]>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[CH:46]=[N:47][N:48]([CH2:51][CH2:52][CH2:53][OH:54])[C:49]=2[Cl:50])=[CH:29][CH:30]=1
Reactant: OCCCn1ncc(Br)c1Cl
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCO)c2Cl)ccc1N
Yield: 47.3 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 284 mg, 1.03 mmol) and 3-(4-bromo-5-chloro-1H-pyrazol-1-yl)propan-1-ol (Compound 49D, 270 mg, 1.1 mmol) to afford 151 mg of the title compound (48%). 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 4.32 (t, J=7.1 Hz, 2H), 3.60 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 2.06 (quin, J=6.6 Hz, 2H). MS (ESI): m/z=310.20/312.18 [M+H]+. UPLC: tR=0.77 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][CH2:12][CH2:13][CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][CH:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH3:11])=[O:6]
Reactant: CCCC(N)CCC
Reactant: O=C(Cl)c1cccc(Br)c1
Product: CCCC(CCC)NC(=O)c1cccc(Br)c1

Procedure:
Reaction of 3-bromobenzoyl chloride with heptan-4-amine gave 3-bromo-N-(heptan-4-yl)benzamide as a white solid which was used in the next step without additional purification. Yield (2.43 g, 90%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=C(C)C)[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:30]=[O+][O-]>CO.ClCCl>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH2:23][OH:30])[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCO
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (20 mg) in a mixture of methanol (0.1 ml) and dichloromethane (5 ml) was passed through ozone at -78° C. for 3 minutes. Nitrogen was bubbled into the solution at the same temperature to remove excess ozone. The solvents were evaporated and the residue was dissolved in methanol (2 ml). To the solution was added sodium borohydride (10 mg) in one portion at 5° C. The mixture was stirred at 5° C. for 10 minutes and then concentrated in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with brine, dried, and evaporated. The crude oil was purified by column chromatography on silica gel eluted with diethyl ether to yield 6-cyclohexylcarbamoyloxy-4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (11.6 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].C(N)CN.O>CN1CCCC1=O.[Cu](I)I>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([Cl:13])[C:4]=1[CH3:12]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Reactant: N#C[Cu]C#N
Agent: I[Cu]I
Solvent: O
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: Cc1c(N)ccc(C#N)c1Cl
Yield: 79 %

Procedure:
Dissolve N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (10 g, 38 mmol) in N-methylpyrrolidinone (60 mL) and sparge with nitrogen. Add copper cyanide (10.2 g, 114 mol) and copper iodide (21.8 g, 114 mol) and stir under nitrogen at 130° C. for 72 h. Cool the reaction and add ethylene diamine (100 mL), along with water (300 mL). Extract the reaction mixture with EtOAc. Separate and dry the organic portion over Na2SO4, filter, and concentrate. Dissolve the resulting residue in 1:1 EtOH/concentrated HCl. Stir at reflux temperature for 30 min, cool and concentrate to half of the volume. Add water (500 mL) and filter. Rinse the filter cake with water and isolate 5.0 g (79%) of the title compound as a white solid. MS: MS (ESI−): 207 (M−1)−. MS (ESI+): 209 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.C([O-])([O-])=O.[Na+].[Na+]>CCO.Cl.[Fe]>[N:18]1[CH:17]=[CH:16][C:15]([C:11]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:14]=[CH:13][N:12]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2-c2ccncc2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Nc1ccc(-n2ccnc2-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-[1-(4-Nitro-phenyl)-1H-imidazol-2-yl]-pyridine (6.16 g, 23.0 mmol) in EtOH (75.0 mL) and 2N HCl (7.0 mL) is added iron powder (325 mesh, 17.40 g, 312 mmol) and refluxed for 1 h. The solution is then cooled to RT and Na2CO3 (4.87 g, 56.0 mmol) is added and the resultant suspension is filtered through a pad of celite (521). The filter cake is then washed with EtOH (100 mL) and the filtrate is concentrated under reduced pressure to a brown solid. The crude sample is then purified by column chromatography (5% MeOH:95% DCM) to afford 4-(2-Pyridin-4-yl-imidazol-1-yl)-phenylamine as a tan solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[OH-].[Na+].[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(COc1cc(C(=O)O)c(O)c2ccccc12)c1ccccc1
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
Into a solution of 0.05 mole of 1,4-dihydroxy-2-naphthoic acid in 70 ml. of DMF were dropped, with introduction of nitrogen gas, 10 ml. of a 40% aqueous sodium hydroxide solution and then a solution of 0.05 mole of phenacyl bromide in 10 ml. of DMF, and the resulting mixture was reacted with stirring at 40° C. for 3 to 4 hours. After completion of the reaction, the reaction liquid was poured into ice-hydrochloric acid to deposit crystals, which were then recovered by filtration and recrystallized from acetonitrile to obtain 1-hydroxy-4-benzoylmethoxy-2-naphthoic acid having having a melting point of 190° C. 0.01 Mole of the thus obtained compound and 0.01 mole of N-(δ-2,4-di-tert-amylphenoxy)butylamine were dissolved in 60 ml. of dehydrated dioxane and added with 0.01 mole of dicyclohexyl carbodiimide. The resulting mixture was reacted with stirring at room temperature for 2 hours. After completion of the reaction, the reaction liquid was subjected to filtration, and the filtrate was vaporized under reduced pressure. The residue was charged with n-hexane to deposit crystals, which werethen recoveredby filtration and recrystallized from benzene-n-hexane to obtain a compound having a melting point of 120° to 121° C. (yield 75%). From the measurement of its elementary analysis values and the like, the thus obtained compound was found to be the coupler (1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[N:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[N:15][C:10]([N:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:11][CH:12]=2)=[O:17])[CH2:23][CH2:22]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)nc3)CC2)c(C)c1
Yield: 42 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 4 and (6-bromopyridin-3-yl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 1, the title compound (180 mg) was obtained.
Reaction SMILES: CC(C)=O.[C:5]([O:9][C:10]([N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([O:33]C)=[O:32])=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>O>[C:5]([O:9][C:10]([N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([OH:33])=[O:32])=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(C(=O)O)c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To 11 mL of acetone solution containing 1.1g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2.2 mL of water solution containing 0.23 g of sodium hydroxide was added at room temperature, and stirred at 50° C. for 30 min. After cooled to the room temperature, the solvent was removed under reduced pressure, 40 mL of water was added, and adjusted to pH 4 with 2 mol/L hydrochloric acid. The resulting solid was filtered to afford 0.97 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH:13][C@:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1>>[OH:13][C@:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH:22]=2)[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Reactant: O=C1CCc2cc(S)ccc2N1
Product: C[C@H]1C[C@@](O)(c2cccc(Sc3ccc4c(c3)CCC(=O)N4)c2)CCO1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 6, 6-mercapto-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran in 25% yield, m.p. 180°-181° C. (recrystallised from ethyl acetate);
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8](O)=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[S:5][N:4]=1)[CH3:2]>O1CCCC1>[CH2:1]([C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[S:5][N:4]=1)[CH3:2]
Reactant: CCc1nsc(-c2ccc(C)cc2F)c1C(=O)O
Solvent: C1CCOC1
Product: CCc1nsc(-c2ccc(C)cc2F)c1CO
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carboxylic acid (150 mg, 0.57 mmol, 1.00 equiv), tetrahydrofuran (10 mL). This was followed by the addition of BH3 (1.7 mL) at 0-5° C. The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 50 mg (35%) of [3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-4-yl]methanol as colorless oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[NH:29][C:30](=[O:52])[N:31]([C:38]1[N:39]=[N:40][N:41]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])[N:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:19].C(OCC)C>ClCCl>[CH3:19][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30](=[O:52])[N:31]([C:38]1[N:39]=[N:40][N:41]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[O:51])[N:42]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)N(c1ccccc1)c1nnn(CCCCCCCCO)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(c1ccccc1)c1nnn(CCCCCCCC=O)n1
Reaction time: 2 h

Procedure:
To a stirred, room temperature suspension of pyridinium chlorochromate (0.720 g, 0.00334 mol) and anhydrous sodium acetate (0.0546 g, 0.000666 mol) in dichloromethane (6 mL) was added dropwise over 20 minutes a solution of N'-[2,6-bis(1-methylethyl)-phenyl]-N-[2-(8-hydroxyoctyl)-2H-tetrazol-5-yl]-N-phenyl-urea (1.09 g, 0.00221 mol) in dichloromethane (6 mL), and the mixture was stirred. After 2 hours, diethyl ether (4 mL) was added and the mixture was filtered through celite. The filtercake was washed with dichloromethane. The filtrate and washings were rotoevaporated, and the residue was chromatographed on silica gel (135 g, 230-400 mesh) using PET etherdiethyl ether (1:2, 15-125 mL) as eluent. Fractions containing product were rotoevaporated from dichloromethane to an oil. The oil was dried in vacuo wherein it solidified, yield 0.7108 g (65%) of the title compound, mp=104°-106° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C@H:6]([OH:10])[CH2:7][C:8]#[N:9])[CH3:2].[CH3:12]C(=O)OCC>IC.[Ag]=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([O:10][CH3:12])[CH2:7][C:8]#[N:9])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: O=[Ag]
Solvent: CI
Product: CCOC(=O)CC(CC#N)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
(R)4-cyano-3-hydroxy butyric acid ethyl ester (1.5 g, 9.54 mmol) was dissolved in iodomethane (20 ml). Silver oxide solid (3.3 g, 14.32 mmol) was added, and the reaction mixture was agitated at room temperature overnight. TLC (PE/EA=2/1) was employed to monitor the reaction. After the reaction completed, the silver oxide solid was removed by filtration, and the solvent was evaporated. Column chromatography (PE/EA=10/1) afforded colorless transparent liquid 1.0 g, yield 63.1%.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O)(C)(C)C.[ClH:20].C(OCC)C.N>C(O)C.O>[ClH:20].[ClH:20].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccnc1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To an ice cooled solution of the compound of step 9a (286 mg, 1.08 mmol) in absolute ethanol (4 mL), was added a hydrogen chloride saturated ethanol solution (4 mL), under nitrogen. The reaction mixture was stirred 18 hours while gradually warming to room temperature. The reaction mixture was then concentrated in vacuo, the product dissolved in absolute ethanol and triturated with diethyl ether. Two recrystallizations from ethanol and diethyl ether yielded pure product in 81% yield as a white powder (174 mg, 87 mmol). MS (DCI/NH3) m/e 165 (M+H)+, 182 (M+NH4)+. 1NMR (D2O, 300 MHz) δ: 8.60-8.59 (d, J=2.9 Hz, 1H), 8.48-8.46 (d, J=5.8 Hz, 1H), 8.25-8.21 (ddd, J=9.0 Hz, J=2.6 Hz, J=1.1 Hz, 1H), 5.05-4.97 (m, 1H), 4.59-4.57 (d, J=4.0 Hz, 2H), 4.22-4.05 (m, 2H), 2.77-2.67 (dd, J=16.9 Hz, J=8.45 Hz, 2H). Anal. calcd. for C9H12N2O.2.7 HCl.0.2 H2O: C, 40.60; H, 5.71; N, 10.52. Found: C, 40.75; H, 5.76; N, 10.51.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:6][C:5]=1[CH:19]=[O:20].O>C(O)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]2[C:11]([CH:10]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:9][CH2:8]2)=[CH:12][C:4]=1[OH:3]
Reactant: O=Cc1cc2c(cc1O)C(Cc1c[nH]cn1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cc2c(cc1O)C(Cc1c[nH]cn1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (8 mg) is added into a solution of 6-hydroxy-1-(1H-imidazol-4-ylmethyl)-indan-5-carbaldehyde (44 mg) in ethanol (6 ml). The mixture is stirred at room temperature for one hour and then poured into water. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent and crystallized from ethyl acetate.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[C:10]([CH3:20])[CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:7][C:8]1[CH:19]=[C:18]2[C:11](=[C:10]([CH3:20])[CH:9]=1)[O:12][CH2:13][CH2:14][C:15]2=[O:17]
Reactant: Cc1cc(Cl)ccc1OCCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cc(Cl)cc2c1OCCC2=O
Temperature: 0 °C
Yield: 50.9 %

Procedure:
Phosphorous pentachloride (0.95 g, 4.6 mmol) was added to a suspension of 3-(4-chloro-2-methylphenoxy)propionic acid (0.59 g; 2.7 mmol; from step (ii) above) in benzene (10 mL). The resultant clear solution was heated quickly to boiling and then cooled on an ice bath. Aluminium chloride (1.0 g; 7.5 mmol) was added in portions and, after complete addition, ice water was added. Extraction with ether, washing of the organic layer with NaHCO3/aq. and NaOH (2M; aq.), drying (Na2SO4) and concentration yielded 0.27 g (50%) of the sub-title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]([C:69]1[CH:77]=[CH:76][C:72]([C:73](O)=[O:74])=[CH:71][CH:70]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[C:61]([C:69]1[CH:70]=[CH:71][C:72]([C:73]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:74])=[CH:76][CH:77]=1)(=[O:68])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 51.6 %

Procedure:
DIPEA (77 mg, 0.103 mL, 0.60 mmol) was added to a stirred solution of 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (102 mg, 0.29 mmol) in DMF (1 mL). HOBT (32 mg, 0.238 mmol) and EDCI.HCl (46 mg, 0.238 mmol) were at room temperature. After 2 minutes, 4-benzoyl-benzoic acid (45 mg, 0.20 mmol) was added. The resulting mixture was stirred at room temperature for four hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 54 mg (51.86% yield) of 4-benzoyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity %: 91.57, HPLC Purity %: 95.52, 1H NMR (DMSO-d6): δ 8.8 (bt, 1H), 8.1-8.0 (d, 2H), 7.9-7.7 (m, 7H), 7.6 (t, 3H), 4.3-4.1 (m, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.1 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5](=[O:13])(=[O:12])[N:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:7].[NH3:15]>>[C:8]([N:6]([CH3:7])[S:5]([CH2:4][C:3]([NH2:15])=[O:2])(=[O:13])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)CS(=O)(=O)N(C)C(C)(C)C
Reactant: N
Product: CN(C(C)(C)C)S(=O)(=O)CC(N)=O
Yield: 84 %

Procedure:
The subtitle compound (3.66 g, 84%) was prepared as a white solid from aqueous ammonia solution (10 ml, s.g.=0.88) and methyl (N-tert-butyl-N-methylsulfamoyl)acetate (from step (a), 4.7 g, 21 mmol), using the method of Example 1(b). m.p. 105-109° C.
Reaction SMILES: O=C[C:3]([O:5][CH2:6][CH3:7])=O.COC1C=C(N)C(N)=CC=1.CO[C:20]1[CH:21]=[C:22]2[C:27](=CC=1)[NH:26][C:25](=[O:30])[CH:24]=[N:23]2>C1(C)C=CC=CC=1.C(O)C>[CH3:3][O:5][C:6]1[CH:7]=[C:27]2[C:22]([N:23]=[CH:24][C:25](=[O:30])[NH:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Reactant: CCOC(=O)C=O
Agent: COc1ccc(N)c(N)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(=O)[nH]c2c1
Yield: 42 %

Procedure:
A 50% solution of ethyl 2-oxoacetate (18.47 mL, 93 mmol) in toluene was added to a solution of 4-methoxybenzene-1,2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was refluxed for 2 h. The reaction was concentrated in vacuo and crystallized from ethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50 mmol, 42% yield). MS (LC/MS) R.T.=0.68; [M+H]+=177.10.