Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:35])[CH:10]([CH:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:11][C:12]([NH2:14])=[O:13])C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[O:34]=[C:16]1[CH:15]([CH:10]([CH2:11][C:12]([NH2:14])=[O:13])[C:9]([OH:35])=[O:8])[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1
Reactant: NC(=O)CC(C(=O)OCc1ccccc1)C1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)CC(C(=O)O)C1Cc2cn(c3ccccc23)CCCCCCNC1=O

Procedure:
A solution of (3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid benzyl ester (190 mg) in THF/EtOH (5/1, 20 mL) was hydrogenated with 10% Pd/C (170 mg) for 8 hours until TLC indicated that the starting compound was consumed. The solution was filtered through a pad of Celite. The filtrate was evaporated and recrystallized (THF/EtOAc) to give 147 mg of (3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid, melting point: 222°-226° C., MS: 604.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]OC)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].C(O)(=O)C>CO>[CH3:23][C:22]([CH3:24])([CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]([OH:18])=[C:7]([C:14]([CH3:17])([CH3:15])[CH3:16])[CH:8]=1)[CH:21]=[O:25]
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 25 grams (0.1 mole) of 2,6-di-tert.butyl-4-methoxymethylphenol and one gram (0.015 mole) of KOH in 100 milliliters of methanol was heated to 60° C. 9 grams (0.125 moles) of isobutyraldehyde was added to the solution during a period of 10 minutes and the reaction mixture was heated under reflux for 3 hours. After the mixture had cooled to room temperature it was poured into 125 milliliters of 1% acetic acid. The solid that precipitated was filtered off and allowed to dry. There was obtained 28.5 grams (98.2% of theory) of 2,2-dimethyl-3-(3,5-di-tert.butyl-4-hydroxyphenyl) propionaldehyde with a melting point of 72° to 74° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][N:6]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O>CO>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][N:6]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH3:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[CH2:48][C:44]2[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=2)=[CH:12][CH:13]=1
Reactant: CCCN(CCC)CCCCN(CCC(=O)OC)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(CCC(=O)OC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.5 %

Procedure:
The compound (48.2 mg) obtained in Example 34-2 was dissolved in anhydrous methanol (1.0 ml) and added with sodium cyanoborohydride (9.90 mg), acetic acid (100 μl), and 1-methyl-2-imidazole carboxaldehyde (12.8 mg) and the whole was stirred at room temperature for 3 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, and the whole was stirred for a while. The solution was subjected to extraction with chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (56.1 mg) of the subject compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:14][N:13]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:12]1)=O.[Cl-].[NH4+]>C1COCC1>[OH:8][CH2:9][CH:11]1[N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:14][N:13]([C:21]([OH:23])=[O:22])[CH2:12]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(C(=O)O)CC1CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of lithium aluminium hydride (0.75 g) in THF (30 mL) was added a solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.2 g) in THF (20 mL) at 0° C. The reaction mixture was subsequently warmed to room temperature. After stirring for 2.5 h, ammonium chloride solution (5 mL) was added to the reaction mixture, which was then filtered through celite, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tent-butyl ester (1.13 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:31])[O:30][CH2:29]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)on2)c(F)c1
Product: CC(C)(O)CN1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)no2)C2CC2)CC1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 4): tR=1.19 min; Mass spectrum (ESI+): m/z=427 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:8](O)[N:7]1[CH:21]=[O:22])=[O:5])[CH3:2].CO.[H][H]>[Ni].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([NH:7][CH:21]=[O:22])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][C:9]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:17][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccccc2[N+](=O)[O-])C(O)N1C=O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)(NC=O)C(=O)OCC
Temperature: 25 °C
Yield: 97.9 %

Procedure:
50.0 g (0.13 mol) of the compound of Example 4 in 500 ml. of methanol and 1 ml of acetic acid was hydrogenated in a rocking autoclave at room temperature and 200 psi in the presence of 6 g. of Raney nickel. After the hydrogen uptake (3 equivalents) was complete the filtered reaction mixture was concentrated in vacuo to a volume of 140 ml. Toluene (600 ml.) was added and the remaining methanol was removed by azeotropic distillation. The mixture was heated at reflux for an additional 30 minutes and then allowed to cool to room temperature. The precipitate was collected, washed with toluene and dried to yield 42.3 g (97%) of white crystals, m.p. 179-180° (lit. m.p. 179°). The analytical sample was prepared by recrystallization from ethaniol: m.p. 180-181°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C@H:23]1[CH2:26][C@H:25]([C:27](O)=[O:28])[CH2:24]1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:27]([C@H:25]2[CH2:26][C@H:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])[CH2:24]2)=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C1)N1Cc2ccncc2C1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(N[C@H]1C[C@H](C(=O)NCCCc2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-phenylpropylamine for 3-phenylpropan-1-amine and trans-3-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)cyclobutanecarboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.75 (t, J=5.5 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.32-7.24 (m, 2H), 7.24-7.13 (m, 3H), 6.58 (d, J=7.6 Hz, 1H), 4.66-4.55 (m, 4H), 4.41-4.27 (m, 1H), 3.11-3.03 (m, 2H), 2.89-2.75 (m, 1H), 2.62-2.52 (m, 2H), 2.39-2.25 (m, 2H), 2.26-2.11 (m, 2H), 1.76-1.63 (m, 2H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27].[CH3:28][S:29][CH2:30][C:31](O)=[O:32].Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:27][C:4]1[CH:5]=[C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:31](=[O:32])[CH2:30][S:29][CH3:28]
Reactant: NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CSCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSCC(=O)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl

Procedure:
To a solution of 0.11 g of 3-(4-aminomethyl-3-chlorophenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole, 0.051 g of (methylthio) acetic acid and 0.048 g of triethylamine in 2 mL of chloroform, 0.092 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the resultant mixture was stirred at room temperature for 15 hours. After the completion of the reaction, 2 mL of a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the organic phase was separated off, followed by purifying the organic phase as it was by preparative medium pressure liquid chromatography eluting with ethyl acetate-hexane (a gradient from 1:4 to 1:1) using a medium pressure preparative apparatus (trade name: YFLC-Wprep; manufactured by Yamazen Corporation) to obtain 0.12 g of the objective substance as a colorless resinoid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][C:13]([CH3:41])([CH3:40])[C:14](=[O:39])[C:15](=[N:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:17].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:5]([O:4][C:2]([N:18]([C:16](=[O:17])[C:15](=[N:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[CH:32][CH:33]=1)[C:14](=[O:39])[C:13]([CH3:40])([CH3:41])[CH3:12])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)c1ccc(N=C(C(=O)Nc2ccc(Cl)cc2Cl)C(=O)C(C)(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(N=C(C(=O)N(C(=O)OCc2ccccc2)c2ccc(Cl)cc2Cl)C(=O)C(C)(C)C)cc1
Yield: 39 %

Procedure:
Benzyl chloroformate (0.16 mL, 1.12 mmol) was added to a solution of N-[4,4-dimethyl-2-[4-diethylaminophenyl]imino-3-oxopentanoyl]-2,4-dichloroaniline, prepared as in Example 5 above (478 mg, 1.07 mmol), triethylamine (0.15 mL, 1.08 mmol) and DMAP (135 mg, 1.1 mmol) in dry dichloromethane (5 mL) and the resultant solution was stirred for 3 hours under nitrogen. Additional benzyl chloroformate (0.2 mL, 1.4 mmol) was then added, followed one hour later by more benzyl chloroformate (0.2 mL, 1.4 mmol) and additional triethylamine (0.15 mL, 1.08 mmol). The resultant solution was stirred under nitrogen for 7 days, after which the solvent was removed. The crude product was purified by flash chromatography on silica gel with 3% ethyl acetate/hexanes as eluant to give slightly impure Dye C. Further purification was effected by a second chromatographic separation on silica gel in the same manner as above. Dye C (240 mg, 39% yield) was obtained as an orange foam which had a principal absorption in the visible region of the electromagnetic spectrum at 438 nm, ε=15,900. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 8 h
Yield: 38 %

Procedure:
600 mg (2.94 mmol) of 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid were dissolved in 30 ml of DMF, 1.92 (5.9 mmol) of cesium carbonate and 1.04 g (7.35 mmol) of iodomethane were added, and the resulting mixture was heated for 4 h to 80° C. The mixture was filtrated and the solvent removed in vacuo. The residue was dissolved in 20 ml of MOH and 5.9 ml of an aqueous 1 M solution of sodium hydroxide. After stirring overnight the reaction was complete. The solvent was removed and the residue subjected to preparative HPLC to give the title compound in a yield of 38%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4]/[C:3]/1=[N:8]\[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]>C(O)C.[Ni]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C@@H:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10]
Reactant: CC1CCCC/C1=N\[C@H](C)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CC1CCCCC1N[C@H](C)c1ccccc1
Yield: 79.1 %

Procedure:
A suspension of (1R,E)-N-(2-methylcyclohexylidene)-1-phenylethanamine (I-8a: 25 g, 116.27 mmol) and Raney-Ni (3.75 g) in ethanol (250 mL) was maintained under hydrogen atmosphere in a Parr hydrogenator using 5 bar pressure for 2 days. The reaction mixture was filtered and filtrate evaporated under reduced pressure. The crude compound was treated with ethereal HCl, and the precipitated salt was filtered, washed with cold ether and dried to afford 20 g (80%) of 2-methyl-N—((R)-1-phenylethyl)-cyclohexanamine (I-8b) as a white solid.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].B(F)(F)F.CCOCC.[C:22]([C:25](=[N:30][O:31][CH2:32][CH3:33])[C:26]([O:28][CH3:29])=[O:27])(=[O:24])[NH2:23].C(N(CC)CC)C>C(Cl)Cl.O>[NH:23]=[C:22]([O:24][CH2:6][CH3:7])[C:25](=[N:30][O:31][CH2:32][CH3:33])[C:26]([O:28][CH3:29])=[O:27]
Reactant: CC[O+](CC)CC
Reactant: CCON=C(C(N)=O)C(=O)OC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCON=C(C(=N)OCC)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Meerwein reagent (triethyloxonium tetrafluoroborate) {prepared from boron fluoride etherate (2.84 g) by a method of Org. Syn., 46, 113 (1966)} in methylene chloride (30 ml) was added methyl 2-carbamoyl-2-ethoxyiminoacetate (syn isomer, 2.6 g) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was cooled in an ice-bath and triethylamine (3 g) was added thereto, followed by an addition of water (20 ml). The organic layer was separated out, dried over magnesium sulfate and evaporated to give crude methyl 3-imino-3-ethoxy-2-ethoxyiminopropionate (syn isomer) (5.0 g) as an oil. ##STR14##
Reaction SMILES: [CH3:1][C:2]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH2:6][O:7]C(=O)C)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl>O>[CH3:1][C:2]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH2:6][OH:7])[C:3]([OH:5])=[O:4]
Reactant: CC(=O)OCC(C)(CC(C)(C)C)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(CO)C(=O)O
Yield: 83.5 %

Procedure:
In a 100 mL 3-necked RB flask, acid (1) (4.8 g, 0.022 mol) was stirred at reflux with a solution of sodium hydroxide (4.0 g) in water (40 mL) for 20 hours. The mixture was cooled and acidified with concentrated HCl. After drying, there was obtained 2-methyl-2-neopentyl-3-hydroxypropionic acid (2) (3.2 g, 85% yield), m.p. 96.5°-100° C.; recrystallized from n-hexane, m.p. 99°-101° C. 1H NMR (CDCl3): 0.97 (s, 9H), 1.31 (s, 3H), 1.74, 1.54 (AB, 2H), 3.88, 3.40 (AB, 2H), ca. 6.75 (s broad, 2H).
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:31]=[CH:30][C:14]2[O:15][C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH:19]([S:20][CH2:21]CN(C)C)[C:13]=2[CH:12]=1.CCCCCC>C(Cl)(Cl)Cl>[Br:3][CH2:2][CH2:21][S:20][CH:19]1[CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[O:15][C:14]2[CH:30]=[CH:31][C:11]([F:10])=[CH:12][C:13]1=2
Reactant: CN(C)CCSC1Cc2ccccc2Oc2ccc(F)cc21
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)C(SCCBr)Cc1ccccc1O2
Reaction time: 0.33 h

Procedure:
To a mixture of 2.3 g of cyanogen bromide and 5.0 g of potassium carbonate in 40 ml of chloroform is added portion-wise over a 50 minutes span a solution of 4.8 of 2-fluoro-10,11-dihydro-11-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, free base of Example 32, in 85 ml of chloroform. After total addition, the mixture is stirred for 20 minutes before being filtered. The filtrate is evaporated to leave an oil which is treated with three portions of boiling hexane. The combined hexane portions are evaporated leaving an oil which is chromatographed through a silica gel column with an eluant of methylene chloride and is recrystallized from cold hexane to give a white powder, mp 46°-48° C. of 11-[β-(bromo)ethylthio]-2-fluoro-10,11-dihydrodibenz[b,f]oxepin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18]CC)=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:14](=[O:15])[C:13]([C:16]([OH:18])=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nc2cccnc2n(-c2ccc(OC)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-n2c(=O)c(C(=O)O)nc3cccnc32)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2.9 g (9 mmol) of ethyl 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate was dissolved in 1,4-dioxane (30 mL). A solution in which 1.8 g (13 mmol) of potassium carbonate was dissolved in water (60 mL) was prepared, and was added to the reaction solution at room temperature, and then the mixture was stirred for one hour at 50° C. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. Water (50 mL) was added, and then the reaction solution was cooled to 0° C., and adjusted to pH 1 using 6 N hydrochloric acid. Subsequently, a solid was separated by filtration and dried, to obtain 2.6 g (yield: 98%) of 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid as yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12](=[O:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[NH4+]>CCCCCC.CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12](=[O:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)CN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
Sodium hydride (152.6 mg, 3.81 mmol, 60% suspension in mineral oil) was washed with hexane (2×2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (500 mg, 1.90 mmol) in dry DMF (10 mL) at 0° C. The reaction mixture was stirred at this temperature for 1 h. Ethyl bromoacetate (0.21 mL, 1.9 mmol) was added at 0° C. and the reaction mixture was allowed to come to r.t. and stirred overnight. After the completion of the reaction as confirmed by TLC, reaction mixture was cooled to 0° C. and saturated solution of ammonium chloride (3 mL) was added dropwise to the reaction mixture. The crude product was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over Na2SO4 and solvents were removed in vacuo to afford 1-ethoxycarbonylmethyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (480 mg, 72%) as a viscous oil which was used as such without any further purification for the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:15][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](N)c1cccc(C(C)C)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](CC(C)C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-isopropylphenyl)-3-methylbutan-1-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 587 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7.4 g of 2-chloro-5-nitrophenol, 5.4 g of allyl bromide, 5.9 g of anhydrous potassium carbonate and 50 mL of dry N,N-dimethylformamide (DMF) was stirred at room temperature over a weekend. Then the mixture was poured into water, and the resulting mixture was extracted twice with ethyl acetate and twice with ether. The combined extracts were washed with water, then with brine, dried (Na2SO4), filtered and stripped of the solvents. The residue was recrystallized from hexane to give 1-(allyloxy)-2-chloro-5-nitrobenzene (3A), as orange needles, m.p.: 58°-59.5° C.