Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:9][CH:8]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:7]1=[O:34])C.[OH-].[Na+]>O1CCOCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]([CH2:5][C:4]([OH:35])=[O:3])[C:7](=[O:34])[CH:8]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:9]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:16]=1
Reactant: CCOC(=O)CN1C(=O)C(NCC(=O)OC(C)(C)C)C=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC1C=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of rac-7-chloro-5-(2-chlorophenyl)-3-[[(1,1-dimethylethoxy)-carbonyl]methylamino]-2,3-dihydro-2-oxo-1H-1-benzazepine-1-acetic acid ethyl ester (1.50 g, 2.89 mmole) in 11 mL of dioxane was added 1.0N aqueous sodium hydroxide solution (4.2 mL, 4.2 mmole). After stirring for 3 hours at ambient temperature, the solution was concentrated under high vacuum. The residue was dissolved in 40 mL of water and acidified to pH 3 with 1N HCl. A thick precipitate formed which was extracted into 100 mL of ethyl acetate. The organic phase was removed, washed with brine, dried (sodium sulfate) and concentrated. The crude product was crystallized from ether-petroleum ether yielding 1.24 g (87%) of white solid. IR (KBr) 1739, 1697 cm-1. Mass spec (FAB+, m/z 491). (Found: C, 58.90; H, 5.10; N, 5.40; Cl, 14.13. Calc for C4H24N2O5Cl2 : C, 58.67; H, 4.92; N, 5.70; Cl, 14.43).
Reaction SMILES: [C:1]([CH2:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[CH2:10][C:9]2[CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=[CH:18][C:8]=2[NH:7]1)([O:3][CH3:4])=[O:2].[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH2:32][NH:33][CH3:34].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.O>[C:1]([CH2:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[CH2:10][C:9]2[CH:15]=[C:16]([C:19]([N:33]([CH3:34])[CH2:32][C:24]3[N:23]([CH3:22])[C:31]4[C:26]([CH:25]=3)=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:21])[CH:17]=[CH:18][C:8]=2[NH:7]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1Nc2ccc(C(=O)N(C)Cc3cc4ccccc4n3C)cc2CN(C)C1=O
Yield: 91.1 %

Procedure:
To a solution of (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.4 g, 1.37 mmole) in dry DMF (10 mL) at RT was added 1-methyl-2-(methylaminomethyl)indole (0.26 g, 1.50 mmole), HOBt (0.20 g, 1.50 mmole), i-Pr2NEt (0.19 g, 1.50 mmole) and EDC (0.29 g, 1.50 mmole). After 18 hr the reaction solution was diluted with H2O (25 mL) and extracted with EtOAc (2×50 mL). The organic fractions were combined, washed sequentially with H2O and brine, then were dried (Na2SO4). Concentration under vacuum followed by chromatography on silica gel (95:5 CHCl3/MeOH) provided the title compound (0.56 g, 92%) as an off-white solid: MS (ES) m/e 449 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[N:26]=1>>[OH:34][C@:30]([C:27]1[N:26]=[C:25]([CH3:24])[O:29][N:28]=1)([CH3:31])[C:32]#[C:33][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@@](C)(O)c3noc(C)n3)cc1-2

Procedure:
10-Bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.05 g) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in Procedure F to afford 8.4 mg of 10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 437 (M)+. 1H NMR (400 MHz, DMSO) δ 11.05 (q, J=4.1 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.68 (s, 1H), 5.02-4.93 (m, 2H), 4.58-4.45 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.61 (s, 3H), 1.84 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[O:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35]([Cl:38])(=[O:37])=[O:36])[CH:33]=2)[N:28]=[CH:27][NH:26]1.Cl>C(Cl)(Cl)Cl.C(O)C.O>[ClH:38].[O:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35]([N:9]3[CH2:8][CH2:7][N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:11][CH2:10]3)(=[O:37])=[O:36])[CH:33]=2)[N:28]=[CH:27][NH:26]1
Reactant: O=c1[nH]cnc2ccc(S(=O)(=O)Cl)cc12
Reactant: CCOC(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(CN1CCN(S(=O)(=O)c2ccc3nc[nH]c(=O)c3c2)CC1)c1ccccc1
Reaction time: 15 h
Yield: 76.2 %

Procedure:
In 200 ml of chloroform was dissolved 11.7 g of 1-(2-ethoxy-2-phenylethyl)piperazine, and then 6.9 g of anhydrous potassium carbonate was added thereto. To the solution thus obtained was added dropwise 100 ml of a chloroform solution containing 12.2 g of 3,4-dihydro-4-oxo-6-quinazolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for 15 hours, and then added with 50 ml of water. After the pH of the reaction solution was adjusted to 7, the chloroform layer was separated therefrom and the aqueous layer was further extracted with chloroform and the chloroform layer obtained was combined with the one previously separated. Then the chloroform layer was washed with water, dried with Glauber's salt and condensed under reduced pressure to give an oily substance. To this oily substance were added 50 ml of ethanol and 10 ml of conc. hydrochloric acid to form a solution, and the solution was condensed to dryness and the residue was recrystallized from ethanol and then from ether to give 18.2 g of 1-(3,4-dihydro-4-oxo-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine hydrochloride having a melting point (decomposition) of 249° C. to 250° C. in a yield of 76%.
Reaction SMILES: [NH2-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[NH2:11])=[CH:16][CH:17]=1
Reactant: NNc1ccc(F)cc1
Reactant: Fc1ccc(CCBr)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(CCc1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (6.0 mL; Aldrich) was charged with sodium amide (0.488 g, 11.89 mmol; Acros) and chilled to 0° C. (4-Fluorophenyl)hydrazine (1.0 g, 7.9 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved. The ice bath was removed and stirring was continued for 1 hour. The solution was chilled again in an ice bath and 1-(2-bromoethyl)-4-fluorobenzene (1.731 ml, 8.72 mmol; Aldrich) was added dropwise. After 10 minutes the ice bath was removed and stirring was continued for 1.5 hours. The mixture was poured into water (5 mL). The tetrahydrofuran was removed under reduce pressure and the residue was diluted with water (20 mL). The aqueous layer was extracted with diisopropyl ether (2×25 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: MS (DCI/NH3) m/z 248.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH2:14][CH2:13]2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:28]([O-])(=[O:32])[C:29]([CH3:31])=[CH2:30].[K+]>CN(C)C=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([O:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:14][CH2:13]2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)O[C@H]2CC[C@H](C(=O)CCCCCBr)CC2)cc1
Reactant: C=C(C)C(=O)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC2CCC(CCCCCCC(=O)C(=C)C)CC2)cc1
Temperature: 72.5 °C
Yield: 97.5 %

Procedure:
55.2 g (0.2 mol) of trans-4-hydroxycyclohexyl allyloxybenzoate prepared as described in Example 1 were dissolved in 300 ml of dry toluene, and 43 g (0.205 mol) of 6-bromohexanoyl chloride (prepared from the free acid by conventional reaction with thionyl chloride; b.p. 60-62° C. at 0.04 mbar) were added dropwise at 105° C. over the course of 60 minutes with stirring. After the mixture had been stirred at 105° C. for a further 90 minutes, the solvent was stripped off under reduced pressure, and the residue was crystallized out using petroleum benzine/methyl tert-butyl ether (20:1), giving 83 g (92%) of trans-[4-(6-bromo-hexanoyl)cyclohexyl] 4-allyloxybenzoate, melting point 56° C. 79 g (0.174 mol) of this ester, 25 g (0.21 mol) of potassium methacrylate and 0.2 g of 2,6-di-tert-butyl-4-methylphenol (stabilizer) were dissolved in 400 ml of dimethylformamide, and the mixture was heated at 70-75° C. for 3 hours with stirring. The solvent was then distilled off under reduced pressure, the residue was taken up in 400 ml of methyl tert-butyl ether, and the solution was washed with water, 0.05 N NaOH, and again with water, dried and evaporated. The residue was recrystallized from methanol, yielding 70 g (87.5%) of the title compound, which melts at 50° C. and clears at 55° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:11](=[O:28])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(Cn2c(=O)nc(-c3ccc(F)c(F)c3)c3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)NC(c3ccc(F)c(F)c3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 9 (9.33 g, 24.6 mmol) in dioxane (250 mL) was added NaBH4 (1.02 g, 27.1 mmol) in one portion. The solution stirred for two hours at room temperature. The solvent was removed in vacuo, and the residue was partitioned between CHCl3 and 1 N HCl. The aqueous layer was extracted with CHCl3, and the combined organic extracts were dried, concentrated, and purified by PCTLC (1:1 EtOAc:Hex). A white solid was obtained. 1H NMR (CDCl3, 400 MHz) 7.30-7.04 (m, 6H), 6.93-6.83 (m, 6H), 5.58 (s, 1H), 5.18-5.04 (q, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][N:14]=[C:15]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])[CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].IC1C=CC=CC=1C(O)=O>C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][N:14]=[C:15]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH:28]=[O:29])[CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:1]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3CO)cc1OCC2
Agent: O=C(O)c1ccccc1I
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3C=O)cc1OCC2
Yield: 93.3 %

Procedure:
A mixture of (1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}pyrrolidin-2-yl)methanol (173 mg, 0.436 mmol), 2-iodobenzoic acid (305 mg, 1.09 mmol) in ethyl acetate (10.0 mL) was refluxed for 6 hr. After filtration, the filtrated was evaporated to afford 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}pyrrolidine-2-carbaldehyde (160 mg, 92% yield) as pale yellow solid. LCMS (ESI) m/z: 394.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[Br:23][CH2:24][C:25](Br)=[O:26].C(OCC)(=O)C>ClCCl>[Br:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:26]
Reactant: COC(=O)c1cc(N)cc(-n2cccc2)c1
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CBr)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of methyl 3-amino-5-(pyrrol-1-yl)benzoate (1.0 g) and pyridine (0.41 ml) in dichloromethane (20 ml) was added bromoacetyl bromide (0.44 ml) under ice cooling. After stirring for 6 hours at room temperature, the reaction mixture was poured into the mixture of ethyl acetate and ice-water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was pulverized from diethyl ether to give methyl 3-bromoacetylamino-5-(pyrrol-1-yl)benzoate (1.51 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].Cl.[NH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1)[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:27]([C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:18]([NH:17][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH3:19])=[CH:25][CH:24]=1)([CH3:30])[CH3:29])#[N:28]
Reactant: CC(N)c1ccc(C(C)(C)C#N)cc1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C(C)(C)C#N)cc1
Reaction time: 0.17 h

Procedure:
N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 1 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (500 mg, 2.36 mmol) prepared according to scheme 2, 2-[4-(1-aminoethyl)phenyl]-2-methylpropanenitrile hydrochloride (525 mg, 2.36 mmol) prepared according to scheme 6, DMAP (570 mg, 4.71 mmol) and HATU (896 mg, 2.36 mmol) in DMF (10.0 mL). The product is purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: SynerSi (4μ) Polar RP, 21.2×50 mm, Mobile phase: A=water (0.05% TFA) B=MeCN, Gradient used 40% to 60% B in A, in 10 min. The fractions are combined, NaOH 1 N is added and the desired compound is extracted with ethyl acetate. The combined organic fractions are concentrated under reduced pressure to yield the product (450 mg, 2.36 mmol, 50%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.49 (d, J=7.03 Hz, 3H) 1.68 (s, 6H) 5.03 (m, 1H) 5.20 (m, 2H) 7.30 (dt, J=11.23, 8.98, 7.32 Hz, 1H) 7.35-7.42 (m, 2H) 7.44-7.54 (m, 3H) 8.56 (s, 1H) MS [M+H], calcd: 383.2. found: 383.3.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C=O)C>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:3]([N:2]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[CH:34][C:24]=3[NH:23][C:20](=[O:22])[CH3:21])[C:27]2=[O:28])[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH3:19]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(O)CC)ccc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 77.2 %

Procedure:
A stirred mixture of 5-amino-5-(3-ethoxy-4-methoxyphenyl)pentan-3-ol hydrochloride(1.15 g, 3.97 mmol), 3-acetamidophthalic anhydride (0.82 g, 3.97 mmol) and triethylamine (0.4 g, 3.97 mmol) in DMF (20 mL) was heated at 80-90° C. for 6 hours. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (80 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 77%) ; 1H NMR (CDCl3) δ9.52 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.09-7.07 (m, 2H), 6.83-6.80 (m, 1H), 5.61-5.55 (J=3.9, 11.9 Hz, 1H), 4.11 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 1H), 1.78 (b, 1H), 1.62-1.52 (m, 2H), 1.45 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ170.39, 169.23, 168.11, 148.94, 148.14, 137.32, 135.83, 131.81, 131.19, 124.72, 120.30, 117.94, 115.31, 112.87, 111.09, 70.01, 64.36, 55.86, 51.29, 37.92, 30.46, 24.92, 14.73, 9.90.
Reaction SMILES: ClC1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].Cl>>[NH2:3][C:4]1[CH:5]=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[CH:8][C:9]=1[C:10]1[NH:14][N:13]=[CH:12][N:11]=1
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cc(N)c(-c2ncn[nH]2)cc1OC

Procedure:
To a flask containing 46 gms. of 5-chloro-8,9-dimethoxy-1,2,4,triazolo[4,3-c]quinazoline is added 1000 ml. of a 10% KOH solution and the resulting mixture heated to reflux. A gentle reflux is maintained overnight after which time the mixture is neutralized to pH 7.0 with cooling and stirring by adding dropwise a 1:1 HCl solution and the resulting precipitate filtered off. The aqueous layer is washed 3 or 4 times with ethyl acetate, dried and evaporated in vacuo to dryness. The residue is recrystallized from ethanol to obtain 5-(2-amino-4,5-dimethoxyphenyl)-s-triazole, m.p. 205°-210° C.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>>[OH:15][CH2:14][C:13]([NH:12][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1cccnc1
Product: CC(C)(CO)NC(=O)c1cccnc1

Procedure:
100 g (0.66 mol) Ethyl nicotinate and 88g (0.99 mol) 2-amino-2-methyl-1propanol were mixed and heated together under reflux for 2 hours. The excess amino alcohol was removed by distillation, bp 50°-60° (1mm). The yellow residue was recrystallized from ether-acetone to give 87.3 g (0.45 mol), 68%, N-(1-hydroxy-2-methyl-2-propyl) nicotinamide, mp 91°-93°; ir (KBr) 3385, 3200, 1665, and 1590 cm-1 ; pmr (CDCl3) δ 8.8 - 7.3 (m, 4H), 6.7 (bs, 1H), 5.0 (s, 1H), 3.7 (s, 2H) and 1.4 (s, 6H) ppm.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>C1COCC1>[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Reactant: CN(C)CCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide was prepared as described in example 1. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.8 g, 2.19 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.). The resulting acyl imidazole was then treated with 4-dimethylaminobutylamine (0.28 g, 2.41 mmol, 1.1 eq.). When complete, the reaction was worked up to leave a yellow oil (0.72 g, 71% yield) which solidified on standing. The free base was converted to the oxalate as described in example 3 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide oxalate (0.61 g) as a white solid.
Reaction SMILES: IC1C=CC=CC=1N([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C(=O)CNC(NC1C=C(C)C=CC=1)=O.[CH3:31][O:32][C:33]1[CH:66]=[CH:65][C:36]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[NH:45][C:46]([CH2:48][NH:49][C:50](=[O:64])[NH:51][C:52]2[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=2)[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])=[O:47])=[O:38])=[CH:35][CH:34]=1>>[C:27]([O:26][C:24]([CH2:23][CH:48]([C:46](=[O:47])[NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37](=[O:38])[C:36]1[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:66][CH:65]=1)[NH:49][C:50](=[O:64])[NH:51][C:52]1[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=1)[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccc(OC)cc2)c1
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2I)c1
Product: C=CCOC(=O)c1cccc(NC(=O)NC(CC(=O)OC(C)(C)C)C(=O)Nc2ccccc2C(=O)c2ccc(OC)cc2)c1

Procedure:
According to the synthesis method of the compound 24, the compound 42b is used to synthesize the titled compound. Mp. 190°-191° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:36][C:34]1[CH:35]=[C:30]([N:16]2[C:17](=[O:18])[C:19]3[C@@H:20]4[C:26]([CH3:28])([CH3:27])[C@@:23]([CH3:29])([CH2:22][CH2:21]4)[C:24]=3[NH:15]2)[CH:31]=[C:32]([Cl:37])[CH:33]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)cc(Cl)c3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (15 mL) was added in one portion to a cooled (0° C.) solution of N′-(3,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜0.19 mmol) in dichloromethane (15 mL). The mixture was stirred at 0° C. for 5 min and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir for 4 h. Volatiles were evaporated under reduced pressure and then under high vacuum. Dichloromethane (200 mL) was added. The solution was washed with water (4×125 mL), and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and dried overnight under high vacuum to give (4S,7R)-2-(3,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7.2 g, 108% of the expected amount). This material was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14]>C(N)CCC>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCCCN
Product: CC(=Cc1ccc(C(=O)O)cc1)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-carboxybenzaldehyde (38.44 g) in nitroethane (360 ml) and butylamine (2 ml) was heated at reflux for 2 hours with azeotropic distillation of water using a Dean and Stark apparatus The solution was cooled to room temperature and the resulting solid was collected and recrystallised from isopropanol (250 ml) with hot filtration to give 1-(4-carboxyphenyl)-2-nitropropene (31.57 g) in the form of a yellow crystalline solid, m.p. 212°-214° C.