Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:16])[C:10]=1[CH2:17][Br:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([Br:19])[Br:16])[C:10]=1[CH2:17][Br:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1CBr
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(C(Br)Br)c1CBr
Yield: 91.5 %

Procedure:
1-Benzoyl-2,3-bis(bromomethyl)benzene (8.0 g, 22 mmol) (crude, Description 7) was dissolved in carbon tetrachloride (50 ml) and recrystallized N-bromosuccinimide (3.9 g 22 mmol) and dibenzoyl peroxide (100 mg) were added. The mixture was heated to reflux for sixteen hours, cooled and filtered. The solid was washed with carbon tetrachloride (2×10 ml) and the combined organic layers were evaporated under reduced pressure to give crude 1-benzoyl-2-bromomethyl-3-(dibromomethyl)benzene (9.0 g, 93% recovery).
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=O)C.C[O-].[Na+].[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:61])[C@@H:38](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OCC=C)[C@H:35]3[S:34][CH2:33][C:32]=2OS(C)(=O)=O)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.CO.Cl.O>[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:61])[CH2:38][C@H:35]3[S:34][CH2:33][C:32]=2[S:4][CH2:5][S:6][C:7]2[N:8]=[N:9][NH:10][CH:11]=2)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)SCSc1c[nH]nn1
Reactant: C=CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2CC(=O)N12
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 83.6 %

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (230 mg : 1.22 mMol.) in dimethylformamide (6 ml) is dropwise added a 1.26N-sodium methoxide in methanol (1.9 ml) at -60° C., and the mixture is stirred at the same temperature for 25 minutes, and cooled to -78° C. To the reaction mixture is dropwise added a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-(2-propenyloxyimino)acetamido]-3 methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (770 mg : 1 mMol.) in dimethylformamide (3 ml), and the mixture is stirred at the same temperature for 40 minutes. The reaction mixture is diluted with 1N-hydrochloric acid (2 ml) and water (50 ml), and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and purified by silica gel chromatography (toluene : ethyl acetate=2:1). The eluted material is crystallized from toluene to give 7β-](Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl) 2-(2propentyloxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4- carboxylic acid diphenylmethyl ester (415 mg) as colorless crystals. Yield : 51%. mp. 167° to 170° C. (decomposition).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[I-:28].[Na+]>C(Cl)Cl.CCCCCC>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][I:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: OCc1ccccc1Oc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ICc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of o-phenoxybenzyl alcohol (5.0 g, 25 mmol) and triethylamine (10.4 mL, 75 mmol) in CH2Cl2 (50 mL) at 0° C. was added methanesulfonyl chloride (3.9 mL, 50 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 3.5 h. The mixture was washed H2O and brine. It was filtered through phase separator paper and concentrated to a yellow oil. The oil was then dissolved in 50 mL of acetone, and sodium iodide (7.5 g, 50 mmol) was then added. The mixture was stirred at more temperature overnight. Hexane was added to the mixture. The solid was filtered off. The filtrate was concentrated and chromatographed on silica gel with hexane to give 5.22 g of yellow oil. MS m/e 183.1, [M+H-HI]+ ; 1H NMR (300 MHz, CDCl3): δ 4.52 (s, 2H, CH2Ar), 6.82-7.48 (m, 9H, ArH). ##STR65##
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[NH:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1>>[ClH:20].[OH:35][CH:32]1[CH2:33][CH2:34][N:30]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:31]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: OC1CCNC1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCC(O)C3)cc12

Procedure:
6-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 23% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 3-pyrrolidinol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:32][CH2:31][CH:27]([C:28]([Cl:30])=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[ClH:30].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:28]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:17])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Cc1ccc(NC(=O)c2ccccc2N)cc1
Product: Cc1ccc(NC(=O)c2ccccc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Product: Cl
Yield: 33.6 %

Procedure:
Using the procedure described in Example 138, N-(4-methylphenyl)-2-aminobenzamide (0.97 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.9 mmol), purifying with RPHPLC Method A, yielded 147 mg (34%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[OH:29][C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:33]([C:30]2([OH:29])[CH2:32][CH2:31]2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(O)C1(O)CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2(O)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.240 g, 0.61 mmol), 1-hydroxy-1-cyclopropanecarboxylic acid (0.074 g, 0.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.175 g, 0.92 mmol), 1-hydroxybenzotriazole (0.124 g, 0.92 mmol), and triethylamine (0.21 mL, 1.53 mmol) were combined in CH2Cl2 (2 mL) and stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (20-90% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH3:14].C(Cl)Cl>C(O)C.O.[Fe]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([C:13](=[O:15])[CH3:14])=[C:4]([Cl:3])[CH:9]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(N)cc1Cl
Reaction time: 0.03 h

Procedure:
Iron (2.7 g) and ammonium chloride (2.6 g) were added to a solution of 2′-chloro-4′-nitroacetophenone (CAS Reg. No. 67818-41-1, 960 mg) in ethanol (68 ml) and water (8.1 ml). The mixture was heated for 1 h under reflux. DCM (35 ml) was added and stirred for 2 min. The mixture was filtered over Celite. Water (100 ml) was added and extracted with DCM (200 ml, and 2×150 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound (837 mg) as light yellow oil. MS (m/e)=170.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[CH2:24](N(C(C)C)C(C)C)C.C[CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([C:8]([N:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:24])[CH2:42][CH2:43][CH2:34]2)=[O:10])=[CH:11][C:12]([F:15])=[CH:13][N:14]=1
Reactant: CC1CCc2ccccc2N1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc2c1N(C(=O)c1cc(F)cnc1Oc1ccc(F)c(Cl)c1)CCC2
Temperature: 100 °C
Yield: 21.3 %

Procedure:
A solution of 2-(3-chloro-4-fluoro-phenoxy)-5-fluoro-nicotinic acid (34.3 mg, 0.12 mmol, 1.0 equiv; Example 86, Step 1) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 100° C. for 20 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 10.6 mg (21%) of the title compound. MS (ISP): 414.9 [M+H]+.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:17][CH2:18][C@@H:19]1[O:27][CH2:26][C:22]2=[N:23][O:24][CH2:25][C@@H:21]2[CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC(C)C)(C)C.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH2:10]([O:17][CH2:18][C@@H:19]1[O:27][CH2:26][C@:22]2([C:39]3[CH:38]=[CH:37][C:36]([F:35])=[CH:41][C:40]=3[F:42])[NH:23][O:24][CH2:25][C@@H:21]2[CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reactant: Fc1ccc(I)c(F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Temperature: -73.5 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (60.1 mL, 474 mmol) was added to a solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C4) (50.0 g, 202 mmol) in a 1:1 mixture of toluene and diisopropyl ether (2 L) at an internal temperature of −76° C. The reaction was stirred at this temperature for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (27.1 mL, 226 mmol). While the reaction temperature was maintained at −76 to −71° C., n-butyllithium (2.5 M in hexanes, 85.7 mL, 214 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (1 L) and partitioned between water (1 L) and ethyl acetate (750 mL). After the heterogeneous mixture warmed to room temperature, the aqueous layer was extracted with ethyl acetate (3×250 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (550 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 70% ethyl acetate in heptane) afforded the product as a yellow oil. Yield: 48.14 g, 133.2 mmol, 66%. 1H NMR (400 MHz, CDCl3) δ 7.94 (ddd, J=9, 9, 7 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=12.0, 8.6, 2.4 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=21.4 Hz, 2H), 4.14 (br dd, J=12.8, 1.3 Hz, 1H), 3.82-3.90 (m, 2H), 3.72 (d, J=7.2 Hz, 1H), 3.54-3.60 (m, 2H), 3.50 (dd, half of ABX pattern, J=10.3, 4.1 Hz, 1H), 3.04-3.13 (m, 1H), 1.86 (ddd, J=14.0, 7.0, 2.0 Hz, 1H), 1.49-1.61 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:45](Cl)=[O:46])[C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:45]([C:33]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:37][CH:36]=4)=[C:29]([CH3:28])[CH:30]=[CH:31][CH:32]=3)=[O:46])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C(=O)Cl)c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To a solution of (5-amino-indan-2-yl)-carbamic acid tert-butyl ester (12.5 mmol) in methylene chloride (75 mL) is added diisopropylethyl amine (3.3 g, 25 mmol) followed by a solution of 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid chloride (12.6 mmol) in methylene chloride. After stirring 16 h, the reaction mixture is poured into ethyl acetate and washed with 1N HCl, NaHCO3 solution, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a solid. Recrystallization from toluene gives {5-[(6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:8]2[N:23]=[CH:24][CH:25]=[CH:26][C:7]=2[C:6]1=O)C.O.[NH2:29]N>CO>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[N:2][NH:29][C:6]=3[C:7]3[CH:26]=[CH:25][CH:24]=[N:23][C:8]2=3)=[O:22])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: NN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Solvent: O
Solvent: CO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2cccnc21
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a slurry of 0.51 g of 6-[(dimethylamino)methylene]-6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 17 ml of methanol under argon is added 0.14 g of hydrazine hydrate. The mixture is stirred overnight and the solvent removed under vacuum. The residue is dissolved in hot chloroform-methanol (95:5) and filtered through silica gel and washed filter pad with chloroform-methanol (95: 5). The filtrate is concentrated to dryness to give 0.48 g of yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]3[CH2:11][CH:6]([CH2:7][CH2:8]3)[C:5]=2[C:4]([CH2:12][O:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[N:3]1.C(Cl)Cl.O.NN>C(O)C>[NH2:14][O:13][CH2:12][C:4]1[C:5]2[CH:6]3[CH2:11][CH:9]([CH2:8][CH2:7]3)[C:10]=2[N:2]([CH3:1])[N:3]=1
Reactant: Cn1nc(CON2C(=O)c3ccccc3C2=O)c2c1C1CCC2C1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cn1nc(CON)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a mixture of 2-[(1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methoxy]-1H-isoindole-1,3(2H)-dione 148 (1.80 g, 5.57 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.32 mL, 5.57 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 149 (0.68 g, 64%) as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1([C:18]([O:20]CC)=[O:19])[CH2:17][CH2:16]1)=[O:14]>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]1)=[O:14]
Reactant: CCOC(=O)C1(C(=O)Nc2cc(Cl)c(Cl)cc2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)c(Cl)cc1NC(=O)C1(C(=O)O)CC1
Temperature: 0 °C

Procedure:
A solution containing 0.34 gram (0.006 mole) of potassium hydroxide and 0.109 gram (0.006 mole) of water in 80 milliliters of ethanol was prepared in a 250 milliliter round bottom flask. With cooling to a temperature of 0° C. in an ice/NaCl bath and stirring, a solution of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate prepared in Example III in a small volume of ethanol was added and the mixture allowed to stir with warming to room temperature over a 72 hour period. The mixture was vacuum evaporated to give a white solid residue which was dissolved in water and extracted twice with ether. The ether extracts were discarded. The water solution was acidified to a pH of 2 with 25% HCl solution causing separation of a solid which was taken up into ether, and the acidified aqueous phase was extracted four times. The combined ether extracts were dried over magnesium sulfate and vacuum evaporated to give a white solid. This white solid was water-washed and dried in a vacuum oven to give 1.85 grams (0.006 mole) of 1-(2-methyl-4,5dichlorophenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 248° C.-251° C. Elemental analysis of the product indicated the following:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][CH2:27][CH:28]1[CH2:31][CH2:30][NH:29]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][N:29]1[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC3CN)nc21
Yield: 51.5 %

Procedure:
A suspension of 1.08 g (4.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.93 g (5.0 mmol) of 2-[(t-butoxycarbonylamino)methyl]azetidine, 1.01 g (10 mmol) of triethylamine and 50 ml of acetonitrile was stirred at reflux for two hours. The solvent was removed in vacuo and the residue was dissolved in 25 ml of trifluoroacetic acid. After stirring at room temperature for two hours, the solvent was removed in vacuo. The residue was suspended in water and the pH adjusted to 11 with 10% sodium hydroxide. The resulting solution was filtered through a fiber glass pad to clarify and the filtrate acidified to pH 7.2 with 1 M hydrochloric acid. The resulting precipitate was removed by filtration, washed successively with water, ethanol, ether and dried in vacuo to give 0.66 g (52%) of the title compound, mp 198°-200° C.
Reaction SMILES: COC1C=CC(C2CCN(C3C=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][N:58]([CH2:57][CH3:56])[C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cccc(N2CCC(c3ccc(OC)cc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1cccc(N2CCC(c3ccc(OC)cc3N)C2)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1CCN(c2cccc(OC)c2)C1

Procedure:
Synthesized from 5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (202 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl{5-methoxy-2-[1-(3-methoxyphenyl) pyrrolidin-3-yl]phenyl}amine (188 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (153 mg).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:17][CH:16]=1>C(O)C>[C:3]([CH:2]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: Clc1ccc(CCCCCBr)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(C)=O
Reaction time: 0.25 h

Procedure:
A solution of 6.0 g (46 mmol) of ethyl acetoacetate in 6 ml of absolute ethanol is added drop by drop, with stirring, to a solution of 23 mmol of sodium ethylate in 18 ml of ethanol. Stirring is continued for another 15 minutes to complete the salt formation, and then a solution of 6.0 g (23 mmol) of 5-(4-chlorophenyl)pentyl bromide in 6 ml of absolute ethanol is added. The mixture is then heated for 3 hours with refluxing, and then completely concentrated by evaporation. Water is added to the concentrate and the mixture is neutralized with 2N hydrochloric acid. Then the organic components are extracted with ether, the combined extracts are dried, and are concentrated by evaporation. The concentrate is chromatographed on silica gel with a mixture of n-heptane and butanone. Yield: 5.8 g (81% of theory) of ethyl 2-acetyl-7-(4-chlorophenyl)heptanoate, a colorless oil.