Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[CH:6]([Cl:10])[C:7]([CH3:9])=[O:8].C([Li])CCC.[CH:17]1([C:22](=[O:27])[CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[CH3:3][O:4][C:5](=[O:11])[CH:6]([Cl:10])[C:7](=[O:8])[CH2:9][C:22]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)([OH:27])[CH2:23][CH2:24][C:25]#[CH:26]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: C#CCCC(=O)C1CCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCC(O)(CC(=O)C(Cl)C(=O)OC)C1CCCC1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A slurry of NaH (3.2 g, 60% suspension in mineral oil, 80 mmol) in dry THF (250 mL) was cooled to −40° C. Methyl-2-chloroacetoacetate (9.74 mL, 80 mmol) was added slowly. The reaction was stirred until all gas evolution had ceased, and then butyl lithium (2.5 M, 32 mL, 80 mmol) was added. The reaction was stirred for 10 minutes, and then 1-cyclopentyl-pent-4-yn-1-one (4.0 g, 27 mmol) from Step 2 above, was added as a solution in 20 mL THF. The reaction was stirred 1 hour, and then warmed to room temperature. The reaction was quenched with 1 N HCl (200 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 and the organic layers were combined. The organic layer was washed with water, and then concentrated by rotary evaporation. The crude product was purified by chromatography to yield the pure product (6.345 g, 78% yield).
Reaction SMILES: [CH2:1]([C:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[C:30]([NH:37][CH2:38][C:39](O)=[O:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:33]([O:32][C:30]([NH:37][CH2:38][C:39]([O:29][C:3]1([CH2:1][CH3:2])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)=[O:40])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCC1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(F)c(F)cc3nc2-1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC1(OC(=O)CNC(=O)OC(C)(C)C)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(F)c(F)cc3nc2-1
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.7 %

Procedure:
A mixture of 5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (200 mg, 0.526 mmol, example 18), N-Boc-glycine (185 mg, 1.051 mmol) and a catalytic quantity of 4-dimethylaminopyridine (20 mg) in anhydrous pyridine (10 ml) is treated at 0° C. and under argon with dicyclohexylcarbodiimide (239 mg, 1.16 mmol), then agitated at ambient temperature for 48 hours. The volatiles are driven off under vacuum and the residue is chromatographed (SiO2, 1% methanol in chloroform) in order to produce the desired intermediate (40 mg, 14%), a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH:45]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][N:15]([CH2:14][CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)[CH2:16][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CSc2ccc(N3C[C@H](CCNCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC(C)(C)[Si](C)(C)OCCN(CC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)CC1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 59 %

Procedure:
Starting from the compound of Example 4 and tert-butyldimethylsilyloxy-acetaldehyde and using procedure E, the title compound was obtained as a yellow foam (55 mg; 59% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[NH2:14][CH:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH:16]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:14][C@H:15]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C@H:16]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:13])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Cc1c[nH]c2ccccc12
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of indole-3-acetic acid (248 mg, 1.42 mmol) in DMF (3 ml) was added 1,1-carbonyldiimidazole (230 mg, 1.42 mmol). After stirring for 2 h a solution of the aminopyrrolidinone of Example S (352 mg, 1.42 mmol) in DMF (1 ml) was added. After stirring for an additional 18 h the solvent was evaporated to give an oil which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (2%-5%) to give 470 mg (91%) of the title compound as a solid. NMR (DMSO) 400 MHz : 3.25δ, m, 1H; 3.59δ, d, 2H; 3.88δ, t, 1H; 4.01δ, t, 1H; 4.65δ, q, 1H; 6.98δ, t, 1H; 7.08δ, t, 1H; 7.15δ, t, 1H; 7.24δ, d, 1H; 7.37, m, 3H; 7.56δ, d, 1H; 7.78δ, d, 2H; 8.62δ, d, 1H.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:31])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCC1(c2noc3cc(Cl)ccc23)CCNCC1
Yield: 98.2 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6 g, 19 mmol), l-[4-(2-chloroethoxy)-3- methoxyphenyl]ethanone (4.3 g, 19 mmol), K2CO3 (2.8 g), a few crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield 8.0 g of yellow solid. The solid was chromatographed on a Waters Prep 500 LC (silica columns, eluting with methylene chloride/methanol, 5%). Concentration of the appropriate fractions yielded 3.2 g of a light yellow solid, which upon recrystallization from ethyl acetate afforded 2.3 g (28%) of 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone as a pale yellow solid, m.p.=133°-135° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7](F)=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4].[CH3:22][NH:23][CH3:24]>CN(C)C=O.O>[CH3:22][N:23]([CH3:24])[C:7]1[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(F)cc1OCC
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(N(C)C)cc1OCC
Temperature: 50 °C
Yield: 95.3 %

Procedure:
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (1.02 g, 3.20 mmol) was taken up in 5 mL of anhydrous dimethylformamide. Dimethylamine (8.0 mL, 15.9 mmol) was added and the reaction mixture was heated at 50° C. for 16 h. The reaction was allowed to cool to room temperature and diluted with water. The product was extracted three times with methylene chloride. The combined organics extracts were washed with brine, dried over magnesium sulfate and concentrated to give ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxy-benzoate as a tan solid (1.05 g, 95%). LC-MS: 345.3 [(M+H)+].
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].C1(Br)CCCC1.C1(O)C=CC=CC=1.ClCl>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[O:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(O)c(OC3CCCC3)c2)c1
Reactant: O=C([O-])[O-]
Agent: BrC1CCCC1
Agent: ClCl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)cc1OC1CCCC1
Yield: 53.9 %

Procedure:
2-Cyclopentyloxy-4-(3-nitrophenyl)phenol (600 mg, 2.45 mmol) was dissolved in DMF (40 ml) and treated with Cs2CO3 (730 mg, 2.24 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol). After stirring overnight at RT some of the phenol remained (SiO2 :t.l.c, CH2 Cl2). Cs2CO3 (870 mg, 2.67 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol) were added. After stirring at RT for 3 h the phenol had been consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in Et2O (50 ml), filtered, and concentrated in vacuo to give a yellow solid which was recrystallised from dichloromethane/hexane to afford the title compound (378 mg) as yellow needles. δH (CDCl3 ; 80 mHz) 1.5-2.1 (8H, br m, (CH2)4), 3.87 (3H, s, OMe), 4.84 (1H, br m, OCHCH2), 6.91 (1H, d, J9.1 Hz, ArH ortho to OMe), 7.0-7.2 (2H, m, ArH meta to OMe), 7.54 (1H, d, J 7.5 Hz, ArH meta to NO2), 7.80 (1 H, ca. dt, J ca 7.5, 1.5 Hz, ArH para to NO2), 8.09 (1H, ca. dt, J ca.8, 1.5 Hz, ArH para to aryl), 8.33 (1H, ca. t, J ca 2 Hz, ArH ortho to NO2 and aryl); m/z 313 (M+, 7%), 246 (17), 245 (M+ -cyclopentyl, 100), 230 (41), 202 (8), and 139 (9).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.C1C=CC=CC=1>C([O-])(=O)C.[NH4+].O>[C:7]1(=[C:3]([C:1]#[N:2])[C:4]([OH:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCCC1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: N#CC(C(=O)O)=C1CCCCC1
Yield: 90 %

Procedure:
170 grams (2 moles) of cyanoacetic acid, 196 grams (2 moles) of cyclohexanone, 10 grams (0.13 moles) of ammonium acetate, 24 grams (0.4 moles) of acetic acid, and 380 milliliters of benzene were combined in a 2-liter round-bottomed flask equipped with a reflux condensor and a water separator, and the mixture heated (with reflux) for 6 hours. Upon cooling, the volatile compounds were removed in vacuo, and the residue washed with water to give 360 grams (1.8 moles, 90% yield) of cyclohexylidene cyanoacetic acid. The cyanoacetic acid was distilled under a vacuum of 50 Torricellis (torr.) thereby producing 196 grams (1.6 moles, 81% yield based on cyclohexanone, or 90% yield based on cyclohexylidene cyanoacetic acid) of cyclohexenyl acetic acid nitrile, which had a boiling point of between 115°-120° C. at 50 torr. (As an alternative to distilling the cyanoacetic acid under vacuum in the lastmentioned step, another portion of the cyclohexylidene cyanoacetic acid when heated to 140°-150° C. under a vacuum of 50-70 torr. for 2.5 hours was found to be readily convertible to an impure cyclohexenyl acetic acid nitrile.)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:7][C:6]=1[C:24](Cl)=[O:25])[CH2:2][CH2:3][CH3:4].[NH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:7][C:6]=1[C:24]([NH:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: NN1CCCCC1
Reactant: CCCCc1c(C(=O)Cl)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of 5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (227 mg, 0.56 mmol) in CH2Cl2 (5 mL), were added 1-aminopiperidine (113 mg, 1.12 mmol) and Et3N (234 μL, 1.68 mmol). The solution was stirred overnight at rt, and then the solvents were evaporated under reduced pressure. The residue was purified by preparative reversed-phase HPLC, using 20 to 100% MeCN in water as gradient, to provide 125 mg (48%) of 5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidazole-4-carboxamide as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.49-7.27 (m, 8 H), 2.93 (t, 2 H), 2.82 (bs, 4 H), 1.77-1.71 (m, 4 H), 1.46-1.37 (m, 4 H), 1.25-1.20 (2 H), 0.79 (t, 3 H). LC-MS m/z 471.33 (MH+), retention time 2.88 min (method 2).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:40][CH:39]([N:41]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:38]1>>[N:41]1([CH:39]2[CH2:38][N:37]([C:13](=[O:14])[C@H:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:40]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCCN(C2CNC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CC(N3CCCCCC3)C2)cc1CC

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 1-azetidin-3-yl-perhydro-azepine.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>CO.COCCOC>[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)Cc1c(Cl)ncnc1OC
Reaction time: 0.5 h

Procedure:
Sodium methylate in methanol (112 ml of a 5.4 molar solution) is added at room temperature to a solution of methyl 4,6-dichloro-pyrimidin-5-yl-acetate (120 g, 0.54 mol) in 1,2-dimethoxyethane (200 ml) with cooling. The reaction mixture is stirred for 30 minutes and poured on crushed ice. The precipitated crystals are filtered and dried to give the methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (106 g), m.p. 64° C.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: ClCc1ccc(Br)cc1
Solvent: CCO
Product: Brc1ccc(COc2ccc(CN3CCCC3)cc2)cc1
Yield: 57.9 %

Procedure:
The mixture of 4-hydroxybenzyl-pyrrolidine (177 mg), 4-bromo-benzylchloride (205 mg), and t-Bu3ONa (192 mg) in ethanol (10 mL) was heated at 80° C. for overnight. Concentration and preparative TLC provided the title compound (200 mg). 1H NMR (400 MHz, CDCI3)δ7.50 (d, J=6.5 Hz, 2 H), 7.32 (d, J=6.5 Hz, 2 H), 7.25 (d, J=6.5 Hz, 2 H), 6.90 (d, J=6.5 Hz, 2 H), 2.84 (s, 2 H), 2.50 (m, 4 H), 1.42 (m, 4 H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH2:24])[C:13]([OH:15])=[O:14].N1C=CC=CC=1.[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34]O.Cl.CN(C)CCCN=C=NCC>O1CCCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH2:24])[C:13]([O:15][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:36])[CH3:31])=[O:14]
Reactant: C[Si](C)(C)CCO
Reactant: C=Cc1ccccc1CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=Cc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid (2.47 g, 7.69 mmol) in tetrahydrofuran (35 mL) and cool in an ice bath. Treat with pyridine (1.6 mL, 20 mmol) and 2-(trimethylsilyl)ethanol (2.3 mL, 16 mmol). Stir for 30 minutes and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (2.21 g, 11.5 mmol). Stir for 22 hours at 5° C., then at room temperature for 1.5 hours. Cool to 0° C., add 0.6 times all reagents and stir at room temperature overnight. Dilute with ethyl acetate (150 mL), wash with 5% sulfuric acid (40 mL) and saturated sodium hydrogen carbonate (40 mL). Back extract with methylene chloride (100 mL), wash with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and purify by silica gel chromatography (2:1 hexane/ethyl acetate) to give the title compound (2.61 g, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C>[N+:11]([C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1O
Reaction time: 8 h

Procedure:
In a 50 mL polystyrene cartridge, to an amino tantagel (1 g, 0.45 mmol) in DMF (15 mL) were added 4-hydroxy-3-nitrobenzoic acid (1a) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), and DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol). After overnight shaking, the reaction mixture was washed with DMF (20 mL, 5 times), methylene chloride, and methanol (20 mL, 5 times each). To remove any undesirable side product, DMF (5 mL) and piperidine (0.5 mL) were-added to the cartridge and allowed to shake for 1.5 h. The resin was filtered and washed with DMF. The resulting piperidine salt was removed via the addition of a 10% HCl solution (in DMF, 20 mL) to the resin that was allowed to shake for 1.5h. The mixture was then filtered, washed with DMF (20 mL, 5 times), methanol, and methylene chloride (20 mL, 5 times each) and dried by nitrogen gas flow.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Cl)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-chloropropionyl chloride (49 ml) in dichloromethane (50 ml) was added to a mixture of anhydrous aluminium trichloride (55.5 g) in dichloromethane (120 ml). The mixture was stirred for 10 minutes at room temperature and then a solution of fluorobenzene (39.5 ml) in dichloromethane (30 ml) was added dropwise. The resulting mixture was stirred for one hour, allowed to stand for 16 hours and then poured on to an icehydrochloric acid mixture. The two phase mixture was vigorously stirred at room temperature for 11/2 hours, separated and the aqueous layer washed with dichloromethane (2×50 ml). The combined organic extracts were then washed with aqueous sodium hydroxide (3N, 2×100 ml), water (1×100 ml) and brine (1×100 ml), dried (MgSO4) and evaporated under reduced pressure to afford 2-chloro-1-(4-fluorophenyl)-1-propanone, 71.3 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](C(N)=O)[CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:27])[N:3]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CCOC(C)=O.CC#[N:57].O>>[NH2:57][C:20]1[CH:19]=[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:27])[N:3]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[N:16][CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)picolinamide (60 mg, 0.13 mmol) in EtOAc/MeCN/H2O (2 mL/2 mL/1 mL) was added iodobenzene diacetate (54 mg, 0.16 mmol) at 0° C. The reaction was stirred at rt for 2 hours, then concentrated in vacuo. The resulted residue was dissolved in EtOAc (10 mL), washed with saturated aq. NaHCO3, and then dried over anhydrous Na2SO4. The organic solution was concentrated in vacuo to give the title compound as a yellow solid (43 mg, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[N:15]1([CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCNCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
Benzyl 4-{[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]methyl}piperazine-1-carboxylate (5.0 g, 12.4 mmol) was dissolved in methanol (50 ml) in a three-necked flask. The air was removed under reduced pressure and replaced with argon before the addition of 10% Pd/C (1.24 g). A balloon of hydrogen was then added and the reaction stirred at room temperature for 18 h. The hydrogen was evacuated and replaced with argon. The catalyst was then filtered and the solvent removed under reduced pressure to afford the desired product as a white foam (3.5 g). The compound was used without further purification.
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][N:17]([CH3:19])[CH3:18])[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1.CI>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH3:1])[C:13](=[O:15])[C:12](=[CH:16][N:17]([CH3:19])[CH3:18])[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1
Reactant: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O

Procedure:
35.6 gm of a methanolic 30% sodium methylate solution were added dropwise to a solution of 46.5 gm of 7-chloro-5-(2'-chloro-phenyl)-1,3-dihydro-3-(dimethylamino-methylene)-2H-1,4-benzodiazepin-2-one in 300 ml of dry dimethylformamide at room temperature, accompanied by stirring, and the resulting mixture was stirred for 30 minutes more at room temperature and subsequently cooled to +5°C while stirring. Then, while maintaining that temperature by cooling, 58 gm of methyl iodide were added at a slow dropwise rate, again while stirring, and the resulting mixture was stirred for 90 minutes more at +5°C. Thereafter, the yellow precipitate which had formed was collected by vacuum filtration, washed with much water, dried and recrystallized from isopropanol, yielding the compound named in the heading above, which had a melting point of 199°-200°C.