Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:52])([F:51])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([NH:45][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[N:33][N:34]3COCC[Si](C)(C)C)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1>[F:52][C:20]([F:19])([F:51])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([NH:45][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 66 °C

Procedure:
12.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-[4-(trifluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 18 hours, the heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with an ethyl acetate/cyclohexane mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 10 cm3 of diisopropyl ether, filtered on a sinter funnel and then washed successively with 10 cm3 of diisopropyl ether and then with 2×2 cm3 of ethyl acetate. After drying (90 Pa; 50° C.), 520 mg of N-[6-[4-(trifluoromethoxy)phenyl]-1H-indazol-3-yl]butanamide are obtained in the form of a white product melting at 234° C.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([CH2:8][C:9]([OH:11])=O)([C:5]([OH:7])=O)O.CCOCCOCCO.C(O)(=O)CCCCCCC/C=C\CCCCCCCC.C(O)C(O)C.[CH3:48][N+:49](CC(O)=O)(C)C.CCCCCCCC/C=C\CCCCCCCCOCCOCCO.C([O-])(=O)C=C.S([O-])([O-])=O.[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[OH-].[NH4+]>O>[NH2:49][C:48]1[CH:1]=[CH:2][C:3]([CH2:5][OH:7])=[CH:8][C:9]=1[OH:11]
Reactant: C[N+](C)(C)CC(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C=CC(=O)[O-]
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCCOCCOCCO
Solvent: CC(O)CO
Solvent: CCOCCOCCO
Solvent: O
Product: Nc1ccc(CO)cc1O
Temperature: 40 °C

Procedure:
To prepare pre-mix: Add to a suitable vessel in the following order, citric acid, ethoxy diglycol, oleic acid, propylene glycol, and cocaamidopropyl betaine, then agitate until fully dispersed, then add Oleth-10, Oleth-2 and acrylate co-polymers, continue the agitation for 10 minutes and transfer to main vessel. To the main vessel then add water (heated to 50° C.), oleic acid, water, sodium sulphite, and EDTA. Next weigh out and add the ascorbic acid, then stir well until dissolved. Separately weigh dyes into a clean beaker and transfer also to the main vessel. Add the dyes and stir until dissolved (heat to 40° C. as necessary). Cool to room temperature with stirring, add the ammonium hydroxide and water with stirring, add citric acid to pH 10, and transfer to the storage container.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][CH2:32][N:33]([C:41](=[O:43])[CH3:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[CH3:44][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][N:33]([C:34]1[CH:39]=[CH:38][C:37]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1)[C:41](=[O:43])[CH3:42]
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(3-dimethylamino-propyl)-N-acetyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C30H32N4O4
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:9]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:8]([Cl:31])=[CH:7][C:3]=1[C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>O1CCCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:9]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:8]([Cl:31])=[CH:7][C:3]=1[C:4]([N:61]1[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]1)=[O:5]
Reactant: CN1CCNCC1
Reactant: COc1ccc(COc2c(Cl)cc(C(=O)O)c(Cl)c2OCc2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2c(Cl)cc(C(=O)N3CCN(C)CC3)c(Cl)c2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of 2,5-dichloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (2.02 g: 4.36 mMol.) and 1-hydroxybenzotriazole (648 mg: 1.1 Eq.) in tetrahydrofuran (40 ml) is added dicyclohexylcarbodiimide (990 mg: 1.1 Eq.), and the mixture is stirred at room temperature for 90 minutes. This solution is mixed with N-methylpiperazine (0.66 g: 1.5 Eq.) and stirred at room temperature for 1 hour. The reaction mixture is filtered to remove solid and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give 1-(2,5-dichloro-3,4-bis(p-methoxybenzyloxy)benzoyl)-4-methylpiperazine (1.7 g) from the fraction eluting with 5% methanol-chloroform. Yield: 71%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[CH3:25][O:26][CH:27]([CH2:30][O:31][CH3:32])[CH:28]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:28][CH:27]([O:26][CH3:25])[CH2:30][O:31][CH3:32]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: COCC(C=O)OC
Product: COCC(C=NOCCC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21)OC

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2,3-dimethoxypropanal by the method of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C=O.Cl[CH2:14][Cl:15].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[Cl:15][CH2:14][C:10]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)OCO2
Reactant: ClCCl
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCOCC
Product: Cc1cc2c(cc1CCl)OCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
At about 0° C., 5-methylbenzo[d][1,3]dioxole (500 mg, 3.68 mmol) and formaldehyde (37% in water, 0.7 mL) were sequentially added to a mixture of dichloromethane (6.8 mL), tetrabutylammonium bromide (80 mg) and concentrated hydrochloric acid (6.5 mL). Under continuous stirring, the mixture was maintained at about 0° C. for about 1 hour and then at ambient temperature for about 4 hours. The mixture was diluted with ether (100 mL). After standard extractive workup, the resulting solid residue was heated with hexanes (100 mL) and the insolubles were removed by filtration. The filtrate was concentrated to give desired product (420 mg, 62%). 1H NMR (300 MHz, CDCl3) δ 6.89 (s, 1H), 6.69 (s, 1H), 5.94 (s, 3H), 4.56 (s, 2H), 2.35 (s, 3H); GC-MS: m/z=184 (MH)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CN(C)CCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.7 mg (0.23 mmol) of N-(2-aminoethyl)-N,N-dimethylamine are reacted together by general method E. 42.5 mg (64.5% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][N:11]1[C@H:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:35]
Reactant: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Yield: 108.8 %

Procedure:
Deprotection of (R)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (410 mg, 0.86 mmol, 1 equiv) was accomplished in 3 hours in the presence of 4M hydrogen chloride solution in dioxane at ambient temperature. The resulting mixture was concentrated and dried in vacuo to afford the hydrogen chloride salt of the title compound as a white solid (355 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.81-1.85 (d, 2H, J=14.0 Hz), 2.66-2.74 (m, 2H); 3.44-3.51 (m, 4H); 3.75 (s, 3H); 4.21 (d, 1H, J=4.4 Hz); 4.84 (d, 1H, J=4.8 Hz); 5.93 (s, 1H); 6.85 (t, 1H, J=7.2 and 7.6 Hz); 6.95 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.39-7.45 (m, 4H); 7.53 (s, 1H); 8.97-9.04 (m, 2H); MS for C22H25N3O3 m/z 380.03 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:9][CH3:10])[S:5][C:6]=1[C:7]#[N:8].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:7]([C:6]1[S:5][C:4]([S:9][CH3:10])=[N:3][C:2]=1[N:1]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:8]
Reactant: CSc1nc(N)c(C#N)s1
Reactant: COC(OC)N(C)C
Product: CSc1nc(N=CN(C)C)c(C#N)s1
Yield: 99 %

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-methylsulfanyl-thiazole-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound as a white foam (0.132, g, 99%).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.Cl[Cu]>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: Cl[Cu]
Solvent: O
Solvent: CCO
Product: Nc1ccn(-c2ccccc2)n1
Reaction time: 3 h
Yield: 79 %

Procedure:
Example 1 was repeated using the following amounts of reagents: 5 g (0.031 mole) of 1-phenyl-3-amino-2-pyrazoline were suspended in 25 ml of ethanol and 2 ml of H2O, under addition of 0.1 g (0.001 mole) of CuCl and 0.064 g (0.001 mole) of Cu, under an oxygen head. Oxidation lasted about 3 hours. 3.9 g of 1-phenyl-3-aminopyrazole were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:37])[NH:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30](=[O:37])[NH:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)CNC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.4 %

Procedure:
To a mixed solution of 6-bromo-2-[4-(methoxycarbonylmethylcarbamoyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) in methanol (3 ml) and tetrahydrofuran (3 ml) was added 8N aqueous sodium hydroxide solution (0.05 ml), and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was acidified with 1N hydrochloric acid and extracted with dichloromethane. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and methanol was added to the obtained residue. The mixture was crystallized to give the title compound (15 mg, 15%).
Reaction SMILES: NC1C=C(C2N=CN(C)C=2C2SC3N=CN=C(N)C=3C=2)C=CC=1.C1(C(=[N:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:45]=[CH:46][N:47]([CH3:59])[C:48]=3[C:49]3[S:58][C:52]4[N:53]=[CH:54][N:55]=[C:56]([NH2:57])[C:51]=4[CH:50]=3)=[CH:40][CH:39]=2)C2C=CC=CC=2)C=CC=CC=1.C1(C(=NC2C=CC=CC=2N2C=C(C3(N)NC=NC4SC=CC3=4)N(C)C2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[CH:46][N:47]([CH3:59])[C:48]=2[C:49]2[S:58][C:52]3[N:53]=[CH:54][N:55]=[C:56]([NH2:57])[C:51]=3[CH:50]=2)=[CH:40][CH:39]=1
Reactant: Cn1cnc(-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)c1-c1cc2c(N)ncnc2s1
Agent: CN1CN(c2ccccc2N=C(c2ccccc2)c2ccccc2)C=C1C1(N)NC=Nc2sccc21
Agent: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Product: Cn1cnc(-c2ccc(N)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 110 but using 6-(4-{4-[(diphenylmethylene)amino]phenyl}-1-methyl-1H-imidazol-5-yl)thieno[2,3-d]pyrimidin-4-amine (Intermediate 111) in place of 6-(4-{3-[(diphenylmethylene)amino]phenyl}-1-methyl-1H-imidazol-5-yl)thieno[2,3-d]pyrimidin-4-amine (Intermediate 109). Colourless solid (276 mg, 87%);
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][C:11]3=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)CC>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:9]1[N:10]=[C:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:25][NH2:26])=[CH:3][CH:4]=1
Reactant: Fc1ccc(-c2nc3n(c2-c2ccc(Cl)nn2)CCC3)c(F)c1
Reactant: NN
Solvent: O
Solvent: CCCO
Product: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Temperature: 105 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A 500 mL round bottom flask was charged with 3-(6-chloropyridazin-3-yl)-2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (7.50 g, 22.5 mmol), 1-propanol (225 mL) and hydrazine hydrate (11.3 g, 225 mmol). The mixture was then heated at about 105° C. for about 10 h. The reaction mixture was cooled to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove about ¾ of the volume. The remaining mixture was stirred with DCM (250 mL) and saturated aqueous NaHCO3 (200 mL). The layers were partitioned, the aqueous layer was diluted with water (100 mL) and extracted with DCM (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with Et2O (50 mL) and the solid was collected by vacuum filtration. The filter cake was washed with additional Et2O (10 mL) and then dried in a vacuum oven for about 1 h at about 60° C. to give the title compound (4.59 g, 62%): LC/MS (Table 1, Method g) Rt=1.41 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: [Cl-:1].[C:2]([O:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])(=[O:5])[CH:3]=[CH2:4].S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O)(=O)CCCC(O)=O.[Na+].[Na+].[Na+].[Na+].C(N(CC([O-])=O)CC([O-])=O)C[N:35](CC([O-])=O)CC([O-])=O.C(OO)(C)(C)C.S(=O)(=O)(O)O.CCCCCCCC/C=C\CCCCCCCC(OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=O>O.C(O)(C)C>[C:2]([NH2:35])(=[O:6])[CH:3]=[CH2:4].[Cl-:1].[C:2]([O:6][CH2:7][CH2:8][N+:9]([CH3:11])([CH3:10])[CH3:12])(=[O:5])[CH:3]=[CH2:4]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: C=CC(=O)OCC[N+](C)(C)C
Agent: CC(C)(C)OO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Solvent: O
Solvent: CC(C)O
Product: C=CC(N)=O
Temperature: 40 °C

Procedure:
General polymerization procedure. AMD, acryloxyethyltrimethylammonium chloride, ammonium sulfate, glutaric acid solution, ethylenediaminetetraacetic acid tetra sodium salt solution, isopropanol, tert-butyl hydroperoxide solution, and DI water are combined and the pH adjusted to 3.5 with sulfuric acid. Sorbitan monooleate is combined with low odor paraffin oil. The aqueous solution is slowly added to the oil solution and the combined mixture homogenized until a viscosity of 1200-1500 cps is obtained. The emulsion is sparged with nitrogen. The emulsion is heated to 40° C. The metabisulfite (MBS) solution is added at a rate to keep the reaction temperature between 40-45° C. This is maintained until the reaction conversion is at least 99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[OH-].[Li+]>O1CCOCC1>[N:17]1([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]=3[CH:10]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1cc2cc(OCCN3CCCC3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.8 %

Procedure:
To an ice-cooled solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid methyl ester (960 mg, 33 mmol) anhydrous ethylene glycol dimethyl ether (10 ml) was added dropwise degassed aqueous lithium hydroxide solution (2.0 ml, 2.0M). After stirring at room temperature for 4 h, the solution was cooled down and the pH was adjusted to 2 with 4.0 MHO in dioxane. A gummy tan precipitate formed. The solvent was removed and the gummy residue was frozen and lyophilized. The tan colored solid was dissolved in boiling 2-propanol (90 ml), the solution was filtered hot and then cooled to give 5-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-2-carboxylic acid as beige colored needles (528 mg). Additional 153 mg was obtained from the mother liquor.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2].[Cl:20]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[C:11]([Cl:20])=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2]
Reactant: COC(=O)c1cccn1Cc1ccccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)n1Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.5 g of methyl 1-(2-nitrobenzyl)pyrrole-2-carboxylate in 50 mL of dry tetrahydrofuran is added 1.54 g of N-chlorosuccinimide. The reaction is allowed to stir at room temperature for 48 hours. To the reaction mixture is added sodium sulfite, the reaction is stirred for an additional 1 hour, filtered and evaporated to dryness. The residue is extracted into 200 mL of ether, the extract is dried over anhydrous magnesium sulfate and evaporated to dryness to yield methyl 1-(2-nitrobenzyl)-5-chloropyrrole-2-carboxylate which is used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[C:6](/[F:12])\[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([F:12])[CH:7]=[O:8]
Reactant: CCOC(=O)/C(F)=C\CCCCl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: O=CC(F)=CCCCCl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4.56 Grams of ethyl (E)-6-chloro-2-fluoro-2-hexenoate was dissolved in 50 ml of hexane under a nitrogen atmosphere. The resulting solution was cooled to -78° C. in a dry ice-acetone bath, and 24 ml of diisobutylaluminum hydride (as 1.0 M hexane solution) was added dropwise. After addition, the solution was stirred at -78° C. for 1 hour. The reaction solution was poured into cooled 5% hydrochloric acid, and after separating the hexane layer, the aqueous layer was extracted twice with ether. The ether extracts were combined with the above hexane layer, and this mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure to obtain 2.35 g of 6-chloro-2-fluoro-2-hexenal [E form/Z form (6.8:1) mixture by NMR determination].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:24])[C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH:16]([CH3:22])[CH2:15]4)[CH:12]=3)[C:7](=[O:25])[CH:6]([CH:26]=[O:27])[CH2:5]2)[CH2:3][CH2:2]1>CO.[O-2].[O-2].[Mn+4]>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:24])[C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH:16]([CH3:22])[CH2:15]4)[CH:12]=3)[C:7](=[O:25])[C:6]([CH:26]=[O:27])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(N2CCN(C=O)C(C)C2)cc2c1C(=O)C(C=O)CN2C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: Cc1c(F)c(N2CCN(C=O)C(C)C2)cc2c1c(=O)c(C=O)cn2C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
1-Cyclopropyl-6-fluoro-7-(4-formyl-3-methyl-1-piperazinyl)-5-methyl-4-oxo-3-formyl-1,2,3,4-tetrahydroquinoline (4.0 g) is dissolved in methanol (150 ml) and thereto is added manganese dioxide (9.3 g), and the mixture is stirred at room temperature for 2 hours. After removing manganese dioxide by filtration with celite, the filtrate is concentrated, and the resulting residue is recrystallized from ethanol to give 1-cyclopropyl-6-fluoro-7-(4-formyl-3 -methyl-1-piperazinyl)-5-methyl-3-formyl-1,4-dihydro-4oxoquinoline (3.9 g), as pale yellow powdery crystals, m.p. 258°-260° C.
Reaction SMILES: [ClH:1].C(OC([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2([NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[CH2:21][CH2:20]2)[C:14](=[O:38])[CH2:13]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[C].[Pd]>[ClH:1].[CH2:36]([O:35][C:33]([NH:32][C:19]1([CH2:18][N:15]2[CH2:16][CH2:17][NH:12][CH2:13][C:14]2=[O:38])[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)[CH2:23][CH2:24]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (0.7 ml) and 10% palladium carbon (500 mg) were added to a solution of 4-benzyloxycarbonyl-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidiny]methyl}-2-piperazinone (1.3 g) in ethanol (50 ml), and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. After the catalyst was removed, the solvent was distilled off to obtain the colorless amorphous title compound (1.15 g).