Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9].[C-:20]#[N:21].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9])#[N:21]
Reactant: [C-]#N
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(CCl)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Dissolve 5-(3-chloromethyl-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in PREPARATION 32), (120 mg, 0.44 mmol) in N,N-dimethylformamide (2.2 mL) and treat with sodium cyanide (86 mg, 1.8 mmol). After stirring for 30 min at room temperature, dilute with ethyl acetate and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 70:30 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (90 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:42]3[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]3)=[O:28])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
1.78 g of N,N'-carbonyldiimidazole was added to a solution of 4.46 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 45 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled with ice, and a solution of 2.05 g of 1-t-butoxycarbonylpiperazine in 45 ml of dry acetonitrile was added to the mixture, which was then allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The ethyl acetate solution was washed with water and with an aqueous solution of sodium chloride and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:2 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 5.4 g of the title compound, as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3O)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C(O)C>[CH:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:10]2[C:5]=1[CH:6]1[O:19][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:7]1[CH2:8][O:9]2
Reactant: O=c1c(-c2ccccc2O)coc2cc(O)ccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
To a stirred solution of 7-hydroxy-3-(2-hydroxy-phenyl)-chromen-4-one (3 gm, 11.8 mmol) in absolute ethanol (30 ml) at 0° C. was added NaBH4 (2.7 gm, 70.8 mmol). The reaction mixture was then stirred for 24 hours at room temperature. The reaction was stopped by adding ice-cooled water and the solution was neutralized with 10% HCl to get the white precipitate. The white precipitate was washed with water and the purified by silica gel column chromatography using hexane-chloroform as the eluent to give 6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (1.6 gm, 57%) as white solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]1[S:17][C:16]2=[N:18][CH:19]=[C:20]([CH:21]=[O:22])[N:15]2[C:14]=1[CH3:23].[Cl-].[NH4+]>CCOCC>[CH3:12][C:13]1[S:17][C:16]2=[N:18][CH:19]=[C:20]([CH:21]([CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[OH:22])[N:15]2[C:14]=1[CH3:23]
Reactant: BrCCCc1ccccc1
Reactant: Cc1sc2ncc(C=O)n2c1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1sc2ncc(C(O)CCCc3ccccc3)n2c1C
Yield: 31.7 %

Procedure:
Magnesium (0.29 g) in ether was treated with 1-bromo-3-phenylpropane (2.38 g) and reacted for 5 hours. Solid 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) (0.72 g) was added and the viscous mixture was reacted for 1.5 hours. The thick suspension was diluted with ether and poured into cold 5% ammonium chloride solution. The mixture was extracted with ethyl acetate, the extract was dried and evaporated to a semi-crystalline residue (1.6 g). The residue, containing unreacted 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6), was triturated with ether, filtered and the filter cake (0.50 g) was recrystallized from acetonitrile to yield pure 2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol (Formula A-9) (0.38 g), m.p. 167-169°.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4]CC1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[H-].[Na+]>CN(C=O)C>[N:16]1([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(n2cncn2)CC1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A solution of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (567 mg, 2.40 mmol) and 1,2,4-triazole (232 mg, 3.36 mmol) in dry DMF (5.00 mL) was treated with sodium hydride 60% (125 mg, 3.12 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 65° C. for 72 h. It was poured in ice water (75 mL), extracted 3 portions of 75 mL of EtOAc. The organic portions were combined, dried over anhydrous Na2SO4 and concentrated. The solid was purified by silica gel column chromatography using a gradient from 100% EtOAc to 5% MeOH:EtOAc as eluent to furnished the final compound I-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,4]triazole as a white solid (247 mg, 49%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[C:7]1([CH3:14])[CH3:13])=[O:5])C.[OH-].[K+]>O>[CH3:13][C:7]1([CH3:14])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reaction time: 2 h
Yield: 95 %

Procedure:
24.7 g. of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropane-1-carboxylic acid ethyl ester (purity: 96%, cis)trans ratio: 40:60), 6.7 g. of a 30% aqueous potassium hydroxide solution and 0.05 g. of polyoxyethylenesorbitane monooleate are stirred at 70° C. for 60 minutes. Stirring is continued with a further 6-g. portion of the potassium hydroxide solution for 60 minutes and with an additional 6-g. portion for 120 minutes. The solution is diluted with 100 ml. of water and 40 ml. fraction is distilled off to remove volatile, non-hydrolyzed substances. To the residual aqueous solution 80 cm3 of hexane is added followed by the addition of 12 g. of a 36% aqueous hydrochloric acid solution at 60° C. with stirring. The reaction mixture is then further manufactured as described in Example 1. 19.8 g. (95%) of 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane-1-carboxylic acid are obtained. Cis/trans ratio: 40:60.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Br:18]Br>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([CH3:10])[C:9]=1[Br:18])=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1Br
Temperature: 62.5 °C
Reaction time: 1.5 h
Yield: 42.53 %

Procedure:
To a stirred solution of methyl-5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (prepared according to the procedure reported in WO 2007092751, 4.0 g, 15.0 mmol) in chloroform (50 ml) at 25° C. was added zinc chloride (2.06 g, 15.0 mmol) followed by the addition of bromine (2.64 g, 0.85 ml, 16.5 mmol) in a dropwise manner under a nitrogen atmosphere. The resulting mixture was stirred at 60-65° C. for 1.5 hr. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C. and quenched with water (30 ml). The resulting organic layer was washed with 10% aqueous sodium bicarbonate solution (2×50 ml) and dried over anhydrous Na2SO4. The solvent in the organic layer was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 3% ethyl acetate in hexanes as an eluent to obtain the title compound (2.2 g, 42.53%);
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:30]1[C:35](=[O:36])[CH2:34][CH2:33][C:31]1=[O:32])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:32]=[C:31]1[CH2:33][CH2:34][C:35](=[O:36])[N:30]1[O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)O
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O

Procedure:
Octanedioic acid mono-tert-butyl ester (3.14 g, 13.63 mmol) was dissolved in THF (100 mL). TSTU (4.9 g, 16.3 mmol) was added and pH was adjusted to 8.5 with DIPEA (2.85 mL).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[ClH:31]>>[ClH:31].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: c1cc(N2CCNCC2)ccn1
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(c4ccncc4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 1-pyridin-4-yl-piperazine, followed by de-protection with HCl.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:13][CH3:12])=[O:5]
Reactant: O=C(Cl)c1c(I)ccnc1O
Reactant: CO
Product: COC(=O)c1c(I)ccnc1O

Procedure:
Thionyl chloride (3.81 ml, 52.2 mmol) was added to a suspension of 2-hydroxy-4-iodonicotinic acid (3.46 g, 13.1 mmol) in dichloromethane (12 mL) in a pressure vessel at room temperature. The reaction mixture was then heated at 75° C. for 3 h. An aliquot was taken and hydrolyzed with methanol. LCMS analysis showed the derived methyl ester seen as major compound. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give 2-hydroxy-4-iodonicotinoyl chloride. 2-hydroxy-4-iodonicotinoyl chloride in MeOH (100 mL) was stirred at room temperature for 2 h. Concentration in vacuo of the reaction mixture afforded methyl 2-hydroxy-4-iodonicotinate (3.64 g, 13.1 mmol, quantitative yield). MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C7H6INO3: 279.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Methyl 5-cyano-2-methoxybenzoate (2 g) obtained in step A of Example 1-3-1 was dissolved in 28 mL of 1,4-dioxane, and 21 mL of an aqueous solution of 2.5 mols of sodium hydroxide was added. After stirring for 30 minutes at room temperature, the reaction mixture was cooled in an ice bath, and neutralized with the use of 50 mL of 1 M hydrochloric acid. The resulting aqueous solution was extracted 6 times with methylene chloride. The respective organic layers were combined, whereafter the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with methylene chloride. The filtrate and the washings were combined, and methylene chloride was distilled off under reduced pressure. The resulting solid was dried under reduced pressure to obtain 1.6 g (87%) of 5-cyano-2-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(OCC)C.C(N(CC)CC)C>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
40.0 g. of p-methoxybenzoyl chloride, 25.0 g. of 2-pyrrolidinone and 110 ml. of absolute diethyl ether are treated at between 0° C. and 10° C. while stirring with 52.5 ml. of triethylamine. The mixture is stirred at room temperature for a further 30 minutes and at reflux for 3 hours, then cooled down and treated at 2° C. with cold water. The insoluble constituents are filtered off under suction and washed with water and diethyl ether. The thus-obtained solid substance is recrystallized from alcohol after drying over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone which melts at 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:30])[N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([O:31][CH3:32])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:30])[N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)=[C:18]([O:31][CH3:32])[CH:17]=4)[CH2:35][CH2:34][N:11]3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(=O)N1CCCC1
Reactant: BrCCBr
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCC(=O)N1CCCC1

Procedure:
Following the procedure described in Example 1 step D, 4-(4-chlorophenyl)-N-(3-methoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-pyrrole-2-carboxamide (11 mg) was alkylated with 1,2-dibromoethane to yield 9.2 mg of the title compound. MS (ESI) 480 (M+H)+.
Reaction SMILES: Cl.O1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16](C(OC(C)(C)C)=O)[NH:17]C(OC(C)(C)C)=O>CC(O)C>[ClH:15].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][NH2:17]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cccc1Br
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NNc1c(Cl)cccc1Br
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 162.1 %

Procedure:
4M Hydrogen chloride in dioxane (28.2 mL, 112.64 mmol) was added to di-tert-butyl 1-(2-bromo-6-chlorophenyl)hydrazine-1,2-dicarboxylate (Intermediate AH1) (9.5 g, 22.53 mmol) in iPrOH (30 mL) at ambient temperature. The resulting solution was heated to 60° C. and stirred for 20 minutes. The reaction mixture was allowed to cool to ambient temperature. A solid was filtered off, and dried under vacuum to afford the product (4.71 g). 1H NMR (400 MHz, DMSO) d 6.97 (1H, s), 7.06 (1H, t), 7.41 (1H, dd), 7.52 (1H, dd), 9.83 (3H, s). m/z M+=220; GC-MS tR=10.419 min.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:13]=[C:14]([C:18](=[O:20])[CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>CO.[OH-].[Na+]>[NH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:13]=[C:14]([C:18](=[O:20])[CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
In a mixed solvent of 3 ml of methanol and 3 ml of 10% by weight aqueous sodium hydroxide solution was dissolved 0.5 g of 6-(4-acetaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid, and the resulting solution was subjected to reaction at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and adjusted to a pH of 6.0 with acetic acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 0.36 g of 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 262°-266° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: COCCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: COCCN1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol), 1-(2-methoxyethyl)piperazine (0.94 mL, 6.5 mmol) and DMSO (3.5 mL) were added and stirred at 100° C. for 1.0 hour. The reaction mixture was added with water and was washed with hexane/ethyl acetate (4/1) to remove impurities. After removing impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4-[4-(2-methoxyethyl) piperazin-1-yl]-2-nitrobenzaldehyde (0.23 g, 68%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][C@@H:36]4[C@@H:38]([CH:37]4[C:40]([N:46]4[CH2:49][CH:48]([OH:50])[CH2:47]4)=[O:41])[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CC(O)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with azetidin-3-ol (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H44Cl2N5O4 [(M+H)+] 704.2765, observed 704.2764.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:7]=1)=[O:5])[CH3:2]>O1CCCC1.C.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10](=[O:11])[NH:9]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(N)cc2)[nH]c1=O
Reaction time: 2 h
Yield: 99 %

Procedure:
4-Ethoxycarbonyl-2-(4-nitrophenyl)-3-pyrazolin-5-one (5.66 g, 20.43 mmol) in distilled tetrahydrofuran (250 ml) containing 10% Palladium|charcoal catalyst (1.13 g) was hydrogenated at atmospheric pressure for 11/2 hours at 0° C. followed by 2 hours at room temperature. The catalyst was then removed by filtration through celite and the celite washed with tetrahydrofuran. The filtrate was then evaporated to dryness to yield the title compound (5.0 g) after trituration (Ether; hexane), νmax (Nujol) 1693, 1675, 1630, 1599, 1585, 1290, 835, 775 cm-1 δ(D6 -Acetone) 1.37 (3H, t, J7 Hz, --OCH2CH3), 3.10 (2H, bs, --NH2), 4.36 (2H, q,J7Hz, --OCH2CH3), 6.80 (2H, d, J9Hz, protons o--NH2), 7.53 (2H, d, J9 Hz, protons m--NH2), 8.35 (1H, s, C3 pyrazole proton). Found: M+, 247.0954; C12H13N3O3 requires M, 247.0956.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.[CH:25](N(CC)C(C)C)([CH3:27])[CH3:26].BrCCC>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][N:23]([CH2:26][CH2:25][CH3:27])[CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCBr
Solvent: C1COCCO1
Product: CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of (±)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) in 1,4-dioxane (0.5 mL) and N,N-diisopropylethylamine (108 mg, 0.83 mmol) were added 1-bromopropane (21 mg, 0.17 mmol) and KI (catalytic amount). The reaction mixture was heated at 100° C. for 15 h. The reaction mixture was cooled to 20° C. then concentrated in vacuo and chromatographed on a silica gel column by elution with CHCl3/MeOH (99/1) to give the title compound (27 mg, 82%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ0.92 (t, J=7.3 Hz, 3H), 1.58-1.75 (br, 2H), 2.03-2.23 (m, 5H), 2.42-2.55 (br, 2H), 2.58-2.67 (m, 1H), 2.75 (t, J=7.4 Hz, 2H), 2.85-2.95 (br, 1H), 2.98-3.12 (br, 1H), 3.31 (dt, J=10.3, 3.6 Hz, 1H), 3.37-3.45 (br, 2H), 6.94 (s, 1H), 6.97 (s, 1H), 7.15-7.20 (m, 2H), 7.36-7.42 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])[NH2:5].[CH3:13][O:14][C:15]1([C:18](OC)=[O:19])[CH2:17][CH2:16]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:18]([C:15]2([O:14][CH3:13])[CH2:17][CH2:16]2)=[O:19])=[CH:3][C:2]=1[Cl:1])([CH3:12])[CH3:11]
Reactant: COC(=O)C1(OC)CC1
Reactant: CC(C)Oc1ccc(N)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC1(C(=O)Nc2ccc(OC(C)C)c(Cl)c2)CC1
Yield: 21.2 %

Procedure:
A mixture consisting of 5.6 g of 3-chloro-4-isopropoxyaniline, 3.9 g of methyl 1-methoxycyclopropanecarboxylate and 1.8 g of sodium methoxide in 50 ml of benzene was refluxed for 3 hours. The reaction mixture was concentrated to a volume of 25 ml, poured over ice water, acidified with hydrochloric acid and extracted with ether. The extract was dried, filtered and concentrated. Purification by silica chromatography gave 1.8 g of product as a white crystalline solid; m.p. 86°-87° C.