Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:3]=1.ClC1N=CN=C(N[C@H]2C[C@@H]3OC(C4C=CC(OC)=CC=4)OC[C@@H]3C2)C=1.[NH2:42][C@@H:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>C(O)CCC>[C@@H:43]1([NH:42][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]3[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]3)[CH:3]=2)[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1
Reactant: OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Reactant: N[C@H]1CCc2ccccc21
Agent: COc1ccc(C2OC[C@@H]3C[C@@H](Nc4cc(Cl)ncn4)C[C@@H]3O2)cc1
Solvent: CCCCO
Product: OC[C@@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Temperature: 180 °C
Yield: 168 %

Procedure:
A mixture of (1S,2S,4R)-4-[(6-chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol (33.1 mg, 0.136 mmol), 6-chloro-N-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]pyrimidin-4-amine (81.6 mg, 0.226 mmol), (S)-(+)-1-aminoindan (0.222 mL, 1.73 mmol) and 1-butanol (1.00 mL) was heated to 180° C. for 6 h in a sealed tube using MWI. The reaction was purified via silica gel chromatography eluting with a gradient of 0 to 15% MeOH in DCM to afford the title compound (77.8 mg, 63%). LC/MS: Rt=1.29 min, ES+ 341 (AA standard).
Reaction SMILES: F[C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)=O.P(Cl)(Cl)(Cl)=O>C(O)C>[C:3]1([C:4]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:21]=3[N:13]([CH2:14][CH2:15]4)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:2]=1
Reactant: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccccc1F
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(C2=Nc3ccccc3N3CCc4cccc2c43)cc1
Reaction time: 1 h

Procedure:
A solution of 15.0 g of 1-(2-benzamidophenyl)indoline of Example 19, and 45 ml of phosphorus oxychloride is refluxed under N2 for 4 hours and then the excess reagent is removed to leave a syrup which is dissolved in absolute ethanol, boiled one hour, then concentrated again to a dark purple syrup which eventually solidifies affter prolonged standing. This material is slurried in absolute ethanol, and treated dropwise with enough Bu3N to change the color from purple to orange-brown, whereupon the product base crystallizes voluminously. After refrigeration overnight, the resultant orange-brown flakes are collected, washed with ethanol and hexane, and dried to afford 1,2-dihydro-6-phenylindolo[1,7-ab][1,5]benzodiazepine, m.p.141°-143° C.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.[OH-].[Na+]>[NH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])ccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc([N+](=O)[O-])ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
N-(4-methoxybenzyl)-4-nitropyridin-2-amine (27.8 g, 0.11 mol) and anisole (13 mL, 0.12 mol) were dissolved in trifluoroacetic acid (112 mL) and heated at 80° C. for 2 h. The reaction mixture was allowed to cool to rt and concentrated. Trituration of the resulting residue with EtOAc and hexanes produced a light yellow solid that was isolated via filtration. The filtrate was allowed to stand overnight and a second crop of crystals was obtained. The combined batches of solids were dissolved in 1N NaOH (250 mL) and extracted with EtOAc (2×250 mL). The combined organic solutions were dried over MgSO4, filtered and concentrated to give 2-amino-4-nitropyridine as an orange solid (10.2 g, 67%). LCMS: (FA) ES+ 140.1.
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.C([CH:7]([C:11]([O-:13])=O)[C:8]([O-:10])=[O:9])C.[K+].[K+].C(#N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Cu](Cl)Cl>[C:11]([CH2:7][C:8]([O:10][CH2:2][CH3:3])=[O:9])(=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCl
Reactant: N#Cc1ccccc1
Reactant: CCC(C(=O)[O-])C(=O)[O-]
Agent: Cl[Cu]Cl
Agent: [K+]
Product: CCOC(=O)CC(=O)c1ccccc1
Temperature: 90 °C
Yield: 68 %

Procedure:
To 100 □ of 1,2-dichloroethane were added 5.5 □ of benzonitrile, 3.6 g of copper chloride and 11 g of potassium ethylmalonate, and then the mixture was stirred at reflux. After the reaction was completed, 100 □ of 6 N hydrochloric was added to the mixture, which then was stirred at reflux at 90° C. for 1 hour. After confirming completion of the reaction by TLC, the solution was cooled to 20° C., and then an organic layer was separated therefrom. The organic layer was concentrated through distillation under reduced pressure. Thus resulted residue was purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=1/20, v/v) to obtain the title compound in the yield of 68% (7.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH2:24]O)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH2:24][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Agent: [Cl-]
Product: COc1ccc(-c2cc(=O)n(CCN3CCCCC3)nc2-c2ccc(OC)cc2)cc1
Yield: 38.1 %

Procedure:
After 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one was reacted with paratoluenesulfonyl chloride in a similar manner as in Example 116-(2), a further reaction was conducted with piperidine, whereby the title compound was obtained in a yield of 38.1%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:14][CH:13]2[N:15](C(OCC)=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:27][Si](C)(C)C>C(Cl)Cl>[I-:27].[C:1]([NH:5][C:6]([C:8]1([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:14][CH:13]2[NH2+:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)I
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)NC(C)(C)C)(C1CCCCC1)C2
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1(C2CCCCC2)CC2CCC(C1)[NH2+]2
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8-azabicyclo[3.2.1]octane-8-carboxylate (1-8) (1.00 g, 2.74 mmol) in DCM (20.0 mL) was slowly added iodotrimethylsilane (2.20 g, 11.0 mmol). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the solid was washed with ether (2×5 mL) to give (1-9 as a yellow solid.
Reaction SMILES: C1([O:6][C:7](=[O:48])[C@@H:8]([NH:40][C:41](OC(C)(C)C)=[O:42])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])CCCC1.[OH-:49].[Na+]>C1COCC1>[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:16]2[C:15]3[C:20](=[CH:21][C:12]([O:11][CH2:10][CH2:9][C@H:8]([NH:40][C:41]([C:15]([CH3:20])([CH3:16])[CH3:14])=[O:42])[C:7]([OH:6])=[O:48])=[C:13]([O:38][CH3:39])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:24][CH:25]=1)(=[O:49])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: [OH-]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(=O)C(C)(C)C)C(=O)O
Reaction time: 6 h
Yield: 241.4 %

Procedure:
To a solution of (S)-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-2-tert-butoxycarbonylamino-butyric acid cyclopentyl ester (17 mg, 0.02 mmol) in THF (1 ml) was added 2M NaOH (0.026 ml, 0.046 mmol, 2 eq). After 16 hours reaction was incomplete so an additional 2 equivalents of NaOH was added. The reaction was completed after 6 hours and the THF was removed under reduced pressure. The aqueous layer was diluted with 3 ml of water and acidified to pH 6 with 1M HCl. The title compound was extracted into ethyl acetate, dried over magnesium sulphate and isolated as a white solid (13.8 mg, 91% yield).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].CC(C)=O.[Br:17]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[Ag+:29]>C(OCCCC)(=O)C>[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1].[Ag+:29].[Ag:29][Br:17]
Reactant: CCCCCCCCCC(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCCCOC(C)=O
Solvent: CC(C)=O
Product: Br[Ag]
Product: CCCCCCCCCC(=O)[O-]
Temperature: 50 °C

Procedure:
A solution prepared by dissolving 8.6 g of capric acid in 100 ml of butyl acetate was cooled to 50° C. and, while stirring, 20 ml of a 2.5% by weight acetone solution of N-bromosuccinimide was added thereto. To this mixture was added 50 ml of an aqueous solution (pH=9.5) of silver nitrate-ammonium complex salt containing 8.5 g of silver nitrate (cooled to 5° C.) to thereby react capric acid, N-bromosuccinimide and silver ion with each other to simultaneously form both silver caprate and silver bromide. The resulting solid phase containing silver caprate and silver bromide was collected (80 g) by centrifugation and dispersed in 120 g of a 15% isopropanol solution of polyvinyl butyral using a mixer to prepare a silver salt polymer dispersion (Polymer dispersion C). To Polymer dispersion C was added 2 cc of a 0.1 wt% aqueous solution of potassium thiosulfate and, after heating for 20 minutes at 40° C. (heating in the presence of the sulfur-containing compound for sensitizing), 72 ml of a 70 wt% methyl cellosolve solution of p-phenylphenol heated to 40° C. was added to prepare a coating dispersion. This was coated on a clay-coated paper in an amount of 0.7 g silver/m2 to prepare a thermally developable light-sensitive material, Sample 7.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([C:33](=[O:35])[CH3:34])[CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(C)=O)CC2C(=O)OCC)cc1
Reaction time: 13 h
Yield: 68.3 %

Procedure:
To a solution of 0.170 g (0.466 mmol) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester in 10 mL of dichloromethane cooled at 0° was added 0.2 mL of triethylamine, 0.05 g of DMAP and 0.3 mL (0.93 mmol) of acetyl chloride. After stirring for 13 h the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (2:1) to provide 0.13 g (68%) of 4-acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester as a brown oil. Electrospray Mass Spec: 409.3 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].CO.[C:14]([O-])([O-])=O.[Cs+].[Cs+].IC>O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:14])=[O:7])=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(C=O)c1
Reaction time: 18 h
Yield: 164.6 %

Procedure:
3-Formylbenzoic acid (3.11 g, 20.7 mmol, Aldrich) in 10:1 methanol:water (110 mL) was treated with Cs2CO3 (3.11 g, 10.4 mmol). After stirring 18 hours, the solvent was evaporated under reduced pressure and the residue was dried under reduced pressure at 60° C. The residue was suspended in DMF (40 mL) and treated with iodomethane (2.58 mL, 41.4 mmol). After stirring at ambient temperature 2 hours, the mixture was poured into water and extracted with diethyl ether. The ether extracts were combined, washed with water, saturated NaHCO3, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a white solid (2.81 g).
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)=[C:6]([CH2:29][CH2:30][CH3:31])[CH:5]=1)#[N:3].C(NCC)C>CN(C=O)C>[NH2:3][C:2]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)=[C:6]([CH2:29][CH2:30][CH3:31])[CH:5]=1)=[S:1]
Reactant: S
Reactant: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 70 °C

Procedure:
Hydrogen sulfide was passed through a solution of methyl {5-[3-(4-cyano-2-propylphenoxy)propoxy]-1H-indol-1-yl}acetate (Example 51, 787 mg, 1.94 mmol) in DMF (15 mL) for 30 minutes at rt. Diethyl amine (0.3 mL, 2.90 mmol) was added, and the solution was heated to 70° C. for 3 h. The reaction mixture was cooled to rt, and the residual H2S was removed by passing argon through the reaction mixture for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica and washed with EtOAc. Concentration of solvent yielded a brown oil which was used in the next step without further purification. LC/MS m/z 441.2 (M+H)+; RT 3.35 min.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5].N1C=CC=CC=1.[F:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[F:28][CH2:29][C:30]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:31]
Reactant: O=C(Cl)CF
Reactant: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 91.2 %

Procedure:
3.3 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-chloroaniline and 1.6 g of pyridine are dissolved in 60 ml of tetrahydrofuran, and 1.93 g of fluoroacetyl chloride are added dropwise thereto under ice-cooling and stirring. The mixture is stirred for 30 minutes under ice-cooling and further stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water is added to the residue and crystalline precipitates are collected therefrom. The crystals are recrystallized from a mixture of dimethylformamide and ethanol (1:3). 3.6 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-chloroaniline are obtained as colorless needles.
Reaction SMILES: CC(C)C[OH:4].CN(C1C=CC=CN=1)C.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCOCC>O1CCCC1.CCCCCC>[C:22]([NH:21][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:4]
Reactant: CC(C)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
Compound 47 (0.45 g., 0.83 mmole) is dissolved in tetrahydrofuran (5 ml.) and 2-methylpropan-1-ol (0.07 g., 0.99 mmole), dimethylaminopyridine (50 mg.), and dicyclohexylcarbodiimide (0.205 g., 0.99 mmole ) are added. The mixture is stirred for three hours. Ether (15 ml.) and hexane (5 ml.) are added. The dicylohexylurea formed is filtered off and the solvent is evaporated. The residual oil is purified by chromatography on silica using 2% methanol in ethyl acetate as eluant, to give Compound 48.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[NH2:18].[O-:19][C:20]#[N:21].[K+].[OH-].[Na+]>O>[CH3:17][O:16][C:15]1[C:7]([O:6][CH3:5])=[C:8]2[C:9]([C:10](=[O:12])[NH:21][C:20](=[O:19])[NH:18]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)O)c(N)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(=O)[nH]c(=O)[nH]c2c1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Acetic acid (177.4 ml., 3.1 moles) was added to a vigorously stirred suspension of 3,4-dimethoxyanthranilic acid (436.5 g., 2.21 moles) in 10 liters of water. Then 2.24 liters of 20% potassium cyanate (5.53 moles) solution was gradually added and the mixture was stirred for one hour at 40° C. After cooling the reaction mixture to 20° C., 3.54 kg. sodium hydroxide pellets were added maintaining the temperature below 40° C. The reaction mixture was heated to 90° C. for 45 minutes and then slowly cooled in an ice bath. The sodium salt of the product was filtered, resuspended in 6 liters of water, acidified with concentrated hydrochloric acid (370 ml.), cooled and filtered to yield 404 grams (82%) of the product. Recrystallization from dimethylformamide gave colorless crystals, M.P. 314°-6° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Yield: 15 %

Procedure:
A solution of 2-chloro-5-trifluoromethyl-pyridine (2.45 g, 13.50 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 16.19 mmol, 1.2 equiv; commercially available) in DMAc (12 mL) was heated by microwave irradiation to 155° C. for 6 h. A solution of 1 M NaOH (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) to yield 0.69 g (15%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.31-1.47 (m, 2H), 1.40 (s, 9H), 1.92-1.98 (m, 2H), 2.81-2.92 (m, 2H), 3.72-3.83 (m, 1H), 3.97-4.03 (m, 2H), 4.77 (d, J=8.1 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 8.25 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ27.45, 31.17, 41.64, 47.51, 78.72, 105.86, 114.65 (q, J=32.8 Hz), 123.58 (q, J=268.6 Hz), 133.26, 145.15, 153.76, 158.36. 19F NMR (282 MHz, CDCl3): 1-61.22. MS (ISP): 346.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:29]I.O>C1COCC1>[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])([CH3:29])[C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 159.6 %

Procedure:
To a solution of 3.00 g (8.19 mmol) of Boc-Orn (Z)-OH in 82 ml of THF were added 1.31 g (32.8 mmol) of 60% sodium hydride and 4.08 ml (65.5 mmol) of methyl iodide with ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was combined with water with ice cooling, and washed with hexane. The aqueous layer was combined with 10% aqueous citric acid solution, extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 3.22 g (100%) of Boc-N-Me-Orn (Me) (Z)-OH.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:15].Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:14]([O:15][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH2:13]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: C=C(O[Si](C)(C)C)c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
Diisopropylamine (16.2 g) was dissolved in tetrahydrofuran (133 ml), and 1.6N n-butyl lithium (100 ml) was dropwise added thereto under ice-cooling. The reaction mixture was stirred at the same temperature for 10 min, and a solution of 2,4-dichloroacetophenone (25.2 g) in tetrahydrofuran (133 ml) was dropwise added under cooling in a dry ice-acetone bath. Hexamethylphosphoramide (26.7 ml) was added little by little. The mixture was stirred at the same temperature for 5 min, and chlorotrimethylsilane (20.3 ml) was dropwise added, which was followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ice-cooled n-hexane and ice-cooled water. The organic layer was washed twice with ice-cooling water and then once with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to dryness to give a crude product (37.5 g) of the objective compound as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(C)cc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C)cc2)n1

Procedure:
93 mg (59.7%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methylphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (95 mg, 0.371 mmol), 1-(2-fluorophenyl)piperazine(76 mL, 0.482 mmol), and NaCNBH3 (70 mg, 1.112 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%. NMR δ(CDCl3) ppm: 1.46(d, J=8.4 Hz, 9H), 2.3(m, 1H), 2.5 to 2.8(m, 1H), 3.08(s, 3H), 3.8 to 4.0(m, 5H), 4.3 to 4.6(m, 1H), 5.3(m, 1H).