Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35]Br.O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:20]=[CH:19][CH:18]=[C:16]([N:17]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:15]=3)=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2[nH]c(Cc3cccc(N)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: BrCCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3cccc(N4CCCC4)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 120 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
To a solution of 6-(5-(6-methylpyridin-2-yl)-2-(3-nitrobenzyl)-1H-imidazol-4-yl)quinoline (500 mg, 1.186 mmol, prepared according to the method described in US 2008/0319012 A1) in MeOH (5 mL) was added Pd/C (0.5 mg, 10% w/w) and the mixture was stirred under H2 at atmospheric pressure for 5 hours. The reaction mixture was filtered through celite and the filterate was concentrated under reduced pressure. The residue was purified by MPLC on silica gel (MeOH:CH2Cl2=1:50) to afford the 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (424 mg, 91%). The obtained compound, 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (30 mg, 0.077 mmol) was dissolved in DMF (3 mL), treated with 1,4-dibromobutane (17 mg, 0.080 mmol), and stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, added H2O (30 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v)) and on NH silica gel (MeOH:CH2Cl2=1:100 (v/v)) to afford the title compound (7 mg, 20.5%). (300 MHz, CDCl3) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H, m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41 (1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
A mixture of 75.0 g. (0.2669 mole) of 2,4-dichloro-3,5-dinitrobenzoic acid and 55.59 g. (0.2669 mole) of phosphorus pentachloride is heated at reflux for ninety minutes and cooled to room temperature. The phosphorus oxychloride is distilled off in vacuo. The residue is recrystallized from cyclohexane to yield 75.9 gm. (95%) of yellow needles melting at 99°-101°.
Reaction SMILES: COP([CH2:7][C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([Cl:23])=[N:11][C:10]=2[CH:9]=1)(=O)OC.C([N-]C(C)C)(C)C.[Li+].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42](=[CH:7][C:8]2[S:16][C:15]3[C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:13][C:12]([Cl:23])=[N:11][C:10]=3[CH:9]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a suspension of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-phosphonic acid dimethyl ester (0.80 gm) in THF (10 mL) at −78° C. was added dropwise lithium diisopropylamide (1.17 mL of a 2.0 M solution in THF/heptane/ethylbenzene). The mixture was warmed to room temperature and a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.48 g) in THF (10 mL) was added via cannula. The mixture was then stirred at room temperature for 2 h, quenched with brine (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were dried (MgSO4), reduced in vacuo and purified by column chromatography to give 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethylene)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.862 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C@H:8]1[CH2:12][CH2:11][C@@:10]([CH3:14])([OH:13])[C@H:9]1[CH3:15])([CH3:7])=[CH2:6].C(OC(=O)C)(=O)C.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:13][C@:10]1([CH3:14])[CH2:11][CH2:12][C@H:8]([C:5]([CH3:7])=[CH2:6])[C@@H:9]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C=C(C)[C@H]1CC[C@@](C)(O)[C@H]1C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C(C)[C@H]1CC[C@@](C)(OC(C)=O)[C@H]1C
Temperature: 45 °C
Yield: 93.9 %

Procedure:
Acetyl chloride (27 g; 0.34 mol) was added dropwise to a stirred solution of (1R,2S,3S)-3-isopropenyl-1,2-dimethyl-1-cyclopentanol (50 g; 0.32 mol), acetic anhydride (20 g; 0.2 mol), pyridine (57 g; 0.72 mol) and toluene (600 ml) at room temperature and heated to 45° C. during 3 days. The cooled reaction mixture was poured onto ice and washed with H2SO4 (10%), water, NaHCO3 solution (5%) and brine, then distilled at 53-56°/0.7 hPa to give 59 g of (1R,2S,3S)-3-isopropenyl-1,2-dimethyl-1-cyclopentyl acetate of 90% purity. Fractional distillation finished 93% pure (1R,2S,3S)-3-isopropenyl-1,2-dimethyl-1-cyclopentyl acetate (48.7 g; 76.6%). This product showed an odor of the lactonic type, with connotations of jasmine and terpenyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([C:17](=[O:20])[CH2:18]Cl)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.O>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:10]2[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:18][C:17]1=[O:20]
Reactant: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 100 g (0.32 mol) of N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline and 110 g (0.82 mol) of aluminum chloride in 400 ml of 1,2-dichlorobenzene is stirred vigorously and heated to 140° for 7.5 hours. The reaction is cooled to room temperature and added to a mixture of 100 ml of 12N HCl and 700 ml of water (cooled to 0-5° in a dry ice/acetone bath). The mixture is extracted twice with 400 ml of methylene chloride and the combined organic layers are washed with 600 ml of 3N HCl. The organic layer is stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO G-60). The solids are filtered through a pad of Celite and the solvents are evaporated under reduced pressure to give a tan solid which is recrystallized from ethanol to give N-(2′-chloro-6′-fluorophenyl)-5-methyloxindole, m.p. 137-140°.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH2:30][CH3:31])=[C:9]([CH3:32])[CH:8]=1)C.C(OC(=O)COC1C=CC(OCC2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2CC)=C(Br)C=1)C.CB(O)O.[F-].[Cs+]>O1CCOCC1.C(Cl)Cl>[CH2:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][C:9]=1[CH3:32])[CH3:31]
Reactant: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CC)c(C)c1
Agent: CB(O)O
Agent: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CC)c(Br)c1
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(OCC(=O)O)cc1C
Temperature: 80 °C

Procedure:
{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-acetic acid ethyl ester To a mixture of {3-Bromo-4-[4-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-acetic acid ethyl ester (100 mg, 0.18 mmol), methyl boronic acid (33 mg, 0.54 mmol) and cesium fluoride (90 mg, 0.54 mmol) in dioxane (2 mL) is added [1,1′]-(bisdiphenylphosphino)ferrocene]-dichloridepalladium (II) complex with methylene chloride (1:1, 29 mg) under nitrogen. The mixture is heated to 80° C. for 18 hrs, cooled to room temperature, loaded on silica gel column. Chromatography gave the title compound (80 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[N:9]2[CH:19]=[N:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:8]2[CH2:7]1>FC(F)(F)C(O)=O>[F:18][C:15]1[CH:16]=[CH:17][C:10]2[N:9]3[CH:19]=[N:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:8]3[CH2:7][NH:6][C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(F)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CNC(=O)c1cc(F)ccc1-2

Procedure:
13.0 g (29.6 mmol) of ethyl 5-(2,4-dimethoxybenzyl)-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are heated to boiling under reflux for 4 hours in 45 ml of trifluoroacetic acid. After evaporation of the dark red suspension in vacuo, the residue is treated with water and made alkaline with ca 100 ml of 15 percent potassium carbonate solution. The separated material is filtered off under suction and washed with water. After recrystallisation from ca 500 ml of ethanol, there is obtained ethyl 8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 298° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1.[H-].[Na+].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.C(OC(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][N:9]1[C:10]2[C:22]3[NH:21][C:20]4[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[CH:16][C:15]=4[C:14]=3[C:13]3[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=3[C:11]=2[C:5]2[C:6]1=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: CN(C)CCCCl
Reactant: COc1ccc2[nH]c3c4[nH]c5ccc(OC)cc5c4c4c(c3c2c1)C(=O)N(C)C4=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(CCCN(C)C)c35)C(=O)N(C)C4=O)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 g (5 mmol) 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole in 100 ml dry dimethylformamide is added dropwise at 20° C. to a suspension of 182 mg (6.1 mmol) sodium hydride (80% in paraffin oil) in 5 ml dimethylformamide. After stirring for 1 hour at 20° C. 738 mg (6.1 mmol) 3-dimethylaminopropyl chloride are added thereto and the reaction mixture is stirred for 20 hours at 20° C. The solvent is distilled off in a vacuum, the residue is mixed with 150 ml ethyl acetate and 150 ml of water and the solid material insoluble in both phases is filtered off. The solid material is taken up in tetrahydrofuran, the tetrahydrofuran solution is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated. The residue, together with the residue from the ethyl acetate solution, is chromatographed on silica gel with ethyl acetate/methanol (4:1 v/v). The fraction with the Rf 0.2 in ethyl acetate/methanol (3:1 v/v) is isolated and stirred with diisopropyl ether/ethyl acetate (9:1 v/v). The crystals formed are filtered off. 12-(3-Dimethylaminopropyl)-6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo-[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of yellow-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:31])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.C(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:33])([F:35])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:31])[CH2:23][NH:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate (Preparation 14) in methanol (10 mL) was added a methanolic solution of HCl (10 mL of 1.25 M). Reaction mixture warmed to 65° C. for 1.5 hours. Reaction concentrated via rotavap to yield a viscuous oil. CH2Cl2 was added and a precipitate formed. Volatiles removed under reduced pressure to yield 573 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 9.8-9.6 (br s, 2H) 7.9-7.8 (m, 3H), 7.75 (d, 2H), 7.63 (d, 2H), 4.64-4.29 (m, 6H)). LC/MS retention time=3.039 minutes, MS calculated for (C19H14Cl2F4N2O), 432.04; found 433.0 M+H.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18]([O:20]C)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.CO.[OH-].[Na+].Cl>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(OCCCCl)cc2)oc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A suspension of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylate ax60 (4.0 g, 12.9 mmol, 1 eq) in a 1:1 mixture of methanol and water (100 ml) is treated with a 1 M solution of sodium hydroxide (14 ml, 14 mmol, 1.1 eq). The mixture is stirred at 60° C. during 2 h, then the mixture is concentrated. The residue is taken up in water (20 ml) and a 1 M hydrochloric acid solution (14 ml, 14 mmol, 1.1 eq) is added. The resulting suspension is filtered and the filtrate is concentrated to give 3.4 g of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylic acid i43.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:29])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:8]1[C:9]2[N:5]3[C:4](=[N:3][C:2]([CH3:1])=[C:6]3[C:7]1=[O:29])[CH:12]=[CH:11][CH:10]=2
Reactant: Cc1nc2cccc3n(CCCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Yield: 79.6 %

Procedure:
To a suspension of 6.26 g (16.1 mmol) of 1,2-dihydro-3-methyl-1-[5-(phthalimido)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 120 ml of ethanol was added 2.42 g (48.3 mmol) of hydrazine monohydrate. The mixture was heated for two hours under reflux. After cooling, the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was added, extracted with chloroform (three times). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 3.31 g of the desired compound (79.6%, pale yellow solid substance).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4].O[Li].O>C1COCC1.CO.O>[CH3:27][CH:24]1[CH2:25][CH2:26][CH:21]([C:19]([N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[C:9]2[CH:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:20])[CH2:22][CH2:23]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCCN(C)C1)C(=O)C1CCC(C)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(CC2CCCN(C)C2)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Temperature: 55 °C
Yield: 118.9 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (162 mg, 0.27 mmol) was dissolved in a mixture of THF:MeOH:H2O (3:2:1, 2.8 mL) and treated with LiOH.H2O (35 mg, 0.81 mmol). The solution was heated at 55° C. for 3 h. The solvents were removed and the residue was acidified using HCl to pH 4. The product was extracted with EtOAc and the organic layers were washed with brine, dried and evaporated to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (146 mg, 92% yield). 1H NMR (CDCl3, 400 MHz): 9.98 (br s, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.48-7.24 (m, 9H), 5.20-5.05 (m, 2H), 4.35-3.95(m, 3H), 3.00 (m, 1H), 2.85-2.52 (m, 2H), 2.15 (m, 1H), 1.82-1.18 (m, 12H), 0.78 (d, 3H), 0.68 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].O>C(#N)C>[CH3:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCNCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A suspension of piperazine (3.0 mmol), N,N-diisopropylethylamine (6.0 mmol), and 2-fluoro-5-nitrotoluene (7.5 mmol) in acetonitrile are stirred at 50° C. for 3 h and then 100° C. for 9.5 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 85% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=2)=[O:8])[CH:2]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccnc2)cc1
Yield: 4 %

Procedure:
In a manner similar to that described in Example 3, 3-pyridinecarbonyl chloride (0.066 g, 0.00039 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.003 g of 4-[4-((pyridin-3-yl)-carbonylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+299.
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:7][C@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]1)[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49](O)=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C)C=O>[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([N:7]1[C@@H:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C@H:6]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:42])([CH3:38])([CH3:39])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CC[C@H](CC)N1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC[C@H](CC)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of ethyl(5S)-5-ethyl-L-prolinate (2.5 mmol), 2-(1H-benzotriazol-1yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.00 g, 3.13 mmol) and N-(tert-butoxycarbonyl)-L-leucine hydrate (0.779 g, 3.12 mmol) were mixed in 4 mL of dimethylformamide. Triethylamine (approx 1.1 mL) was added until the pH reached about 6 (wet pH paper). After stirring for 16 hours, the mixture was concentrated under reduced pressure and the residue partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with saturated NaHCO3, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash chromatography (30% to 50% ethyl acetate/hexane) to provide the titled compound. MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:29])[NH:22][C:21]([CH3:30])=[C:20]1[C:31]([O:33][CH3:34])=[O:32].[OH-].[Na+]>[N+]([O-])(O)=O>[OH:1][C@H:2]([CH2:35][O:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:29])[N:22]=[C:21]([CH3:30])[C:20]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNC[C@H](O)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1cc([N+](=O)[O-])ccc1OCCCCNC[C@H](O)COc1ccccc1
Temperature: 80 °C
Yield: 48.2 %

Procedure:
In 100 ml of 2N nitric acid under vigorously stirring was suspended 10 g of dimethyl 4-[2-[4-[[(S)-2-hydroxy-3phenoxypropyl]amino]butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and the suspension heated at 80° C. for one hour. After cooling, the reaction mixture was made alkaline with a 10% sodium hydroxide aqueous solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent distilled off under reduced pressure. The resultant residue was subjected to silica gel column chromatography and eluted with chloroform - methanol (98:2) to give 4.8 g of oily dimethyl 4-[2-[4-[[(S)-2-hydroxy-3-phenoxypropyl]amino] butoxy]-5-nitrophenyl]-2,6-dimethylpyridine-3,5-dicarboxylate
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:11])[CH:12]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(c1ccc(Cl)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
This is an example of Procedure B in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (0.6 g 1 eq) were dissolved in CH3CN (5 mL). Ca(OTf)2 (0.456 g, 0.5 eq) was added into the mixture. Reaction mixture was stirred at RT for overnight, then 80-85° C. for 8 h. After concentrating and adding EtOAc 20 mL to the residue, the organic phase was washed with H2O, dried over Na2SO4. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 1.01 g of desired product as a sticky oil (92% yield). * It is important to note that during workup, the organic phase should be washed with H2O and saturated NaCl solution, not saturated NaHCO3 solution.