Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[NH:7][C:6]3=[O:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A mixture of 1-(3-bromopropyl)-2,4(1H, 3H)-quinazolinedione (2.12 g), 1-diphenylmethylpiperazine (2.07 g), anhydrous potassium carbonate (3.1 g) and N,N-dimethylformamide (14 ml) was stirred for 2.5 hours at 100° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water and then stirred to give precipitates. The precipitates were collected by filtration and they were dissolved in hot chloroform containing a little quantity of methanol. The resultant solution was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crystal, which was washed enough with methanol and dried to give 1-[3-{4-(diphenylmethyl)-piperazin-1-yl}propyl]-2,4(1H, 3H)-quinazolinedione (1.6 g). This crystal was dissolved in 2N hydrochloric acid solution and then the solution was concentrated in vacuo to give a white crystal, which was washed with methanol, dissolved in water with warming and the solution was evaporated in vacuo. The resultant crystal was washed enough with methanol, to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H, 3H)quinazolinedione.2HCl.0.7H2O (1.6 g). m.p. 261°-264° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[S:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[N:15]=1.[CH:19](O)([CH3:21])[CH3:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:19]([O:17][C:16]([C@@H:14]1[CH2:13][S:12][C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[N:15]1)=[O:18])([CH3:21])[CH3:20]
Reactant: CC(C)O
Reactant: COc1ccc(C2=N[C@H](C(=O)O)CS2)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C2=N[C@H](C(=O)OC(C)C)CS2)c(OC)c1

Procedure:
Next, 2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylic acid is reacted with isopropanol; DCC; and 4-(dimethylamino)pyridine (DMAP) in tetrahydrofuran (THF) at room temperature to form isopropyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). (1R,2S)-2-(3-Methyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.068 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.064 g, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 7 h. The solution was poured into a 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, (1R,2S)-2-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.3 mmol), as a light yellow oil, which was used directly for next step. LC-MS (ESI) calcd for C23H34N4O7S2 542.19, found 543.3 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:6](=[C:7]([CH3:23])[CH:8]=[CH:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[S:5][C:4](=[S:24])[NH:3]1.[OH-].[Na+].Cl>O>[O:1]=[C:2]1[C:6](=[C:7]([CH3:23])[CH:8]=[CH:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[S:5][C:4](=[S:24])[NH:3]1
Reactant: CCOC(=O)COc1ccc(C=CC(C)=C2SC(=S)NC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C=Cc1ccc(OCC(=O)O)cc1)=C1SC(=S)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.12 g of the isomer A of ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-buten-1-yl]phenoxyacetate prepared as described in Example 13, 5 ml of water and 1 ml of a 5% aqueous sodium hydroxide solution was stirred at room temperature for one hour. To the reaction mixture was added 10% hydrochloric acid to precipitate crystals. The crystals were recovered by filtration and washed with methanol to give 0.07 g of the isomer A of the desired 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-buten-1-yl]phenoxyacetic acid and also 0.07 g of the isomer B thereof.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:18]=2[N:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14]3)=[N:7][CH:8]=1.[C-:21]#[N:22].[K+]>CCO.O>[CH3:20][O:19][C:16]1[N:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[C:9]2[C:6]1[N:7]=[CH:8][C:3]([CH2:2][C:21]#[N:22])=[CH:4][CH:5]=1
Reactant: COc1ccc2nccc(-c3ccc(CBr)cn3)c2n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc2nccc(-c3ccc(CC#N)cn3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a stirred solution of 8-(5-bromomethylpyridin-2-yl)-2-methoxy[1,5]naphthyridine (0.70 g, 2.12 mmole), in EtOH (50 mL) at 60° C. was added KCN (0.21 g, 3.18 mmole) in H2O (3 mL). After 1.5 h, the reaction contents were cooled to RT and concentrated under vacuum. The aqueous residue was dissolved in EtOAc and washed with H2O, and dried over Na2SO4. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (0.38 g, 65%) as light yellow solid: LC-MS (ES) m/e 277 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14](OC)=[O:15])=[N:10]2)=[C:5]2[NH:18][CH:19]=[CH:20][C:4]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]2)=[C:5]2[NH:18][CH:19]=[CH:20][C:4]=12
Reactant: COC(=O)c1ncn(-c2ncc(OC)c3cc[nH]c23)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cnc(-n2cnc(CO)n2)c2[nH]ccc12
Yield: 50.7 %

Procedure:
To a solution of methyl 1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3-carboxylate (220 mg, 0.805 mmol) in THF (20 mL) was added LiAlH4 (1.208 mL, 2.415 mmol) dropwise over 5 min period at room temperature. The solution was refluxed for 1H and then cooled in an ice bath. The reaction mixture was quenched with water and extracted with EtOAc (3×100 ml). The organic layers were combined, washed with brine (30 ml), dried under MgSO4 and concentrated. The residue was purified by prep. HPLC to give (1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)methanol (100 mg, 0.408 mmol, 50.6% yield). LCMS: m/z 246.2 (M+H)+, 1.36 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 9.24 (s, 1H) 7.53 (s, 1H) 7.47 (d, J=3.05 Hz, 1H) 6.68 (d, J=2.75 Hz, 1H) 4.84 (s, 2H) 4.03 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]([Cl:14])[CH:4]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH:23]([OH:30])[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.[OH-].[Na+].Cl>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)(=O)C.CCOCC.O1CCCC1>[ClH:13].[Cl:14][C:5]1[CH:4]=[C:3]([CH2:2][O:30][CH:23]([C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]=1
Reactant: Clc1ccc2nc(Cl)cc(CBr)c2c1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(C(Cn2ccnc2)OCc2cc(Cl)nc3ccc(Cl)cc23)c(Cl)c1

Procedure:
8.7 g of 4-bromomethyl-2,6-dichloroquinoline (0.03 mol), 7.7 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.03 mol), 30 g of sodium hydroxide (0.75 mol) dissolved in 30 ml water, 0.5 g of benzyltrimethylammonium chloride and 100 ml of tetrahydrofuran are reacted as described in Example 1. Work up of the mixture results in an oil, which after treatment in boiling ether, is dissolved in 250 ml of ethyl acetate. To the charcoaled solution is added etheral hydrochloric acid. The precipitated hydrochloride is filtered off, washed with ethyl acetate, treated with boiling acetonitrile and finally with anhydrous ether. Yield 4.9 g (32.6%); m.p. 192°-194° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10](O)[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH2:1]([O:8][CH2:9][C@@H:10]([N:39]1[C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]2[C:35]1=[O:45])[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCC[C@@H](O)COCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCC[C@@H](COCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-benzyloxy-2-(R)-hydroxy-5-hexene (2.18 g, 10.5 mmol), triphenylphosphine (3.32 g, 12.7 mmol) and phthalimide (1.86 g, 12.7 mmol) was added diisopropyl azodicarboxylate (2.62 ml, 12.7 mmol) at rt, and the resulting mixture was stirred for overnight at rt. The mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyloxy-2-(S)-phthalimido-5-hexene (2.95 g, 83%) as a colorless oil: 1H-NMR (CDCl3) δ 1.76–1.84 (m, 2 H), 2.06 (dd, J=14.4, 6.8 Hz), 2 H, 2.12–2.22 (m, 1 H), 3.69 (dd, J=10.0, 5.6 Hz, 1 H), 4.00 (t, J=9.6 Hz, 1 H), 4.46 (d, J=12.0 Hz, 1 H), 4.53 (d, J=12.0 Hz, 1 H), 4.51–4.58 (m, 1 H), 4.91–4.99 (series of m, 2 H), 5.72–5.79 (m, 1 H)7.21–7.26 (m, 5 H), 7.71–7.83 (series of m, 2 H); MS (ESI) m/z, 336 (M++H).
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([NH2:33])[N:27]=1>CC#N>[NH2:33][C:28]1[N:29]=[C:30]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:11]2)[CH:31]=[C:26]([Cl:25])[N:27]=1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1nc(Cl)cc(N2CCC[C@@H](C(=O)Nc3ccccc3)C2)n1
Temperature: 160 °C
Yield: 43.4 %

Procedure:
To a solution of (3R)—N-phenyl-3-piperidinecarboxamide (339 mg, 1.66 mmol) in CH3CN (3 mL) in a 5 mL microwave vial, was added Hunig's base (0.87 mL, 4.98 mmol) and 4,6-dichloro-2-pyrimidinamine (299 mg, 1.83 mmol), and the reaction mixture was heated at 160° C. under microwave conditions for 0.5 hours. A solid formed upon cooling of the reaction mixture. The solid was then isolated by filtration, washing with CH3CN to afford the crude title compound (239 mg) as a light brown solid. LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[N:3]=1.[H][H]>[Pd].C(O)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2
Reactant: [H][H]
Reactant: Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2c(N)cccc2n1
Yield: 50.4 %

Procedure:
2-Methyl-5-nitroquinoline (25 g, 132.85 mmol) and palladium on carbon (2.5 g) in 8 ml of glacial acetic acid are stirred for 5½ hours in a hydrogen atmosphere at normal pressure. The catalyst is suctioned off and washed with ethyl acetate. The combined filtrates are concentrated by evaporation. Column chromatography of the residue on silica gel with dichloromethane-acetone yields 10.6 g of the product.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[S:26][C:27]5[CH:32]=[CH:31][N:30]=[CH:29][C:28]=5[N:33]=4)[N:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:12]=[N:11]1>CO.Cl>[S:26]1[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[N:33]=[C:25]1[CH2:24][N:21]1[C:19]2=[N:20][C:15]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=3)=[CH:16][CH:17]=[C:18]2[N:23]=[N:22]1
Reactant: c1cc2sc(Cn3nnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nc43)nc2cn1
Agent: Cl
Solvent: CO
Product: OCCn1cc(-c2ccc3nnn(Cc4nc5cnccc5s4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3-(thiazolo[4,5-c]pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (20 mg, 0.04 mmol) was dissolved in MeOH/HCl (2 mL). The reaction mixture was stirred at room temperature for 1 h, and then concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 379 (M+1)+.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=[C:8]1[S-:18].[K+].CI>CN(C)C=O>[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=[C:8]1[S:18][CH3:2]
Reactant: Cn1c([S-])nc2c(c1=O)CCCC2
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2c(c(=O)n1C)CCCC2
Temperature: 25 °C

Procedure:
To a mixture of 10 ml of tetrahydrofuran and 5 ml of dimethylformamide, 340 mg of potassium 3-methyl-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-2-thiolate was added, followed by addition of 210 mg of methyl iodide and an overnight's stirring at room temperature. The solution was concentrated, to which chloroform was added, followed by washing with saturated brine and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 310 mg (quantitative) of 3-methyl-2-methylthio-5,6,7,8-tetrahydro-3H-quinazolin-4-one was obtained.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26])=[O:9])=C.BrC1C=CC(NC2N(C)C(=O)C=CC=2C(O)=O)=C(F)C=1.C(OCCON)=C>>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26])=[O:9]
Reactant: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: C=COCCON
Agent: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)NOCCO)ccc1=O
Yield: 60 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide: 2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.020 g, 0.059 mmol) was coupled as described previously in Example 154 using O-(2-vinyloxy-ethyl)-hydroxylamine to yield 0.015 g (60%) pure desired product as a yellow solid.
Reaction SMILES: [CH:1]([NH:14][C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CCC(=O)CC2)C=CC=CC=1.C1(C(C2C=CC=CC=2)N)C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]([NH:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(N[C@H]2CC[C@@H](c3ccccc3)CC2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NC(c1ccccc1)c1ccccc1
Agent: O=C1CCC(c2ccccc2)CC1
Solvent: ClCCCl
Product: c1ccc(C(N[C@H]2CC[C@H](c3ccccc3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cis-N-benzhydryl-4-phenylcyclohexanamine: To a solution of 4-phenylcyclohexanone (500 mg, 2.87 mmol) and diphenylmethanamine (526 mg, 2.87 mmol) in DCE (4 mL) at 0° C. was added sodium triacetoxyborohydride (912 mg, 4.30 mmol) by portions slowly. A white suspension resulted and was stirred for 5 min before the ice-water bath was removed. The reaction was stirred at rt for 1.5 h. The reaction was quenched with water carefully, then saturated NaHCO3 was added carefully and the aqueous portion was extracted with DCM (3×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0-100% hexane/EtOAc) to give Intermediate 1A (734 mg, 2.15 mmol, 74.9% yield) and trans-N-benzhydryl-4-phenylcyclohexanamine (191 mg, 0.559 mmol, 19.5% yield), LC-MS (ESI) m/z 342.1 (M+H), RT=1.76 min (Method B). 1H NMR (400 MHz, chloroform-d) δ ppm 7.37 (4H, d, J=7.33 Hz), 7.23-7.31 (6H, m), 7.11-7.23 (5H, m), 4.91 (1H, s), 2.80-2.88 (1H, m), 2.46-2.56 (1H, m), 1.74-1.90 (4H, m), 1.60-1.70 (2H, m), 1.47-1.59 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][N:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[N+:25]([O-])=O)[C:12](=O)[CH2:11][CH:10]1[C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>O.[Ni]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][N:13]2[C:12](=[N:25][C:16]3[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:23]=[CH:24][C:15]=32)[CH2:11][C@@H:10]1[C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(N2CC(NC(=O)OC(C)(C)C)C(c3cc(F)c(F)cc3F)CC2=O)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc1n2C[C@H](NC(=O)OC(C)(C)C)[C@@H](c2cc(F)c(F)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step A was added 15 mL of THF, and 2 mL of a slurry of Raney 2800 nickel in water. The mixture was then stirred under hydrogen (1 atm) for 1 h, filtered trough a pad of Celite and the filter cake washed with 50 mL of methanol and 25 mL of methylene chloride. The solution was concentrated in vacuo, the product dissolved in 15 mL of a 13:1 solution mixture of toluene/acetic acid and the mixture heated to reflux for 2 h. After cooling to ambient temperature, the mixture was concentrated in vacuo and the product purified directly by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 80% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 476.4 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:20][CH2:19][CH2:18][N:9]2[CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:25][CH:24]=1)#[N:22]
Reactant: NCCN1Cc2ccccc2CC1Cc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine (27 mg, 0.1 mmol) obtained in Example 1-f), 4-cyanobenzylbromide (20 mg, 0.1 mmol), and potassium carbonate (17 mg, 0.12 mmol) were dissolved in 1 mL of acetonitrile, followed by stirring at 60° C. for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 14 mg (yield 36.7%) of a title compound as a colorless oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[CH2:17][CH2:16]3)=[C:11]([CH3:30])[C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O.CO>[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[CH2:21][N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=3[C:11]=2[CH3:30])[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2c(C)c(N3CCN(Cc4c(Cl)cccc4Cl)CC3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)O)cc12
Reaction time: 2 h
Yield: 166.9 %

Procedure:
To a solution of 5-[4-(2,6-Dichloro benzyl)-piperazine-1-yl]-4-methyl-benzofuran-2-carboxylic acid ethyl ester (0.08 g, 0.0001 mol) in THF:Water:Methanol (3:2:1) mixture (19 ml) was added lithium hydroxide (0.02 g, 0.0005 mol) at 0° C. The reaction mixture was stirred for 2 hours. The completion of the reaction was confirmed by TLC. Solvent was concentrated under reduced pressure added ice water. The pH of the mixture was made acidic with 1N HCl and the solid separated was filtered. After drying under vacuum, isolated 5-[4-(2,6-Dichloro benzyl)-piperazine-1-yl]-4-methyl-benzofuran-2-carboxylic acid (70 mg, 94%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:31])([F:30])[C:24]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:24]([OH:29])([C:23]([F:31])([F:30])[F:22])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC1(C(F)(F)F)CCNC1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC(O)(C(F)(F)F)C1
Yield: 47.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 40 mg, 141 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 32.4 mg, 169 μmol) to obtain the title compound (28 mg, 47%) as off-white solid, MS (EI): m/e=422.3 [MH+].