Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[C:14](Cl)(Cl)=[S:15]>ClCCCl.C(Cl)Cl.O>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:13])[F:12])[N:3]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ccc(N)nc1C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: N#Cc1ccc(N=C=S)nc1C(F)(F)F
Temperature: 80 °C
Yield: 65 %

Procedure:
A mixture of 6-amino-2-(trifluoromethyl)nicotinonitrile (648 mg, 3.5 mmol) and thiophosgene (0.4 mL, 5.2 mmol) in DCE (8 mL) was heated to 80° C. overnight. The mixture was cooled to room temperature and diluted with DCM/water. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 521 mg of 6-isothiocyanato-2-(trifluoromethyl)nicotinonitrile (70% pure) as a brown oil. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, 1H), 7.93 (d, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].[Cl-].[NH4+].CCO>[Zn].C1COCC1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:11]
Reactant: Cc1ccncc1-c1ccc([N+](=O)[O-])cc1OCCF
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccncc1-c1ccc(N)cc1OCCF
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Intermediate 16C (254 mg, 0.919 mmol), Zinc (361 mg, 5.52 mmol), and ammonium chloride (344 mg, 6.44 mmol) were taken in a flask followed by addition of EtOH (2 mL) and THF (2 mL). The reaction mixture was stirred at room temperature for 2 hours and filtered through a pad of CELITE®. The filtrate was concentrated to give Intermediate 16 (220 mg, 0.893 mmol, 97% yield) as a yellow solid. MS (ES): m/z=247.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3 H) 4.07 (dd, J=7.40, 3.39 Hz, 1 H) 4.13-4.20 (m, 1 H) 4.53 (dd, J=4.64, 3.14 Hz, 1 H) 4.65 (dd, J=4.77, 3.26 Hz, 1 H) 5.29 (s, 2 H) 6.28 (dd, J=8.03, 2.01 Hz, 1 H) 6.33 (d, J=2.01 Hz, 1 H) 6.81 (d, J=8.03 Hz, 1 H) 7.23 (d, J=5.02 Hz, 1 H) 8.22 (s, 1 H) 8.32 (d, J=4.77 Hz, 1 H). Intermediate 16 was used in the synthesis of Example 22.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1([F:13])[CH2:9][CH:8]([C:10]([O-:12])=[O:11])[CH2:7][CH2:6][CH2:5]1>CO.C1COCC1.O>[F:3][C:4]1([F:13])[CH2:9][CH:8]([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5]1
Reactant: O=C([O-])C1CCCC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2 M aqueous solution of lithium hydroxide (26 mL) was added to a solution of methyl (1R,2R)-2-2-bromophenyl)-5,5-difluorocyclohexanecarboxylate (1.81 g, 5.46 mmol) in a mixture of methanol (20 mL) and THF (10 mL) with rapid stirring at room temperature for 15 hours. The reaction mixture was then diluted with water and extracted with ether prior to acidification to pH 2 with 2 M HCl followed by extraction with ethyl acetate (2×). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4), and concentrated to afford (1R,2R)-2-2-bromophenyl)-5,5-difluorocyclohexanecarboxylic acid as a tan foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.CS(O[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)(=O)=O>>[O:44]1[CH2:45][CH2:46][CH:41]([N:34]2[CH:35]=[C:31]([C:9]3[C:8]4[C:3]([O:2][CH:1]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[N:4][CH:5]=[CH:6][C:7]=4[NH:11][N:10]=3)[CH:32]=[N:33]2)[CH2:42][CH2:43]1
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1cc2[nH]nc(-c3cnn(C4CCOCC4)c3)c2c(OC2CCOCC2)n1
Yield: 41 %

Procedure:
Prepared according to the general procedure described in example 92, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with tetrahydro-2H-pyran-4-yl methanesulfonate to give the title compound (26.5 mg, 41% over two steps). LC-MS (Method G): m/z=300.1 [M+H]+; 3.09 min. 1H-NMR (400 MHz, DMSO): δ 13.26 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.85 (d, J=5.3, 1H), 7.08 (d, J=5.6, 1H), 4.51 (s, 1H), 4.06 (s, 3H), 4.04-3.93 (m, 2H), 3.58-3.44 (m, 2H), 2.13-1.92 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]([CH2:20][CH2:21]O)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:19]3[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2nc3cccnc3n2CCO)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCn3c2nc2cccnc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2-{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethanol (2.2 g) and triethylamine (10 mL) in THF (100 ml) was added methanesulfonyl chlorode (1.1 mL) at 0° C., and the mixture was stirred at 0° C. for 2 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. A mixture of the residue and potassium carbonate (3.1 g) in NMP (30 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water. The formed crystals were collected by filtration to give the title compound (1.7 g).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:4][F:5].O.[OH-].[Li+]>C1COCC1.O>[F:1][CH2:2][CH:3]([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:4][F:5]
Reactant: O=C(COC(CF)CF)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COC(CF)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Benzyl 2-(1,3-difluoropropan-2-yloxy)acetate (0.91 g, 3.73 mmol) was dissolved in THF (14 mL)/water (7 mL) mixture and treated with lithium hydroxide monohydrate (0.469 g, 11.18 mmol) and allowed to stir for 16 hours at room temperature. The mixture was concentrated, redissolved in water and extracted with ethyl acetate. The aqueous phase was treated with 2M HCl and NaCl then extracted with ethyl acetate (3×). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title product (0.388 g, 67% yield).
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6][N:7]=[C:8]=NCC.O[C:14]1C=CC(CC(O)=O)=C[CH:15]=1.O.[OH:25]N1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.O>[C:4]([NH2:3])(=[O:25])[C:5]1[CH:15]=[CH:14][CH:8]=[N:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 257.1 %

Procedure:
Exo-N-(8-aza-bicyclo[3.2.1]oct-3-yl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide (310 mg, 0.86 mmol, see Preparation 35) was added to 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (185 mg, 0.95 mmol), 4-hydroxyphenylacetic acid (134 mg, 0.86 mmol) and 1-hydroxybenzotriazole hydrate (128 mg, 0.95 mmol) in dichloromethane (5 ml) containing 4-methylmorpholine (104 μl, 0.95 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and the organic phase was concentrated in-vacuo and then purified by chromatography on silica gel using methanol in dichloromethane containing ammonium hydroxide solution as eluant (gradient from 1:99:0.1 to 5:95:0.5). The material obtained was triturated with methanol and isolated by filtration then dried in-vacuo to give exo-5-fluoro-2-(4-fluoro-phenoxy)-N-8-[2-(4-hydroxy-phenyl)-acetyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-nicotinamide (270 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH2:10][CH2:9][N:8]([CH2:11]/[CH:12]=[CH:13]/[CH2:14]O)[CH2:7][CH2:6]1>ClCCl>[ClH:3].[O:5]1[CH2:10][CH2:9][N:8]([CH2:11]/[CH:12]=[CH:13]/[CH2:14][Cl:3])[CH2:7][CH2:6]1
Reactant: OC/C=C/CN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClC/C=C/CN1CCOCC1
Reaction time: 3 h

Procedure:
Thionyl chloride (0.96 ml) was added dropwise to a solution of (E)-4-morpholino-2-buten-1-ol (1.03 g) in dichloromethane (10 ml) at ice-bath temperature. After 3 hours, the reaction mixture was evaporated under reduced pressure and the resulting residue was triturated with ethyl acetate to give (E)-4-morpholino-2-butenyl chloride hydrochloride (0.98 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.C(OCC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O1CCCC1>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][S:19][C:18](=[NH:20])[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 50 mg, 0.18 mmol) in DMF (1 mL) was added 2-bromomethylnaphthalene (38.8 mg, 0.18 mmol) in one portion. The reaction mixture was stirred at room temperature for 1 hr then heated at 60° C. for 2 hrs. After this time, the solvent was removed in vacuo to leave an oily residue which was triturated with diethyl ether to give a yellow-brown solid. The solid was dissolved in 5 mL of tetrahydrofuran: 5 mL diethyl ether and treated with saturated sodium bicarbonate (10 mL). The organic layer was separated, dried over magnesium sulfate and evaporated to give a yellow oil. The product was purified by chromatography on silica gel (2% methanol: 98% dichloromethane). H1 NMR (acetone d6) δ: 8.81 (bs, 1H), 7.92-7.85 (m, 4H), 7.61 (bs, 1H), 7.50-7.39 (m, 4H), 7.09-6.91 (m, 7H), 5.81 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([NH2:9])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[H-]>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH2:7][NH2:9]
Reactant: NC(=O)COc1cccc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCOc1cccc(N)c1
Temperature: 25 °C

Procedure:
A mixture of 3-aminophenoxyacetamide (10.0 g., 0.05 M), lithium aluminum hydride (6.8 g., 0.18 M) and ether (250 ml.) is refluxed under dry nitrogen for four days. It is then cooled to room temperature and water slowly added to decompose unreacted hydride. The precipitated salts are removed by filtration and the filtrate concentrated to an oil under reduced pressure. The crude oil is chromatographed on silica gel using 20% methanol/ethyl acetate as eluting agent. Concentration of appropriate fractions affords 4.83 g. (53%) of product as an oil. It is used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+].C(Cl)(Cl)Cl>C(O)C>[O:1]([C:8]1[C:9]2[CH:4]=[C:3]([C:2]([OH:1])=[O:15])[O:14][C:10]=2[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)c1cc2c(Oc3ccccc3)cccc2o1
Reaction time: 2 h

Procedure:
14.0 g of meta-phenoxyphenol was dissolved in 700 ml of 95% ethanol. 468 g of sodium hydroxide was then added rapidly. The resulting suspension was heated to 70°-80° C. Then 558.7 g of chloroform was added, at such a rate that gentle reflux was maintained; the addition required 10 hours. The mixture then was stirred for 2 hours at 75°-80° C., held at room temperature overnight and filtered. The solid product was dissolved in 1000 ml of water. The solution was acidified to pH=2 with concentrated hydrochloric acid, then was extracted with ether. The ether layer was dried (MgSO4) and concentrated. The residue was extracted with hot petroleum ether. The extract was dried (Na2SO4) and concentrated to give an oil, which was wet column chromatographed over silica gel, using first a 9/1 v/v mixture, then a 4/1 v/v mixture of petroleum ether and ether as eluent. The fourth fraction obtained, after removal of the solvents, was identified as 2-hydroxy-6-phenoxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24](CC5C=CC=CC=5)[CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)[Cl:35]>>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: COc1ccc(S(=O)(=O)n2ccc3cc(N4CCN(Cc5ccccc5)CC4)ccc32)cc1
Product: COc1ccc(S(=O)(=O)n2ccc3cc(N4CCNCC4)ccc32)cc1
Product: Cl
Reaction time: 2 h

Procedure:
N-(4-Methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole (0.25 g, 0.54 mmol) was dissolved in DCM (4 mL), a-chloroethyl chlorofonnate (0.150 g, 1.05 mmol) was added and the mixture left at room temperature for 2 h after which it was concentrated. MeOH (10 mL) was added and the mixture refluxed for 2 hrs and then concentrated to give the product (0.22 g, quantitative yield). 1H NMR (MeOH d6) δ 3.39–3.47 (8 H, m), 3.77 (3 H, s), 6.64 (1 H, d, J=3), 6.94 (2 H, d, J=9), 7.15 (1 H, dd, J=9, 2), 7.26 (1 H, d, J=2), 7.59 (1 H, d, J=4), 7.80 (2 H, d, J=9) and 7.90 (1 H, d, J=9); MS (posES-FIA) 371.1304 M+; Purity (HPLC chromsil C18) >98%. Examples 89–95 were prepared using the same procedure as in example 88.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]=[C:6]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]2[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH:8]2[CH2:7]1.O>C(O)(=O)C>[N+:1]([C:14]1[CH:15]=[CH:16][C:10]2[N:9]3[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20][CH:8]3[CH2:7][C:6](=[O:5])[NH:12][C:11]=2[CH:13]=1)([O-:4])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2c3ccc([N+](=O)[O-])cc3NC(=O)CC2C1
Reaction time: 3 h

Procedure:
Nitric acid (65% solution, 0.20 mL, 3.2 mmol) was added to a solution of Example 1C (1.0 g, 3.2 mmol) in acetic acid (5 mL) at room temperature. The solution was stirred for 3 hours, and then the reaction mixture was poured into water (200 mL). The precipitate was collected by filtration from the aqueous solution to afford the title compound. 1H NMR (300 MHz, DMSO-d6) d ppm 8.00 (dd, J=8.92, 2.58 Hz, 1 H), 7.79 (d, J=2.78 Hz, 1 H), 7.24 (d, J=9.12 Hz, 1 H), 3.86-4.10 (m, 2 H), 3.36-3.50 (m, 1 H), 3.20-3.29 (m, 1 H), 2.81-2.99 (m, 1 H), 2.62-2.77 (m, 1 H), 2.18 (d, J=13.48 Hz, 1 H); MS (APCI+) m/z 307 (M+H-tBu)+.
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14]C)=O)=O.[OH-].[NH3+:17][NH2:18]>>[C:12]1(=[O:14])[C:4]2[CH:5]=[C:6]3[N:11]([C:3]=2[CH:1]=[N:18][NH:17]1)[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: COC(=O)c1cc2n(c1C=O)CCCC2
Reactant: N[NH3+]
Agent: [OH-]
Product: O=c1[nH]ncc2c1cc1n2CCCC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with methyl 3-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (127d) (600 mg, 2.9 mmol) and hydrazinium hydroxide (20 mL). The reaction mixture was heated at 100° C. for 4 hours. After this time the reaction was cooled to room temperature and filtered to afford 127e as a yellow solid (413 mg, 75%). MS-ESI: (M+H)+ 190.1. 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.24 (s, 1H), 6.33 (s, 1H), 4.16 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.00-1.96 (m, 2H), 1.84-1.79 (m, 2H).
Reaction SMILES: [C:1]([C:5]1([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CSC2(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Dissolve 1-(carbomethoxy)-1-(4-methoxylbenzylthio)cyclopentane (3.3 mmol) in 95% ethanol (18 mL), water (9 mL), and tetrahydrofuran (10 mL). Treat with potassium hydroxide (0.91 g, 16 mmol). Stir at room temperature for 2 hours and evaporate the solvent in vacuo. Partition between water (50 mL) and ethyl ether (30 mL). Acidify the aqueous phase with cold concentrated hydrochloric acid and extract with methylene chloride (50 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give 1-(carboxy)-1-(4-methoxybenzylthio)cyclopentane as a pale yellow oil (483 mg, 72%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH:37]1[CH2:42][CH2:41][CH:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1>C1COCC1>[CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.[C:49]([N:46]1[CH2:45][CH2:44][CH:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:9]([NH2:11])=[O:8])[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.1 %

Procedure:
To a solution of CBz-D-phenylglycine (877 mg, 3.1 mmol) in anhydrous THF (40 ml) at −25° C. was added N-methylmorpholine (336 μl, 3.1 mmol) and isobutyl chloroformate (419 μl, 3.1 mmol). The resulting suspension was left to stir for 5 min at this temperature and then the t-Butyl 4-(piperidin-4-yl)piperidine-1-carboxylate (825 mg, 3.1 mmol) in anhydrous THF (5 ml) was added in one portion at −25° C. and the reaction mixture allowed to warm to room temperature over 1 hour. The N-methylmorpholine hydrochloride was filtered off and the THF removed under vacuo. The resulting solid was treated with TFA/DCM (20 ml, 1:1) and the reaction mixture left to stir for 2 hours. The organics were removed under vacuo, the residue dissolved in ethyl acetate (100 ml), washed with aq. sodium bicarbonate solution, brine, dried and concentrated to yield the title compound as a clear oil (1.12 g, 84% over two steps).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)=[CH:23][CH:24]=1)#[N:29]
Reactant: N#Cc1ccc(CCC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 90 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(4-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (270 mg, 0.69 mmol, prepared in Synthetic Example 8) in DMF (5 ml) was added hydrazine monohydrate (80%, 102 μl, 2.55 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 9 to give 3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (243 mg, 90%).
Reaction SMILES: [C:1]([CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=O)(=[O:3])[CH3:2].[OH-].[K+]>O1CCCC1.CO>[C:8]1([C:5]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:4][C:1](=[O:3])[CH:2]=[CH:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(C=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g) in a mixture of tetrahydrofuran (55 ml) and methanol (30 ml) was added 10% aqueous solution of potassium hydroxide (15 ml) at room temperature. The solution was stirred for 2 hours and evaporated in vacuo. To the residue was added brine and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 4,4-diphenyl-2-cyclopenten-1-one (39.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[N:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[N:5][CH:4]=1
Reactant: C=CCn1c(=O)ccc2ncc(OC)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(Methoxy)-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (5.046 g, 23.361 mmol) was dissolved in 1,4-dioxane (100 mL) and water (100 mL). Sodium periodate (12.49 g, 58.402 mmol) was added, followed by osmium tetroxide (5 mL of 4% aqueous solution). The mixture stirred at rt for 1 h, water (200 ml) was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 300 ml and extracted with 20% MeOH/DCM (3×400 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) as a yellow solid (3.807 g, 75%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 2.77 g (6.33 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate, obtained in step 4.1, and 15.80 ml (31.67 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by recrystallization from ethyl acetate, 1.69 g of product are obtained in the form of a white solid.