Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(S(OC)=O)C=CC=CC=1>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Reaction time: 0.13 h
Yield: 81 %

Procedure:
To a solution of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (2.87 g, 8.61 mM) in 29 ml dioxane was added 60% sodium hydride in mineral oil (0.79 g, 19.8 mM). The reaction was stirred 8 minutes, then methyl benzenesulfinate (1.80 ml, 13.8 mM) was added. The reaction was stirred an additional 1.5 hours, then diluted with 43 ml dioxane and 1.13 ml acetic acid. The mixture was refluxed 1 hour, diluted with ethyl acetate, and extracted with saturated NaHCO3 two times, then with brine. After drying (NaSO4), evaporation in vacuo afforded 4.90 g. The mixture was purified by column chromatography on silica gel (elution with toluene/methylene chloride) to afford 2.31 g (81%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (DMSO-d6) δ 10.25 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 3.8 (s, 3H). IR (CHCl3, cm−1) 1723, 1685, 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES) m/e 330, 332.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[O:4].[NH:15]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[N:15]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccnn1CC(=O)c1ccc(OC)c(OC)c1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (1.95 g, 7.53 mmol) and ethyl 1H-pyrazole-3-carboxylate (1.22 g, 8.72 mmol) in acetone (36 mL) at room temperature was added potassium carbonate (1.28 g, 9.23 mmol). Mixture stirred vigorously overnight and then was concentrated under reduced pressure. Resulting residue was taken up in ethyl acetate and washed with 4:1 water/brine. Layers were separated and aqueous was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (10-60% ethyl acetate in hexanes) to yield ethyl 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-5-carboxylate 5.01.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:2]1=2.O1CCCC1.[C-]#N.[Li+].[C:20](P(=O)(OCC)OCC)#[N:21].CC(O)(C)C.[I-].[Sm+2].[I-]>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:20]#[N:21])[C:2]1=2
Reactant: CCOP(=O)(C#N)OCC
Reactant: O=Cc1cccc2ccsc12
Agent: [C-]#N
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#CCc1cccc2ccsc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Add Benzo[b]thiophene-7carboxaldehyde (2.34 g, 14.4 mmol) and lithium cyanide tetrahydrofuran complex (LiCN*1.5 Tetrahydrofuran, 204 mg, 1.44 mmol) to tetrahydrofuran (40 mL) under nitrogen. Add dropwise neat diethyl cyanophosphonate (2.8 mL, 18.4 mmol) to the stirring reaction mixture. Stir at room temp under nitrogen for 60 hours. Add 2-methyl-2-propanol (1.4 mL, 14.6 mmol). Add the reaction mixture via cannula to a stirred 0.1 molar solution of samarium(II) iodide in tetrahydrofuran (360 mL, 36.0 mmol) at 25° C. under nitrogen. If the resulting reaction mixture is not deep blue add al samarium(II) iodide solution until deep blue color persists. Stir the reaction at 25° C. for 1 hour. Concentrate under reduced pressure, dilute with ethyl acetate, diethyl ether (1:1), wash with aqueous 0.1 M hydrochloric acid, and aqueous saturated sodium chloride. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 25% ethyl acetate in hexane to obtain the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5]2.C(O)C.C([O-])=O.[NH4+]>[Pd].O1CCCC1>[NH2:12][C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2NC1=O
Temperature: 65 °C
Yield: 92.7 %

Procedure:
tert-Butyl 6-bromo-8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (628 g) was added to ethanol (3.1 L), and the mixture was heated at 65° C. To the mixture, 10% Pd—C (water content: 53%) (67.1 g) and ammonium formate (1.03 kg) were sequentially added, and the resultant mixture was stirred for 10 minutes under heating and reflux. Tetrahydrofuran (2.5 L) was added to the reaction mixture so as to dissolve the precipitates, and undissolved matter was removed through filtration with Celite. The filtrate was concentrated under reduced pressure, and water was added to the residue. The formed precipitates were recovered through filtration. The thus-obtained solid was dried, whereby the title compound (418 g) was yielded as a powdery compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:17]=[C:16]([CH:18]([CH:20]2[CH2:22][CH2:21]2)[OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:17]=[C:16]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(O)C2CC2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 5-(cyclopropyl-hydroxymethyl)-N-methyl-N-propyl-isophthalamic acid ethyl ester (122 mg, 0.38 mmol) and Dess-Martin periodinane (245 mg, 0.57) in CDCl3 (5 mL) and stir at room temperature for 2 h. Quench the reaction mixture with premixed sodium thiosulfate (500 mg) in 5% aqueous sodium carbonate solution (5 mL). Separate the organic layer and extract the aqueous layer with dichloromethane (2×5 mL). Combine organic layers and concentrate to give the title compound as a crude residue which is used in the next step without further purification.
Reaction SMILES: C(O[CH:5]([C:28]1[N:44]=[C:31]2[N:32]=[CH:33][C:34]3[CH2:35][C:36]4([O:43][CH2:42][CH2:41][O:40]4)[CH2:37][CH2:38][C:39]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C>C1COCC1.[Pd]>[N:29]1[N:30]2[C:39]3[CH2:38][CH2:37][C:36]4([O:43][CH2:42][CH2:41][O:40]4)[CH2:35][C:34]=3[CH:33]=[N:32][C:31]2=[N:44][C:28]=1/[CH:5]=[C:6]1\[C@@H:7]2[N:11]([C:12]\1=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]2
Reactant: CC(=O)OC(c1nc2ncc3c(n2n1)CCC1(C3)OCCO1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3nc4ncc5c(n4n3)CCC3(C5)OCCO3)C(=O)N12
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (300 mg, 0.43 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 9%; Yellow crystals; mp>250° C. (Dec); (M+H+Na) 435.9. 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 6.97(s, 1H), 6.85(s, 1H), 6.38(s, 1H), 4.05 (s, 4H, OCH2CH2O), 3.28(m, 2H), 3.07 (s, 2H), 2.13(t, 3H, CH3, J=4.8 Hz).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].ICCCCCI>O.C(COC)OC>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCCC
Reactant: O=S(=O)(Cc1cnccc1Cl)c1ccc(Cl)cc1
Agent: ICCCCCI
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cnccc2Cl)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.58 ml, 0.913 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 4-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (138 mg, 0.457 mmol) obtained in Example 104. At −78° C., the resulting mixture was stirred for 20 minutes and then 1,5-diiodopentane (0.068 ml, 0.457 mmol) was added thereto. The temperature of the reaction mixture was gradually raised to room temperature, at which stirring was performed for 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (30 mg, 18%) as a white solid. The resulting solid was washed with ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH:18]=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[Cl-].[C:21]([O:25][C:26]([N:28]1[CH2:36][CH2:35][C:31]2([CH2:34][NH2+:33][CH2:32]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH2:18][N:33]2[CH2:34][C:31]3([CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:36][CH2:35]3)[CH2:32]2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[NH2+]C2
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(CN3CC4(CCN(C(=O)OC(C)(C)C)CC4)C3)c12
Reaction time: 2 h

Procedure:
To a solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (25.0 mg, 0.098 mmol), 7-(tert-butoxycarbonyl)-7-aza-2-azoniaspiro[3.5]nonane chloride (39.0 mg, 0.15 mmol), and triethylamine (0.054 mL, 0.39 mmol) in 1,2-dichloroethane (2 ml) was added sodium triacetoxyborohydride (41.0 mg, 0.20 mmol). After 2 h, the reaction was quenched with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give tert-butyl 2-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]methyl}-2,7-diazaspiro[3.5]nonane-7-carboxylate. LRMS (ESI) calculated for C25H35N6O3 [M+H]+, 467.3; found 467.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: [H][H]
Reactant: CC1=CC(C)(C)Nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC1CC(C)(C)Nc2ccccc21
Yield: 89 %

Procedure:
In 10 ml of ethanol was dissolved 2.0 g (11.5 millimoles) of 1,2-dihydro-2,2,4-trimethylquinoline, and 0.4 g of 10% Pd-C was added to the solution and reaction was carried out at 60° C. in a hydrogen atmosphere for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 1.8 g (the yield was 89%) of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline in the form of a light-brown oil. To 0.5 g (3.7 millimoles) of 4-hydroxymethylimidazole hydrochloride was added 3 ml of thionyl chloride and reaction was carried out at 50° C. for 2 hours. The excess of thionyl chloride was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of DMF and a solution of 1.1 g (6.3 millimoles) of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline in 5 ml of DMF was added to the above solution at 100° C. Reaction was carried out for 1 hour. DMF was removed from the reaction mixture by distillation under reduced pressure. An aqueous solution of sodium hydrogen-carbonate was added to the residue and the mixture was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light-green oil. The oil was purified by the silica gel column chromatography (developing solvent; ethyl acetate) to obtain 0.35 g (the yield was 39%) of 4-[1-(2,2,4-trimethyl-1,2,3,4-tetrahydroquinolyl)methyl]imidazole in the form of a colorless crystal. Reaction was carried out in the same manner as described in Example 3 by using 4-[1-(2,2,4-trimethyl-1,2,3,4-tetrahydroquinolyl)methyl]imidazole to obtain 0.35 g (the yield was 30%) of intended compound No. 8 in the form of a light-brown oil.
Reaction SMILES: CO.[OH-].[Na+:4].[CH2:5]([C:7]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40]C)=[O:39])=[C:33]([F:42])[CH:32]=2)=[C:27]([CH3:43])[CH:26]=1)([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([CH2:22][CH3:23])([OH:21])[CH2:19][CH3:20])=[C:12]([CH3:24])[CH:11]=1)[CH2:8][CH3:9])[CH3:6].[Cl-].[NH4+]>O1CCCC1>[CH2:5]([C:7]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O-:40])=[O:39])=[C:33]([F:42])[CH:32]=2)=[C:27]([CH3:43])[CH:26]=1)([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([CH2:19][CH3:20])([OH:21])[CH2:22][CH3:23])=[C:12]([CH3:24])[CH:11]=1)[CH2:8][CH3:9])[CH3:6].[Na+:4]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)c(F)c3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)[O-])c(F)c3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
Methanol (1.3 mL), tetrahydrofuran (1.3 mL) and a 1 M sodium hydroxide aqueous solution (0.133 mL, 0.133 mmol) were added to methyl (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetate (23.5 mg, 0.044 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (chloroform/methanol=10/1). The purified product was diluted with methanol. After addition of sodium methoxide, the mixture was dried under reduced pressure to give the title compound (17.7 mg, 78%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:16][CH:17]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH2:18]1)=[O:4].[OH-].[Na+].CO>C1COCC1>[O:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH2:18][CH:17]1[CH2:16][O:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To 1.31 g of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester in 95 ml of THF were added 5.62 ml of 2 M aqueous sodium hydroxide and 30 ml of methanol. After 1 h at reflux and 16 h at room temperature the organic solvents were removed in vacuo. The residue was treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, and concentrated and dried in vacuo to yield 0.94 g of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)OC(C)(C)C)(C)(C)C.C(=O)([O-])O.[NH4+:44].Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([NH2:44])=[O:27])[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2ccc(CC(=O)O)cc2OCc2ccccc2)cc1
Reactant: [NH4+]
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1ccc(Cc2ccc(CC(N)=O)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a mixture of [3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetonitrile (0.41 g) in ethanol (5 mL) and water (10 mL) was added potassium hydroxide (0.68 g), and the mixture was heated under reflux for 4 hours. To the reaction mixture was added 2 mol/L hydrochloric acid to acidify, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g). To a solution of the obtained [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g) in tetrahydrofuran (10 mL) were added pyridine (0.19 mL), di-tert-butylcarbonate (0.50 g) and ammonium hydrogen carbonate (0.18 g), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]-acetoamide (0.38 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:15](OCC)(OCC)OCC>>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[N:4][C:3]2[C:12](=[O:13])[NH:14][CH:15]=[N:1][C:2]=2[CH:7]=1
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2cc(C(F)(F)F)cnc12
Temperature: 120 °C
Yield: 83.7 %

Procedure:
A vial was charged with 3-amino-5-(trifluoromethyl)picolinamide (615 mg, 3.00 mmol) and triethyl orthoformate (2496 μl, 14.99 mmol). The vial was sealed and the mixture was heated at 120° C. for 17 h. Upon cooling, the heterogeneous mixture was filtered and the solids were washed with heptane. 7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (540 mg, 2.51 mmol, 84% yield) was isolated as a tan solid. LC/MS (ESI+) m/z=216.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[O:12])=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)(=[O:36])=[O:12])=[CH:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(S(=O)(=O)CCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of rac.-4-[[2-(2-naphthalenyloxy)ethyl]sulfinyl]-alpha-oxobenzeneacetic acid methyl ester (1 g) in dichloromethane (50 mL) was treated with 85% metachloroperbenzoic acid (0.81 g) and stirred at room temperature for one hour. The mixture was washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered, passed through silica gel (5 g) and the product eluted with dichloromethane. Crysallization from dichloromethane-hexane gave 0.61 g of 4-[[2-(2-naphthalenyloxy)ethyl]sulfonyl]-alpha-oxobenzeneacetic acid methyl ester, mp 110°-111° C.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25]C)=[O:24])=[N:21][CH:22]=1)=[O:16].[OH-].[Na+].Cl>C(O)C>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc2c3c(c1)CCCC3CCC2)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A suspension of methyl 5-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carbamoyl]pyridine-2-carboxylate (0.222 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.206 g, yield: 97%) as pale yellow needles (melting point: 239-240° C.).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=O)(C)(C)C.Br[CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[C:23]1=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=3)[CH2:23]2)=[C:13]([CH:18]=1)[O:12][CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: O=C1c2ccc(F)cc2CC1Br
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(c1)CC(Oc1ccc(Cl)cc1OC1CNC1)C2
Temperature: 25 °C
Yield: 89.9 %

Procedure:
The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), the title compound of Step A (0.5 mmol), and K2CO3 (1 mmol) in acetonitrile (3 mL) was heated at 100° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (150 mg). To this product was added DCE (5 mL), Et3SiH (1 mL) and TFA (3 mL). The mixture was stirred at 80° C. for 16 h. After concentration, the title compound was obtained (91 mg). MS (ESI): mass calcd. for C18H17ClFNO2, 333.1; m/z found, 334.1 [M+H]+. 1H NMR (CDCl3): 7.20-7.13 (m, 1H), 6.96-6.60 (m, 5H), 5.18-5.08 (m, 1H), 4.93-4.83 (m, 1H), 3.98-3.70 (m, 4H), 3.38-3.05 (m, 4H).