Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2[N:36]([CH2:49][CH2:50][CH2:51][OH:52])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[C:32]=2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2[N:36]([CH2:49][CH2:50][CH:51]=[O:52])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:41][CH:40]=3)[C:32]=2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Dess-Martin periodinane (1.43 g, 3.36 mmol) was added portion wise to a stirred solution of 1-(3-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.30 g, 3.05 mmol) in CH2Cl2 (15 mL) at 0° C. under N2. Then the reaction was stirred at 0° C. for 15 min and allowed to warm to room temperature. After stirring at room temperature for 1.5 h the reaction was diluted with Et2O (50 mL) and saturated NaHCO3 (15 mL) was added slowly (caution! gas evolution). Then Na2S2O3.5H2O (5.31 g, 21.4 mmol) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with Et2O (2×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated. MPLC (1-10% MeOH/CH2Cl2) afforded the aldehyde in 79% yield (1.02 g). TLC (silica, 10% MeOH/CH2Cl2): Rf=0.67. MS (electrospray) calculated for C21H24F3N3O3, 424.2 ([M+H]+), m/z found, 424.2. 1H NMR (400 MHz, CDCl3): 9.82 (s, 1H), 7.65 (br d, J=8.0 Hz, 2H), 7.54 (br s, 2H), 4.53 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.68 (br s, 2H), 3.04 (t, J=6.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CN1C(=O)CCC1>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=2[C:4]#[N:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(Cl)ccc1N
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.15 g of 2-amino-5-chloro-benzonitrile and 0.23 g of 4-tert.butyl-benzenesulfonyl chloride is dissolved in 2 ml of NMP (N-methyl 2-pyyrolidone) and cooled in an ice bath to 5°. 2.5 ml of a solution of potassium-tert.butylat (1 N in THF) is added, the mixture obtained is stirred for 30 min, quenched with water and from the mixture obtained solvent is evaporated. The evaporation residue is dissolved in EtAc, washed with saturated NaHCO3 solution and dried. Solvent is evaporated and the evaporation residue is subjected to chromatography on a reversed phase column. 4-tert.Butyl-N-(4-chloro-2-cyano-phenyl)-benzenesulfonamide is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc2cc(OCc3ccccc3)ccc2c1
Yield: 25.6 %

Procedure:
Prepared according to the method described in Example 24b) from 6-(benzyloxy)-2-naphthol (2.2 g; Chem. Ber., (1965) 98, 1233), (±)-α-(chloromethyl)-3-pyridinepropanol (1.89 g; from Example 24a) above) and sodium hydroxide (0.8 g) in ethanol (30 ml) and water (10 ml) with heating at reflux for 6 hours to give the title compound as a solid (0.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=[S:15])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([S:15][CH3:18])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CSC1=Nc2ccc(F)cc2Nc2sc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Stir 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (61.5 g, 0.233 mol) and DMF (310 mL) under nitrogen for 15 minutes at ambient temperature. Add powdered potassium carbonate (67.7 g, 0.490 mol); stir 15 minutes at ambient temperature. Add iodomethane (22 mL, 0.35 mol); stir 4 hours at ambient temperature. Cool to 0-5° C. and add deionized water (150 mL) dropwise, keeping the temperature below 15° C. Extract the product with ethyl acetate. Wash the organic solution with brine four times, then dry over magnesium sulfate, filter and concentrate under reduced pressure to give 74.0 g of crude product. Purify by flash chromatography, eluting with 2:1/methylene chloride:heptane, then methylene chloride to give 55.0 g (85%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.11 (bs, 1H), 6.87 (m, 1H), 6.73 (m, 1H), 6.50 (s, 1H), 6.44 (m, 1H), 2.41(s, 3H), 2.25 (s, 3H). HRMS (ES) exact mass M+H calcd for C13H11FN2S2 279.0426; found 279.0416.
Reaction SMILES: N1C(C([O-])=O)=C[N:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.[OH-:15].[Na+]>C(O)C>[CH2:13]([O:12][C:10]([C:3]1[N:4]=[N:4][C:3]([C:10]([OH:11])=[O:15])=[CH:2][CH:2]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cnc(C(=O)[O-])cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.15 g of ethyl pyrazine-3,6-dicarboxylate was dissolved in 34.5 mL of ethanol, and 5.64 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitated salt was collected by filtration and dissolved in a small amount of water, and then this solution was acidified (pH=2) with a 1 M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain 435 mg of 6-(ethoxycarbonyl)pyridazine-3-carboxylic acid.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(O)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N:16](C)[C:15](=[O:38])[CH:14]=1>CC(O)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[NH:16][C:15](=[O:38])[CH:14]=1
Reactant: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(CCc2cccc(Cl)c2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 110 °C

Procedure:
To a solution of tin(II) chloride dihydrate (121 mg, 0.536 mmol, 4 equip) and concentrated HCl (0.168 ml) in AcOH (4 ml) was added 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one (68 mg, 0.134 mmol, 1 equip). The resulting solution was heated to 110° C. for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was taken up in dichloromethane, washed with saturated NaHCO3, dried (Na2SO4), and concentrated. The residue was purified by MPLC using dichloromethane-methanol as the eluent to yield a tacky, off-white solid. The solid was triturated repeatedly with ethyl ether to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>CN(C)C=O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(c1ccc(C=Cc2nc(CS(=O)(=O)c3ccc(Br)cc3)co2)cc1)C(F)(F)F

Procedure:
A solution of 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole (0.5 g, 1.5 mmol) and sodium 4-bromobenzenesulfinate (0.72 g, 3 mmol) in N,N-dimethyl formamide (20 ml) was stirred for 3 h at 60° C. After cooling the mixture was poured onto water, extracted with ethyl acetate (3×50 ml), the combined organic layers were washed with water, dried over sodium sulfate, concentrated in vacuo and crystallized from ether yielding 4-(4-bromo-benzenesulfonylmethyl)-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole as white crystalline product. Yield 0.6 g (77%)
Reaction SMILES: [CH2:1]([C:3]1[NH:8][CH:7]=[N:6][C:5](=O)[C:4]=1[CH3:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]([CH3:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1[nH]cnc(=O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ncnc(Cl)c1C
Temperature: 25 °C
Yield: 84.3 %

Procedure:
6-Ethyl-5-methyl-4(1H)-pyrimidinone (Intermediate 40, 1.382 g, 10 mmol) was added to a stirred solution of phosphorus oxychloride (4.66 ml, 50.0 mmol) and the reaction mixture was heated under reflux for 2 hours. After this time the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The viscous residue was dissolved in DCM and the resulting residue was poured into a stirred mixture of ice and 2M aqueous hydrochloric acid and the extracted with DCM (×3). The DCM layers were combined dried suing a hydrophobic frit and evaporated under reduced pressure to give the product, 4-chloro-6-ethyl-5-methylpyrimidine (1.32 g, 8.43 mmol) as an oil. m/z (ES+) 157/159 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[N+:15]=[N-:16]
Reactant: Nc1ccc(C=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a 500-mL round bottom flask with stirbar was added 4-amino-benzaldehyde (2.0 g, 0.0165 mol) and diluted hydrochloric acid (4 N, 150 mL). The mixture was cooled in ice-water bath to keep the temperature around 0° C. Sodium nitrite (2.28 g, 0.033 mol) solution in water (20 mL) was added to the above mixture at 0° C. and stirred for 0.5 h, and then sodium azide (2.15 g, 0.033 mol) solution in water (20 mL) was added to the above mixture dropwise to keep the temperature at 0° C. (a lot of foam were formed in this process). The reaction was warmed gradually to room temperature over 1 h, and then permitted to react at room temperature overnight. TLC showed that there was only one main product in the reaction mixture so the reaction was stopped. The crude product was extracted with EtOAc (50 mL×5) and the combined organic layers were dried with anhydrous MgSO4. After removing the solvent, a light yellow liquid was obtained as the pure final product (2.30 g, 95% yield). IR (neat): 3062, 2114, 1693, 1597, 1578, 1503, 1282, 1166, 1126, 852 cm−1. 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 7.91 (dt, J=8.8, 2.0 Hz, 2H), 7.19 (dt, J=8.8, 2.0 Hz, 2H); 1H NMR (400 MHz, MeOD): δ 7.45 (dt, J=8.8, 2.0 Hz, 2H), 7.08 (dt, J=8.8, 2.0 Hz, 2H), 5.38 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 190.7, 146.4, 133.2, 131.6, 119.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:45]=[CH:44][C:22]([CH2:23][N:24]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25](=[O:35])[C:26]5[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.[Cl-].[Na+].O>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([N:24]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[N:15]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:9][CH:10]=4)[O:18][N:17]=3)=[CH:45][CH:44]=2)=[O:35])=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc([N+](=O)[O-])cc5)cc4)no3)cc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)no3)cc2)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of tert-butyl 2-(N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-58 (7.25 g, 12.0 mmol) in THF (30 mL) was added water (10 mL) and sodium dithionite (6.26 g, 36.0 mmol) and then heated to 65° C. for 3 h. The reaction mixture was allowed to cool to room temperature and then diluted with brine (300 mL) and extracted into EA (300 mL) and THF (250 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The solid was dried under vacuum for 18 h to afford 7.17 g (100%.) of tert-butyl 2-(4-amino-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-59 as a pale yellow powder. LCMS-ESI (m/z) calculated for C35H34N4O4: 574; found 519 [M-t-Bu+H]+, tR=3.12 min (Method 10).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:27](=[O:28])[NH:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (about 1.15 mmol) in dry THF (10 mL) was added carbonyl diimidazole (373 mg, 2.3 mmol). The reaction mixture was stirred at room temperature until completion judged by LCMS. Aqueous sodium bicarbonate was added and the mixture extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated and the residue purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 279 as a colorless solid (308 mg). 1H NMR (dmso-d6, 400 MHz) δ 12.32 (s, 1H), 7.75-7.59 (m, 4H), 7.42 (m, 1H), 7.27-7.21 (m, 2H), 6.53 (s, 1H), 4.21 (t, 2H), 2.97 (t, 2H). MS (ESI) 476.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cn34)ccnc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCc3nnc4ccc(C5=CCNCC5)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
tert-Butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.113 g, 0.23 mmol) was dissolved in methanol (3 mL) then added concentrated hydrochloric acid (0.500 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The remaining solid was suspended in methanol (1 mL) then added triethylamine (0.40 ml, 2.9 mmol). The clear solution was stirred at room temperature for 2 hours then concentrated under vacuum. The sample was purified by flash chromatography eluting with 8% 7N ammonia in methanol/dichloromethane to afford 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (0.038 g, 42% yield) as a tan solid. MS (ESI pos. ion) m/z: 388.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:17][CH2:18][CH2:19][CH3:20])[N:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH3:23])[CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[O:7])=[C:4]([S:17][CH2:18][CH2:19][CH3:20])[N:3]=1
Reactant: CCCSc1nc(Cl)ccc1C(=O)NC1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)ccc1C(=O)N(C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 116.7 %

Procedure:
6-chloro-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.410 g, 1.3 mmol) in DMF (4 mL) was added portionwise to sodium hydride (60% dispersion in oil) (0.063 g, 1.56 mmol) in DMF (2 mL) cooled to 0° C. over a period of 2 minutes under nitrogen and stirred for 25 minutes. Methyl iodide (0.069 ml, 1.1 mmol) was added in one portion and the suspension was warmed and stirred at 20° C. for 72 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) then diluted with EtOAc (50 mL), and washed sequentially with water (10 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.422 g, 99%) as a colourless clear gum.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].B(Br)(Br)Br.N#N>C(Cl)Cl>[CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNc2cc(OC)ccc21
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: CCC1CCNc2cc(O)ccc21
Temperature: 0 °C
Yield: 97.5 %

Procedure:
In a flame dried 100 mL rb flask equivuipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methyloxyquinoline (21 mg, 109.9 μmol) in CH2Cl2 (4 mL). The solution was cooled to 0° C. and a 1.0M solution of BBr3 in CH2Cl2 (0.33 mL, 320 mmol, 2.75 equiv) was added slowly by syringe. The solution was warmed to rt and stirred under a blanket of N2 for 9 h. The reaction was quenched by addition of sat. NaHCO3 solution (5 mL), extracted with CH2Cl2 (3×25 mL), washed with brine (2×20 mL), dried (Na2SO4) and concentrated in vacuo to give 19 mg (99%) of the desired phenolic amine as a clear yellow oil. Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 6.85 (d, J=8.1, 1H), 6.11 (dd, J=2.4, 8.3, 1H), 5.98 (d, J=2.3, 1H), 3.25 (m, 2H), 2.57 (m, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 0.940 (t, J=7.4, 3H).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:44][C:43]2[C:38](=[C:39]([O:51]C)[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42]=2[O:45]C)[CH2:37]1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:37][C:38]2[C:39](=[O:51])[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42](=[O:45])[C:43]=2[CH2:44]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCCCCCC1(C(=O)OCC)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
A water (1 ml) solution of CAN (342 mg, 0.624 mmols) was dropwise added to an acetonitrile (2 ml) solution of ethyl 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoate (100 mg, 0.208 mmols), with cooling with ice. The reaction mixture was stirred for 15 minutes and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane only to hexane:ethyl acetate=4:1) to obtain the entitled compound (69 mg) as an oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[CH2:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCCc3ccccc32)cc1
Reaction time: 3 h

Procedure:
1,2,3,4-tetrahydroquinoline (2.66 g, 0.02 mol), benzaldehyde (3.12 g, 0.03 mol) and glacial acetic acid (0.67 ml, 0.012 mol) were dissolved in methanol (10 ml). Sodium cyanoborohydride (0.675 g, 0.0107 mol) was added portionwise, controlling the resulting vigorous gas evolution by the rate of addition. After 3 hours, the reaction mixture was poured into 50 ml 1N HCl and extracted 3×40 ml ether. The organic layers were combined, dried (MgSO4) and stripped to yield crude title product contaminated with benzyl alcohol. The crude product was dissolved in 50 ml ether, cooled to 0° C. and diffused with HCl gas until precipitation of hydrochloride salt was complete. The ether was decanted from the resulting semi-solid salt. The salt was washed with 20 ml fresh ether, the ether decanted, and the washed salt taken up in 50 ml of fresh ether and 50 ml of H2O. The pH was adjusted to 12 with 1N NaOH, and the ether layer separated, dried (K2CO3) and stripped to 2.47 g of product still containing some residual benzyl alcohol. Repeated conversion to hydrochloride salt and back to free base gave purified title product, 2.02 g.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]([CH3:18])=[O:17].O>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:15][C:16]([CH3:18])=[O:17])=[O:8])=[O:11]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 125 ml of ethanol were dissolved 14.2 g of sodium ethoxide, followed by the dropwise addition of a mixed liquid of 25 ml of diethyl oxalate and 13.5 ml of acetone over 20 minutes. The resulting mixture was stirred at room temperature for 3 hours. After the completion of the reaction, water was added to the reaction mixture. Ethanol was then evaporated under reduced pressure. The residue was extracted with chloroform. After the chloroform layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was then evaporated, whereby ethyl acetopyruvate (1) was obtained (O. S., Coll. Vol. 1, 238(1958)).