Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22]Cl>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[Br:1]
Reactant: Clc1nc(Br)[nH]c1Cl
Reactant: ClCCCCOCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ClCCCCOCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a mixture of 1.08 g of 2-bromo-4,5-dichloroimidazole, 0.51 g of triethylamine and about 30 ml of toluene was added dropwise 0.79 g of 4-chlorobutoxymethyl chloride at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The deposited crystal was filtered off and washed with about 10 ml of toluene. The filtrate thus obtained was concentrated under reduced pressure, and the residual oily product was purified by column chromatography on silica gel to obtain 0.60 g of 1-(4-chlorobutoxymethyl)-2-bromo-4,5-dichloroimidazole.
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.[N:27]#[C:28]Br>CO>[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:28]([NH2:27])=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: N#CBr
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: CO
Product: Nc1nnc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 45 °C
Yield: 21 %

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (195, 0.434) in methanol (5 mL) was treated with a solution of cyanogen bromide (115 mg, 1.1 mmol) in methanol (1 mL) at room temperature. The reaction vessel was sealed and heated at 45° C. for 2 h, cooled to room temperature, quenched upon addition of saturated sodium bicarbonate and extracted with ethylacetate. The combined organics were dried over sodium sulfate and concentrated and the residue purified by flash column chromatography (1-10% MeOH in methylene chloride to give 287 (43 mg, 21% yield). MS (ESI): 475.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:42]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([N:50]1[CH2:51][CH2:52][N:47]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:33]3[N:32]([CH3:31])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=3)[CH:42]=2)[CH2:48][CH2:49]1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2cccc(N3CCN(C(=O)C4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of morpholine-3,4-dicarboxylic acid-4-tert-butyl ester (0.16 g, 0.71 mmol) in acetonitrile (8 mL) was added CDI (0.16 g, 0.71 mmol) and the resulting suspension was stirred at room temperature overnight. 1-Methyl-2-(3-piperazin-1-yl-phenyl)-1H-benzoimidazole dihydrochloride (0.20 g, 0.55 mmol) (obtained as described in method C) and DIPEA (0.19 mL, 1.10 mmol) were added and the resulting solution heated at 65° C. overnight. The reaction was then cooled to room temperature, the solvent removed, the crude product was dissolved with dichloromethane (15 mL) and washed with saturated NaHCO3 solution (2×3 mL) The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: gradient from cyclohexane to cyclohexane:EtOAc 2:1) to afford 0.11 g (40%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=1>C(#N)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:2]([NH:1][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[C:3]([CH:10]=1)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Reactant: COc1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Temperature: 70 °C
Yield: 74.2 %

Procedure:
A solution of 8 (3.75 g, 17.3 mmol) in 50 mL of acetonitrile was treated with p-toluenesulfonic acid monohydrate. The reaction mixture was heated to 70° C. with stirring. 4-Methoxybenzyl alcohol (2.63 g, 19.0 mmol) in acetonitrile (3 mL) was added dropwise via syringe keeping the reaction temperature at 70° C. The reaction was stirred at 70° C. for 12 h, allowed to cool to ambient temperature, and concentrated in vacuo. Chromatography afforded 9 (4.3 g, 75%) as light yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:43][N:44](C)C(=O)C>O>[CH3:34][C:13]1[CH:12]=[C:11]([CH3:35])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27]([C:43]#[N:44])[C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(C)c(CN2CCOc3c(Br)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C)c(CN2CCOc3c(C#N)cc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Temperature: 120 °C
Yield: 19 %

Procedure:
To a solution of 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 98 mg, 0.18 mmol) in N,N-dimethylacetamide (2 mL) was added cuprous cyanide (50 mg, 0.55 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 20 hours, cooled to room temperature then additional cuprous cyanide (25 mg, 0.26 mmol) was added and the reaction was heated at 150° C. in a sealed tube for 5 hours. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with methyl tert-butyl ether (2×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue was taken up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL, 2 mmol) and stirred at room temperature overnight then concentrated under vacuum. The residue was purified by reverse phase HPLC to provide the title compound (Example 116, 13 mg, 19% yield). 1H NMR (700 MHz, DMSO-d6) δ 7.47 (s, 1H), 5.93 (br. s., 1H), 4.58-4.69 (m, 3H), 4.12 (br. s., 2H), 2.19 (d, J=12.91 Hz, 6H), 2.14 (s, 3H), 1.26 (d, J=6.02 Hz, 6H): MS 396 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1.ON1C2C=CC=CC=2N=N1.[CH2:31]([CH2:33][NH2:34])[OH:32].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[OH:32][CH2:31][CH2:33][NH:34][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])[CH:7]=1
Reactant: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C)c1COc1cccc(CC(=O)NCCO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid (Step C, 6.0 g, 22.2 mmol), 1-Hydroxybenzotriazole (7.19 g, 53.2 mmol), and Ethanolamine (2.70 g, 44.2 mmol) in methylene chloride (30 ml) and DMF (5 ml) was added EDCI (7.66 g, 40 mmol) at 0° C., the resulting reaction mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and washed with NaHCO3, 0.1M HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 9:1) to provide the title compound.
Reaction SMILES: [S:1]([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38]>>[CH2:37]([N:39]([CH2:40][CH3:41])[C:14]1[C:15]2[C:16](=[O:26])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23](=[O:25])[C:24]=2[C:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])=[CH:12][CH:13]=1)[CH3:38]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Product: CCN(CC)c1ccc(S(=O)(=O)c2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 91 %

Procedure:
1-(diethylamino)-4-tosylanthraquinone was prepared by reaction of 1,4-ditosylanthraquinone with diethyl amine. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR11## The yield was 91% and the m.p. 140°-141° C. Mass spec m/e 449 (M+), 434 (M-CH3), 420 (M-C2H5), 294 (M-C7H7SO2), 266 (294-CO), 155 (C7H7SO2), 91 (C7H7): H-NMR (CD2Cl2)δ8.19-8.13 (m, 2H), 7.97-7.68 (m, 4H), 7.30-7.15 (m, 4H), 3.48-3.24 (q, 4H), 2.26 (s, 3H), 1.22-1.06 (t, 6H); IR (Nujol) 1172 cm-1 (symmetrical SO2 stretch), 945 cm-1, 872, 830, 820, 800, 785, 765 (S--O--C stretch); UV/VIS max (Xylenes) 506 nm (ε3650).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[CH:4][N:3]=1.CN(C=O)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)ncnc1NCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-(4,6-dichloropyrimidin-5-yl)acetate (1.00 equiv; 65.10 mmol; 14.39 g) in DMF (0.5 M; 1.68 mol; 130.20 mL), add 4-methoxybenzylamine (1.10 equiv; 71.61 mmol; 9.36 mL) and DIPEA (1.20 equiv; 78.12 mmol; 13.62 mL) and stir the mixture at 60° C. for 1 h. Quench with ice-water, extract with EA, and wash the organic layer with 1N HCl, water and brine, dry over MgSO4, filter and concentrate in vacuo to the title compound (54.98 mmol; 17.69 g; 84.45%) as a yellow solid and use without further purification. 1H NMR (300 MHz, DMSO): 8.20 (s, 1H), 7.21-7.18 (m, 2H), 6.89-6.85 (m, 2H), 4.53 (d, J=5.8 Hz, 2H), 3.76 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2].[CH3:12][O:13][CH2:14][CH2:15]Br.O>CS(C)=O>[C:1]([C:5]1([CH2:15][CH2:14][O:13][CH3:12])[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COCCBr
Reactant: COC(=O)C1CSCCC1=O
Solvent: CS(C)=O
Solvent: O
Product: COCCC1(C(=O)OC)CSCCC1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 5.3 g (25 mmol) of potassium enolate of 4H-2,3,5,6-tetrahydro-3-carbomethoxythiopyran-4-one in 50 ml DMSO, was added 3.47 g (25 mmol) of 2-bromoethyl methyl ether. The solution was stirred under N2 at room temperature for 4 days. The reaction mixture was poured into 500 ml H2O and extracted three times with ethyl acetate. The combined ethyl acetate solution was washed with water; 5% NaOH; H2O and brine; dried over magnesium sulfate, filtered and concentrated in vacuo to give about 5 g crude product. Chromatographed through a pressure column eluting with 10% ethyl acetate-n-hexane to give 2.49 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:8]([CH3:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][NH:4][C:3]1=[O:14].C=O.[OH-].[Na+].[CH2:19]([OH:21])C>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:8]([CH3:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][N:4]([CH2:19][OH:21])[C:3]1=[O:14]
Reactant: C[C@@H]1C(=O)NCc2ccccc2[C@@H]1C
Reactant: CCO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C[C@@H]1C(=O)N(CO)Cc2ccccc2[C@@H]1C
Yield: 61 %

Procedure:
A solution of 5.7 g. (0.030 moles) of cis-4,5-dimethyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one, 9 ml. (0.09 moles) of 35% aqueous formaldehyde solution and 0.05 g. of sodium hydroxide in 50 ml. of 92% ethanol is heated for 5 hours at 80° C., while stirring. The reaction mixture is cooled and the solvents are evaporated off in vacuo. The oil obtained is taken up in chloroform, washed several times with water and then dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo, the residual syrup is purified by recrystallization from diisopropyl ether. 4 g. (61% of theory) of cis-4,5-dimethyl-2-hydroxymethyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained. M.P. 91°-92° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1>[N:3]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
4,4′-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml), and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) was added dropwise thereto over 1 hour while keeping the solution neutral by adding a 6 M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. CHCl3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain benzyl 4,4′-bipiperidine-1-carboxylate (1.5 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:15]=1[O:16][CH:17]([CH3:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:14]1[CH:28]=[C:27]([O:29][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=3)[N:3]=2)[CH:26]=[CH:25][C:15]=1[O:16][CH:17]([CH3:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]
Reactant: Fc1ccc2nc(Cl)cnc2c1
Reactant: CCCOC(=O)C(C)Oc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1F
Temperature: 120 °C
Yield: 41.8 %

Procedure:
A mixture of 2-chloro-6-fluoroquinoxaline (1.0 g; 5.48 mmole), n-propyl 2-(2-fluoro-4-hydroxyphenoxy)propionate (1.33 g; 5.49 mmole), anhydrous potassium carbonate (0.8 g) and anhydrous dimethylformamide (40 ml) was stirred and heated at a temperature of 120° C. for a period of 3.5 hours. The solvent was evaporated from the reaction mixture under vacuum, the residue was treated with water and the mixture was extracted with diethyl ether. The etherial extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under vacuum to give a brown oil. The product was purified by preparative thin layer chromatography over silica gel (eluant chloroform/ethanol, 95:5) to give the title compound (0.89 g; 41.8%) as a solid; mp 49°-51° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:25]=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:25]([OH:32])=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.2 %

Procedure:
To a stirred solution of 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (70 mg, 0.17 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (97 mg, 0.71 mmol), 2-methyl-2-butene (0.12 mL, 1.06 mmol) and sodium chlorite (98.0 mg, 1.06 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carboxylic acid (40 mg, 57% yield) as a light yellow solid. HR-MS m/e calcd for C24H25N1O7 (M−H+) 412.1391, found 412.1394; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][NH2:6])=[O:4].C(=O)(O)[O-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1.O>[C:14]([NH:6][NH:5][C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(C)(C)C(=O)NN
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NNC(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethyl-propionic acid hydrazide (2.32 g, 20 mmol), sodium bicarbonate (1.68 g, 20 mmol) in tetrahydrofuran and water (1:1, 40 mL) was added acetyl chloride (1.56 g, 20 mmol) dropwise. The mixture was stirred overnight and concentrated in vacuo. The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give a white solid. The solid was recrystallized from tetrahydrofuran and hexane (1:8) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.14 (m, 9 H) 1.83 (s, 3 H) 9.28 (br s, 1 H) 9.53 (br s, 1 H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:13][C:3]1[C:2]([CH:14]=[CH2:15])=[C:11]([F:12])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c(F)cc2ncccc2c1F
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
6-Bromo-5,7-difluoro-quinoline (v) (1 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.041 mmol) and tributyl(vinyl)tin (1.34 g, 4.10 mmol) were put together with dioxane (3.7 mL) in a microwave reactor and stirred for 25 min at 150° C. under microwave irradiations. The solvent was removed and the residue was purified by MPLC with hexane and EtOAc. The title compound was obtained as a colorless oil (tR 1.1 min (conditions 2), MH+=192).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:33])([F:32])[CH2:29][CH2:30][NH2:31].[BH3-]C#N.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH:18]([NH:31][CH2:30][CH2:29][C:28]([F:33])([F:32])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: NCCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCC3NCCC(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and NaBH3CN (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous Na2SO4. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m/z 497.98 ([M−H]−); IR (thin film) 3027, 1654, 815 cm−1.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]2[S:14][C:15]3[CH2:20][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:17][C:16]=3[C:3]1=2.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CCOC(=O)N1CCc2c(sc3nc(-c4cccnc4)[nH]c(=O)c23)C1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1CCc2c(sc3nc(-c4cccnc4)nc(Cl)c23)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4.1 g of 5,6,7,8-tetrahydro-4-oxo-7-ethoxycarbonyl-2-(3-pyridyl)pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine was added to 40 ml of phosphorus oxychloride, and stirred at 80 to 100° C. for 3 hours. After phosphorus oxychloride was distilled off under reduced pressure, 50 ml of water was added to the reaction residue. The reaction solution was made alkaline with an aqueous saturated solution of sodium hydrogen carbonate while cooling, and extracted with chloroform. The organic layer was washed with saturated salt water and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off. The filtrate was concentrated under reduced pressure to give 5.0 g of 5,6,7,8-tetrahydro-4-chloro-7-ethoxycarbonyl-2-(3-pyridyl)pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine.