Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: NC(N)=O
Reactant: O=C(Cc1cccc(F)c1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(F)c2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of 2-(3-fluorophenyl)-1-phenylethanone (commercially available) (200 mg, 0.93 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (197 mg, 0.93 mmol), urea (168 mg, 2.8 mmol), conc. hydrochloric acid (0.5 mL) in ethanol (3 mL) was refluxed for 61 hours. After cooling to room temperature, the mixture was evaporated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to give Compound 115 (85.8 mg, yield 20%). HNMR (DMSO-d6 400 MHZ): δ 10.31 (brs, 1H), 8.82 (s, 1H), 7.59 (s, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.31-7.22 (m, 6H), 7.10-7.00 (m, 1H), 6.84-6.80 (m, 1H), 6.64-6.56 (m, 2H), 5.26 (d, J=2.4 Hz, 1H), 4.15-4.00 (m, 2H), 1.36 (t, J=6.8 Hz, 3H). MS (ESI): m/z 450.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([CH:7]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1cccc(CC(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)c1
Yield: 66 %

Procedure:
tert-Butyl 3-(2-(3-methoxyphenyl)acetyl)-4-oxopiperidine-1-carboxylate (388 mg, 66%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 2-(3-methoxy-phenyl)acetyl chloride according to the general procedure for the preparation of diketones.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][N:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:3][CH2:2][O:1][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(CCCNCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CCCc1ccc(C#N)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution of 4-[3-(2-hydroxyethylamino)propyl]benzonitrile (4 g, 0.0196 mol; see step (v) above) in dry DCM (80 mL) were added, at 0-5° C., triethylamine (5.9 g, 0.0588 mol) and mesyl chloride (5.6 g, 0.049 mol). The resulting mixture was then stirred at room temperature for 30 min, after which the reaction was quenched by addition of water (50 mL). The resulting aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine. Solvent was removed under reduced pressure and the crude product was recrystallised from methanol to yield 4.2 g (62%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8]C#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].BrC1C=CC(C=C)=CC=1.Cl[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH:7]([C:1]1[CH:2]=[CH:3][C:4]([P:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][CH:6]=1)=[CH2:8]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C#CC#Cc1ccccc1
Agent: C=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Polymerizable Gold Complex (3-1) was synthesized by reacting the gold complex obtained by the reaction between sodium tetrachloroaurate (III) and triphenylphosphine having a polymerizable functional group, with phenylbutadiyne synthesized by a known method (see, P. Cadiot and W. Chodkiewicz, Chemistry of Acetylenes, H. G. Viehe, ed., Marcel Dekker, New York (1969)). More specifically, 20 ml of dried THF was added to 341 mg (14 mmol) of magnesium and thereto, a 10 ml THF solution containing 2.70 g (15 mmol) of 4-bromostyrene was added dropwise to prepare a Grignard reagent. To the resulting solution, a 10 ml THF solution containing 2.50 g (11 mmol) of chlorodiphenylphosphine was added dropwise and stirred at room temperature of 1.5 hours. After removing the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from a hexane solution to obtain 2.30 g (8.3 mmol) of (4-vinylphenyl)diphenylphosphine Compound (B).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])[CH3:30].[CH2:41](N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:31][C:29]([C:32]1[CH:37]=[CH:36][C:35]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:34][CH:33]=1)([CH3:41])[CH3:30]
Reactant: CCN(CC)CC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(C(C)(C)O)cc2)c2ncnn12
Reaction time: 16 h
Yield: 41 %

Procedure:
To a suspension (26 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.86 g), (4-acetylphenyl)boronic acid (0.83 g), triethylamine (0.86 mL), pyridine (1.7 mL) and molecular sieves 4A (1.7 g) in dichloromethane was added copper(II) acetate (0.84 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. Methyllithium (2.2M diethyl ether solution, 0.94 mL) was added to the obtained residue at −78° C. The reaction mixture was stirred at the same temperature for 1 hr, and extracted with saturated aqueous ammonium chloride solution and diethyl ether. The diethyl ether layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.47 g, 41%).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.ClCCl.[CH3:15][NH:16][C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18]>O>[CH:2]([C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[C:17]([NH:16][CH3:15])=[O:18])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNC(=O)c1cc2ccccc2[nH]1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1[nH]c2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Oxalyl chloride (2.6 mL, 30 mmol) was added drop-wise to an ice-cooled solution of dimethylformamide (34 mL) and dichloromethane (90 mL), then N-methyl-1H-indole-2-carboxamide (3.51 g, 20 mmol) was added and the mixture stirred at rt for 1 h. Water was added and the resulting precipitate filtered, washed with water and diethyl ether. The product was dried to afford the title compound (2.03 g, 50%). 1H NMR (300 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.2 (s, 1H), 9.51 (s, 1H), 8.26 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.47-7.10 (m, 2H), 2.73 (d, J=4.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])=[C:24]([CH3:38])[C:23]=4[CH3:39])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:39][C:23]1[C:24]([CH3:38])=[C:25]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:26]([CH3:29])=[C:27]([CH3:28])[C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:40])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH:17]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(C)c(OCCCS(C)(=O)=O)c(C)c4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of methyl[(3S)-6-({2′,3′,5′,6′-tetramethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.457 g, 0.806 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.417 g, yield 94%) as colorless crystals.
Reaction SMILES: [Na].[NH2:2][CH2:3][CH2:4][SH:5].Cl[C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:8]=1[C:16](OCC)=[O:17].Cl>C(O)C>[S:12]([C:10]1[S:11][C:7]2[S:5][CH2:4][CH2:3][NH:2][C:16](=[O:17])[C:8]=2[CH:9]=1)(=[O:14])(=[O:13])[NH2:15]
Reactant: CCOC(=O)c1cc(S(N)(=O)=O)sc1Cl
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(s1)SCCNC2=O
Reaction time: 0.08 h

Procedure:
To a round bottomed flask were added ethanol (200 mL) followed by solid sodium (1.0 g, 43.5 mmole). After the sodium dissolved, 2-aminoethanethiol was added (1.57 g, 20.4 mmole). The reaction was stirred for approximately 5.0 minutes and 5-chloro-4-carboethoxythiophene-2-sulfonamide (5.0 g, 18.5 mmole) was added. The reaction was heated at reflux for 24 hrs. The cooled reaction mixture was acidified (6.0N HCl) and the solvent was removed under vacuum. The residue was triturated with water and the resulting solid collected: 4.77 g (98%) mp>270° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19](C4CCCCO4)[N:18]=3)[C:13]([Cl:29])=[CH:12][N:11]=2)=[C:4]([CH3:30])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>C1(C)C=CC=CC=1.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>[Cl:29][C:13]1[C:14]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[N:15][C:10]([NH:9][C:5]2[C:4]([CH3:30])=[CH:3][C:2]([C:36](=[O:38])[CH3:37])=[C:7]([CH3:8])[CH:6]=2)=[N:11][CH:12]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)c(C)cc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C)c(Nc2ncc(Cl)c(Nc3cc(C)[nH]n3)n2)cc1C
Temperature: 100 °C

Procedure:
A mixture of N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (166 mg, 0.34 mmol), tributyl(1-ethoxyvinyl)stannane (146 mg, 0.41 mmol) and Pd(PPh3)4 (39 mg, 0.034 mmol) in toluene (2 mL) was degassed and heated at 100° C. under N2 for 14 h. After cooling down to room temperature, the mixture was concentrated. The resulting residue was redissolved in acetonitrile (2 mL) and treated with 1N HCl (2 mL) for 14 h. After extraction with EtOAc (3×15 mL), the combined organic layers were treated with saturated aqueous KF (10 mL). The resulted organic layer was collected and treated with brine and dried over MgSO4. After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, 0-100% EtOAc in hexanes gradient) to provide 1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone as a white solid; ESMS m/z 371.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.C1C2C(=C(NC(=O)C)C=CC=2)CC1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:44][C@H:45]1[C@@H:52]2[N:48]([C:49](=[O:66])N(C3C4CCCCC=4C(C#N)=CC=3)[C:51]2=[O:53])[CH2:47][CH2:46]1>>[OH:44][C@H:45]1[C@@H:52]2[N:48]([C:49](=[O:66])[N:1]([C:4]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[C:51]2=[O:53])[CH2:47][CH2:46]1
Reactant: N#Cc1ccc([N+](=O)[O-])c2cccnc12
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: CC(=O)Nc1cccc2c1CCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2cccnc12

Procedure:
The title compound was synthesized from compound 12C by procedures analogous to those described in Experiment 3A and Experiment 2 (2E to 2F). 99.8% at 2.05 min (retention time) (Conditions: YMC S5 ODS (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient; (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 4 mL/min. UV detection at 220 nm). LC/MS nm/z 309 [M+H]+.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]1([CH3:26])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.C(O)(C)C.O>CC(C)=O>[CH3:26][C:16]1([C:15]([OH:3])=[O:14])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: CC(C)=O
Reactant: CC1(CO)COc2ccccc2O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC1(C(=O)O)COc2ccccc2O1

Procedure:
Jones' reagent (33.3 ml.) was added dropwise to a stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxan (5 g.) in acetone (300 ml.) at 5° C., then the reaction was allowed to attain room temperature. Isopropanol (10 ml.) was then added followed by water (200 ml.), the solution extracted with chloroform and the extracts evaporated in vacuo. The residual oil was taken up in chloroform (200 ml.) then extracted with dilute sodium bicarbonate solution and the aqueous phase further washed with chloroform. The aqueous phase was then acidified with hydrochloric acid, extracted with chloroform, the combined extracts washed with water, dried (MgSO4) and evaporated in vacuo ti give 2-methyl-1,4-benzodioxan-2-carboxylic acid (1.7 g.). A sample was recrystallized from toluene, m.p. 133°-134° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:32]=[O:33])(=[O:3])[CH3:2].O.P([O-])(O)(O)=[O:36].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:32]([OH:36])=[O:33])(=[O:3])[CH3:2]
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Reactant: O=P([O-])(O)O
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(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.4 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (60 mg, 0.13 mmol) in t-butanol (0.5 mL) and water (0.5 mL) solution was added sodium dihydrogenphosphate monohydrate (73 mg, 0.53 mmol), 2-methyl-2-butene (0.090 mL, 0.80 mmol) and sodium chlorite (72.2 mg, 0.80 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 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid (13 mg, 21% yield) as a yellow solid. HR-MS m/e calcd for C25H25N1O8 (M−H+) 468.1653, found 468.1657; 1H NMR (300 MHz) compatible.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:12]([CH2:13][CH2:14][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)#[N:15]
Reactant: c1c[nH]c(Cn2ccnc2)c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCCn1cccc1Cn1ccnc1
Reaction time: 18 h

Procedure:
2-(Imidazol-1-ylmethyl)pyrrole (4.41 g) and acrylonitrile (6.0 ml) were dissolved in dioxan (75 ml) and benzyltrimethylammonium hydroxide (1.5 ml of 40% solution in methanol) was added. The mixture was warmed to 55° for 1 hour and then allowed to stand at room temperature for 18 hours. It was then poured into water and the mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave 1-(2-cyanoethyl)-2-(imidazol-1-ylmethyl)pyrrole (5.0 g) as an oil.
Reaction SMILES: B#B.[C:3]([C:18]1[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[NH:21][CH:22]=1)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.O>O1CCCC1>[CH2:3]([C:18]1[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[NH:21][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Agent: B#B
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Reaction time: 8 h
Yield: 12.7 %

Procedure:
A solution (30 ml, 90 mmol) of ca. 3M diborane in tetrahydrofuran was added to 1.80 g (5.4 mmol) of methyl 4-tetradecanoylpyrrole-2-carboxylate prepared in Synthetic Example 6, and then 1 ml of boron trifluoride-diethyl ether complex was further added thereto. The mixture was allowed to stand overnight at room temperature. Methanol and water were successively added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/3) to obtain 0.22 g (13% yield) of methyl 4-tetradecylpyrrole-2-carboxylate, m.p. 80°-82° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:29])[O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:21]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)=[O:22])[CH:20]=1)[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:44]1([C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:18]=[C:19]([CH:20]=[C:5]([O:4][C@@H:3]([CH3:29])[CH2:2][OH:1])[CH:6]=3)[C:21]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)=[O:22])=[CH:17][CH:16]=2)=[O:15])[CH2:43][CH2:42][CH2:39]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[(1H-pyrazol-3-ylamino)carbonyl]phenoxy}benzoic acid (130 mg, 0.327 mmol), HATU (156 mg, 0.41 mmol), azetidine hydrochloride (38 mg, 0.41 mmol) and DIPEA (0.143 mL; 0.82 mmol) in DMF (2 mL) was stirred at ambient temperature for 16 hours. Water was added to the reaction mixture and it was extracted into ethyl acetate (3×30 mL). The organic phases were combined, washed with brine solution and dried (MgSO4). The filtrate was concentrated in vacuo and the residue chromatographed, eluting with 0-50% methanol in DCM, to give a clear oil which gave a foam under high vacuum (65 mg, 46%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH2:13][S:14][CH2:15][C:3]1=2.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2=[CH:13][S:14][CH:15]=[C:3]12
Reactant: Cn1c2c(c(=O)c3ccccc31)CSC2
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cn1c2ccccc2c(=O)c2cscc21
Yield: 70 %

Procedure:
2.17 Parts of 1,4-dihydro-4-methylthieno-[3,4-b]-quinolin-9(3H)-one are reacted with 0.88 part by volume of sulfuryl chloride in 25 parts by volume of methylene chloride at 0° C. for 0.5 hour. The end product is isolated from the reaction mixture by the method described in Example 5c. 1.50 parts (70% of theory) of 4-methyl-thieno-[3,4-b]-quinolin-9(4H)-one of the melting point 188°-190° C. are obtained.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:15]1[O:16][CH2:17][CH2:18][O:19][N:20]([CH3:22])[CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:32](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:41]1[CH:48]=[CH:47][C:44]([O:45][CH3:46])=[CH:43][CH:42]=1)[C:33]1[CH:40]=[CH:39][C:36]([O:37][CH3:38])=[CH:35][CH:34]=1.CO>N1C=CC=CC=1.CCOC(C)=O.CN(C1C=CC=CN=1)C>[CH3:46][O:45][C:44]1[CH:43]=[CH:42][C:41]([C:32]([O:27][CH2:26][C@H:25]2[O:28][C@@H:14]([N:13]3[C:29]4[N:30]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[NH:8][C:9](=[O:31])[C:10]=4[N:11]=[CH:12]3)[C@H:15]([O:16][CH2:17][CH2:18][O:19][N:20]([CH3:22])[CH3:21])[C@@H:23]2[OH:24])([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:33]2[CH:40]=[CH:39][C:36]([O:37][CH3:38])=[CH:35][CH:34]=2)=[CH:48][CH:47]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@H](OCCON(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To N2-isobutyryl-2′-O-(dimethylaminooxyethyl) guanosine (42.63 g, 27.44 mmol) and dimethylaminopyridine (168 mg, 1.37 mmol) dissolved in anhydrous pyridine (274 mL) was added DMT-Cl (9.30 g, 27.44 mmol). After several hours additional DMT-Cl (9.30 g, 27.44 mmol) was added. After several more hours MeOH (22 mL, 543 mmol) was added, and the reaction mixture was stirred for 30 minute. The solvent was evaporated in vacuo to give an oil which was dissolved in EtOAc (550 mL). The resulting suspension was washed with a mixture of H2O (50 mL) and brine (25 mL) twice, then with brine (50 mL). NEt3 (5 mL) was added, the organic phase was dried with MgSO4 and the solvent was evaporated in vacuo to give a foam. The foam was purified by column chromatography (silica pretreated with 1% NEt3) using CH2Cl2-EtOAc-MeOH-NEt3, 75:25:10:1, to afford the title compound as a foam (16.3 g, 80%).