Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[C:22]([N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][CH2:24]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:33]([O:35]C)=[O:34])[CH:19]=4)[N:14]=3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1>CO.O>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[C:22]([N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][CH2:24]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:33]([OH:35])=[O:34])[CH:19]=4)[N:14]=3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCCO4)c(N3CCCc4ccccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc4c(c3)OCCO4)c(N3CCCc4ccccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Sodium hydroxide (21.6 mg, 0.54 mmol) was added to a solution of methyl 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (65 mg, crude) in methanol (5 ml) and water (1 ml) and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in water (30 ml), adjusted to pH=5 with hydrochloric acid (3 N), and the precipitate was collected by filtration to afford 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (31.8 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[C:22]1=[O:34])(=O)C.Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Li+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C.C1COCC1.O1CCOCC1>[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:34])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[C:38]([NH:44][C:45]4[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=4)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)[C:6]=1[CH2:5][OH:4])[CH2:29]2)([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)nn1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 103f (556 mg, 1.20 mmol), 105a (300 mg, 1.00 mmol), sodium carbonate (424 mg, 4.00 mmol), water (4 mL) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 20 min, tetrakis(triphenylphosphine)-palladium(0) (115 mg, 0.100 mmol) was added, and the reaction mixture was heated at 100° C. for 4 h. After this time, the reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with a 1:10 mixture of methanol and methylene chloride (30 mL). The filtrate was concentrated under reduced pressure to afford a brown residue. Another 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with residue obtained above, THF (5 mL), ethanol (5 mL), water (5 mL) and lithium hydroxide (86.4 mg, 3.60 mmol). The mixture was stirred at 50° C. for 2 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 35% (190 mg) yield of 105 as a white solid: mp 225-227° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.72 (d, 1H, J=7.5 Hz), 7.71 (s, 1H), 7.61 (d, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.22 (s, 1H), 5.88 (s, 1H), 4.89 (s, 2H), 4.88 (t, 1H, J=4.5 Hz), 4.35 (d, 2H, J=4.5 Hz), 3.57 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 512.3 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12.Cl>C1COCC1>[Cl:30][C:29]1[C:24]([N:21]2[C:17]3=[N:18][CH:19]=[N:20][C:15]([O:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])=[C:16]3[CH:23]=[N:22]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](O)COC(C)C
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Sodium hydride (1.84 g, 45.9 mmol) was added to a stirred solution of (S)-methyl 2-hydroxy-3-isopropoxypropanoate (Intermediate C7a) (6.0 g, 30.6 mmol) in anhydrous THF (200 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (8.14 g, 30.59 mmol) in dry THF (50 mL) was added dropwise, maintaining the temperature below 5° C. The reaction mixture was stirred at 0° C. for 10 minutes. Then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M HCl. The majority of the THF was evaporated in vacuo and then EtOAc (100 mL) was added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 70% EtOAc in isohexane to afford (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (7.76 g, 64.8%), ee 53%. A sample of this (1.48 g) was purified by preparative chiral-HPLC on a 50 mm 20um chiralcel OJ column, eluting with 30% isopropanol in isohexane (modified with 0.1% TEA), to give (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (1.03 g, 99% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.14 (6H, m), 3.68-3.75 (4H, m), 3.98-4.00 (2H, m), 5.80-5.82 (1H, m), 7.74-7.77 (1H, m), 8.33-8.35 (1H, d), 8.59 (1H, s), 8.64 (1H, s), 8.67-8.68 (1H, m); m/z (ESI+) (M+H)+=392; HPLC tR=2.13 min.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[C:13]1([NH:19][C:20]([CH:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]2=[O:12])=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccccc21
Reactant: S=C=Nc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2CC1C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (60% dispersion in mineral oil, 0.25 g, 6 mmol) and indan-1-one, Compound 1a, (0.50 g, 3.79 mmole) in THF (5 mL) were mixed under argon. The mixture was stirred at ambient temperature for 5 min. Then, phenylisothiocyanate, Compound 1b, (0.46 mL, 3.79 mmole) was added to the mixture. After an additional 5 min, the reaction was completed as shown by TLC analysis and the reaction mixture was poured into NH4Cl solution and then filtered subsequently. 1-Oxo-indan-2-carbothioic acid phenylamide (Intermediate A), was crystallized from CH3CN as a yellow solid. MS m/z 268 (M+H)+; 1H NMR (DMSO-d6):3.5 (dd, 0.3H), 3.8 (d, 0.15H), 3.9 (s, 1.55H), 4.3 (dd, 0.3H), 7.3 (t, 1H), 7.4–7.8 (m, 7.4H), 7.9 (d, 0.6H), 10.6 (s, 0.7H), 12.1 (s, 0.3H), 14.1 (s, 0.7H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[C:14]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([Cl:13])[C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: Clc1ccc2c(c1Cl)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2ccc(Cl)c(Cl)c2C1
Reaction time: 4 h

Procedure:
A mixture containing (100 g., 0.425 m.) 7,8-dichlorotetrahydroisoquinoline hydrochloride and (41 g., 0.5 m.) sodium acetate in 760 ml. of acetic acid and 430 ml. of acetic anhydride was heated at 100° C. with stirring for four hours. The cooled reaction mixture was diluted with 800 ml. of water and brought to pH 8 by addition of 5% aqueous sodium carbonate (1400 ml.). The tan precipitate was collected by filtration, dried and recrystallized from isopropanol to give N-acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline having a melting point of 98°-100° C.
Reaction SMILES: [C-:1]#[N:2].[CH3:3][C:4]1[CH2:13][NH:12][C:11]2[N:10]=[C:9]([NH2:14])[NH:8][C:7](=[O:15])[C:6]=2[N:5]=1>>[C:1]([C:4]1([CH3:3])[CH2:13][NH:12][C:11]2[N:10]=[C:9]([NH2:14])[NH:8][C:7](=[O:15])[C:6]=2[NH:5]1)#[N:2]
Reactant: CC1=Nc2c(nc(N)[nH]c2=O)NC1
Reactant: [C-]#N
Product: CC1(C#N)CNc2nc(N)[nH]c(=O)c2N1

Procedure:
The first synthesis of 6,6-disubstituted tetrahydropteridines utilized nucleophilic addition of cyanide across the 7,8 double bond of 6-methyl-7,8-dihydropterin, yielding 6-cyano-6-methyltetrahydropterin (Viscontini et al., Helv. Chim. Acta, 54, 811-818 (1971)). After a number of intermediate steps, the nitrile was reduced and the final compound, 6-aminomethyl-6-methyl-5,6,7,8-tetrahydropterin, was obtained. This molecule proved to be less stable than expected, since upon oxidation the resulting quinoid dihydropterin was able to reform the starting 6-methyl-7,8-dihydropterin by loss of the amino methyl group as ammonia and formaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:8]2[CH:7]=[CH:6][C:5]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:22]=3[CH3:23])=[O:17])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1
Reactant: CN(C)CCCl
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCN(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (2 g), 2-dimethylaminoethyl chloride hydrochloride (0.85 g) and potassium carbonate (0.8 g) were added to dimethylformamide (20 ml) and the mixture was stirred at 60° C. for 3 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. Ethanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.3 g), melting point: 185° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.C(N(CC)CC)C.Cl.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:47](=N)OCC)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1>CO>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:47]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:45][CH2:46]2)[CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2cccc(OC)c2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cccc(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)c1
Temperature: 130 °C

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (60 mg, 0.17 mmol) in methanol (0.5 mL) and acetic acid (150 μL, 2.7 mmol) was added triethylamine (94 μL, 0.67 mmol) and a solution of ethyl 1-(3-methoxyphenyl)cyclopropanecarbimidate hydrochloride (40 mg, 0.16 mmol) in methanol (0.3 mL). The reaction mixture was heated in a microwave for 45 min at 130° C. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 446.3; HPLC retention time 2.3 min (Method A).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:37][CH2:38][Sn](CCCC)(CCCC)CCCC.[OH-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:38][OH:37])[CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(CO)cc12
Yield: 12.6 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-5-bromo-1-methyl-1H-indole (from Example 79, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added hydroxymethyltributylstannane (253 mg, 0.79 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (30 mg). The mixture was heated to reflux for 8 hours, and then cooled. Sodium hydroxide solution (1M) was added and the mixture boiled to dissolve the product. The solution was decanted clear of an insoluble tar residue, and washed with diethyl ether. After acidification with concentrated hydrochloric acid, the aqueous mixture was extracted with ethyl acetate. The organic extract was dried (magnesium sulphate) and the solvents were evaporated in vacuo. The residue was flash chromatographed using 2% methanol in dichloromethane as eluant to give the title compound (35 mg).
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.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([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:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)c(F)c2)c2ncnn12
Reaction time: 16 h
Yield: 89.8 %

Procedure:
To a suspension (15 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (3-fluoro-4-methoxyphenyl)boronic acid (0.45 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.49 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. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 90%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:21]=[C:20]([O:22][CH:23]([C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:41])[CH2:24][CH3:25])[C:19]([F:42])=[CH:18][C:15]=1[C:16]#[N:17].O>O1CCCC1.C(O)(C)(C)C>[F:42][C:19]1[C:20]([O:22][CH:23]([C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:41])[CH2:24][CH3:25])=[CH:21][C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: CCC(Oc1cc(F)c(C#N)cc1F)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCC(Oc1cc(OCC(F)(F)F)c(C#N)cc1F)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 342 mg of trifluoroethanol in 2.1 mL of tetrahydrofuran at 5° C. was slowly added 4 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 1.25 g of 2,5-difluoro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile in 5.6 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 70/ethyl acetate 30) to give 1.09 g of 5-fluoro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-(2,2,2-trifluoro-ethoxy)-benzonitrile.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[N:19][C:20]#[N:21])SC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:22][NH2:23]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:23][CH3:22])=[N:19][C:20]#[N:21])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(=N)N)n1
Solvent: CCO
Product: CNC(=NC#N)NCCCCCc1csc(NC(=N)N)n1
Reaction time: 8 h

Procedure:
To a solution of 2-guanidino-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole in ethanol was added ethanolic methylamine (33% w/v, 15 ml.). The mixture was allowed to stand overnight and then evaporated to dryness. The residue was crystallized from acetonitrile to give 2-guanidino-4-[5-(2-cyano-3-methylguanidino)pentyl]thiazole, m.p. 109°-113° C.
Reaction SMILES: [CH2:1]1SSO[C:4]([C:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[NH:10][CH:9]=2)([O:5]CC)[O:3][CH2:2]1>C(O)C.[Ni]>[CH2:13]([C:11]1[NH:10][CH:9]=[C:8]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCC(=O)c1cc(C2(OCC)OCCSSO2)c[nH]1
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCCc1cc(C(=O)OCC)c[nH]1
Yield: 88.9 %

Procedure:
A mixture of 3.74 g (9.1 mmol) of ethyl 5-tridecanoylpyrrole-3-carboxylate dithioethylene ketal prepared in Sythetic Example 5 and 30 ml of Raney-nickel in 200 ml of ethanol was heated under reflux for 2 hours. After filteration through celite, the separated Raney-nickel was washed well with ethanol. The solvent was removed under reduced pressure, the residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/7) to obtain 2.60 g (89% yield) of ethyl 5-tridecylpyrrole-3-carboxylate, m.p. 59.5°-60.5° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]2[C:3]3[N:4]([N:8]=[C:9]([Cl:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: Clc1nc2c(Br)cccn2n1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cccn3nc(Cl)nc23)C1

Procedure:
3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (475.0 mg, 2.372 mmol) in a manner analogous to Example 2d. Product isolated as pale yellow viscous oil (0.544 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.88 (d, J=6.6 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 4.98 (br s, 1H), 3.65-3.08 (m, 6H), 2.64-2.51 (m, 1H), 2.15-2.05 (m, 1H), 1.80-1.65 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:10])[CH2:9][CH2:8][CH2:7]1)=[O:5].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)C1(N)CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
methyl-1-aminocyclobutanecarboxylate hydrochloride (300 mg, 1.81 mmol) was dissolved in CH2Cl2 (7 ml), added with 2-nitrobenzene-1-sulfonyl chloride (441 mg, 1.99 mmol) and triethylamine (1 ml, 7.24 mmol) and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(2-nitrophenylsulfonamido)cyclobutanecarboxylate (512 mg, 1.63 mmol, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C@@H:14]([OH:23])[C@H:13]1[OH:24].[CH2:25]([N:27]1[CH:31]=[C:30]([CH2:32][CH2:33][NH2:34])[N:29]=[CH:28]1)[CH3:26]>>[NH2:1][C:2]1[N:10]=[C:9]([NH:34][CH2:33][CH2:32][C:30]2[N:29]=[CH:28][N:27]([CH2:25][CH3:26])[CH:31]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C@@H:14]([OH:23])[C@H:13]1[OH:24]
Reactant: CCn1cnc(CCN)c1
Reactant: CC(C)C(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CCn1cnc(CCNc2nc(N)c3ncn([C@@H]4C[C@H](NC(=O)C(C)C)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
N-[(1S,2R,3S,4R)-4-(6-Amino-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-isobutyramide is reacted with and 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine to give the title compound Lasing a procedure analogous to that of Example 9. MS (ES+) m/e 458 (MH+).