Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH3:18][C:19]1[N:20]=CNC=1CSCCN>C(O)C>[C:1]([NH:3][C:4]([NH:20][CH2:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamino (9.0 g) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (5.0 g), prepared from 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure of Example 97, in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2; S, 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].CC(C)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)C.O>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([N:24]=[N+:25]=[N-:26])(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4,6-triisopropylbenzenesulfonyl chloride (18.2 g, 60.0 mmol) in reagent acetone (70 mL) is added a solution of sodium azide (4.3 g, 60 μmol) in ethanol-H2O 1:1 (40 mL). The temperature of the mixture rises from 21° C. to 29° C. during the addition. After stirring at room temperature for 2 hours, the reaction mixture is partitioned between dichloromethane and half saturated brine. The aqueous solution is extracted with dichloromethane (3X), the combined organic solution is washed with half saturated brine, and dried (magnesium sulfate). Removal of solvent in vacuo gives a colorless oil which is purified by flash chromatography (silica gel, hexane-ethyl acetate/4:l) to yield the title compound as a white solid, 18.5 g; mp 44°-44.5° C. (Evans, D. , et al, Journal of the American Chemical Society 112:4011 (1990); mp 43°-44° C.).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-])=O)=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2.[H][H].[C:22]([OH:25])(=[O:24])[CH3:23]>[Pd]>[CH3:11][C:2]([CH2:23][C:22]([OH:25])=[O:24])=[O:1].[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[CH:9]=2)[C:4]([CH3:19])=[N:3][C:2]=1[OH:1]
Reactant: COc1cc2c(C)nc(O)c([N+](=O)[O-])c2cc1OC
Reactant: CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Product: CC(=O)CC(=O)O
Product: COc1cc2c(C)nc(O)c(N)c2cc1OC
Yield: 95.6 %

Procedure:
3-Hydroxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (16.0 grams, 60.54 mmol) was slurried in 600 ml glacial acetic acid and hydrogenated over 1.5 grams of a 10% palladium on carbon catalyst (Pd/C) at 17 psi hydrogen pressure at room temperature in a Parr hydrogenator for 1.5 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was evaporated to dryness in vacuo to provide 20.48 grams of the diacetate solvate of the title compound as a dark greenish-yellow solid (95.6% yield) having a melting point of 111°-115° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:23]1([CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.93M stock solution, 53.2 mmol) cooled to −78° C. was treated with (4-methoxy-phenyl)-acetic acid (4.21 g, 25.35 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (5.85 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at −78° C. for 45 min and at 0° C. for 1 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxy-phenyl)-propionic acid (2.76 g, 43.8%) as a yellow solid: mp 119–121° C.; EI-HRMS m/e calcd for C15H20O3 (M+) 248.1412 found 248.1415.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: O=C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In N,N-dimethylformamide (10 ml) was suspended piperidin-4-one (monohydrochloric acid monohydrate, 1.54 g), followed by the addition of diisopropylethylamine (3.48 ml) and 6-chlorobenzo[b]thiophene-2-sulfonyl chloride (2.68 g). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was then added to the residue, followed by washing with 1N hydrochloric acid. After extraction, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate methylene chloride=3:1), followed by washing with hexane, whereby the title compound (colorless prism crystals, 1.92 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([C:14]2[CH:13]=[N:12][C:7]3[NH:8][CH2:9][C:10](=[O:11])[N:5]([CH2:4][C:3]4[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:2]=4[Cl:1])[C:6]=3[CH:15]=2)=[CH:30][CH:29]=1)[CH3:24]
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(F)ccc(F)c1Cl
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)C(=O)CN3)cc1
Temperature: 130 °C
Yield: 19 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (280 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A, with the modification that the mixture was heated to 130° C. in a microwave oven for 5 minutes. The title compound was obtained as a white solid after silica gel chromatography (19% yield). M.p. 180-182° C., LCMS: m/z=458.37 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.34 (t, J=7.1 Hz, 3H), 4.08 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 5.39 (s, 2H), 7.18 (bs, 1H), 7.29-7.33 (m, 1H), 7.39-7.47 (m, 1H), 7.42 (s, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.97 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: COC(=O)c1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using methyl 1H-indole-6-carboxylate and iodobenzene: ESMS m/e: 252.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.N1CCCCC1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)C=CCc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1
Temperature: 110 °C
Yield: 81 %

Procedure:
A mixture of 2 g (12.53 mmol) of 4-phenylbut-2-enoic acid, 1.8 mL (14.8 mmol) of 4-methoxybenzenethiol, and 0.4 mL (3.7 mmol) of piperidine is heated at 110° C. in a bomb for 18 hours. The reaction is partitioned between ethyl ether and 1N HCl. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash silica gel chromatography affords 3.07 g (82%) of 3-(4-methoxyphenylsulfanyl)-4-phenylbutyric acid as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17]([O:19][CH:20]([C:24](OC)=[O:25])[C:21]([CH3:23])=[CH2:22])=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.O1C2C=CC=CC=2C=CN1.O>C1(C)C=CC=CC=1.C[O-].[Na+]>[F:1][C:2]1[C:15]([N:16]2[C:24](=[O:25])[C:20](=[C:21]([CH3:22])[CH3:23])[O:19][C:17]2=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC(C(=C)C)C(=O)OC)cc21
Agent: C1=Cc2ccccc2ON1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 25 °C

Procedure:
To a solution of 7-fluoro-6-(1-methoxycarbonyl-2-methyl-2-propenyloxycarbonylamino)-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (10 g) in toluene (100 g), sodium methoxide was added in an amount of 0.05 equivalent to one equivalent of the benzoxazine. The resulting mixture was refluxed for 3 hours, cooled to room temperature, combined with water and extracted with ethyl acetate. The organic layer was washed with water three times, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate as the eluent to give Compound No. 9 (6.1 g). m.p., 194°-198° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[OH-:15].[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([OH:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2nc(Cl)nc(O)c2c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinazoline (4.20 g, 18.5 mmol, 1.0 eq.) in THF (60 mL) and 1120 (60 mL) was treated with NaOH (4.00 g, 100 mmol, 5.4 eq.). The resulting mixture was stirred at 40° C. for 2 h. The reaction color turned to dark green and then a precipitate formed. After the reaction was completed, the mixture was cooled to room temperature. The precipitate was filtered off and the filtrate was concentrated down to 60 mL. The pH was then adjusted to 6 by adding 2N HCl in water. The precipitate which formed was collected and dried in vacuo to give 4.00 g of 2-chloro-6-methoxyquinazolin-4-ol as a grey solid (98%). LCMS m/z=211.1, 213.0 (M+1) (Method B) (retention time=1.11 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:20]([C:21]2[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=2[F:31])[C:19]2[C:18](=[O:32])[CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][C:14]=2[NH:13][C:12]=1[CH3:40])=[O:10].CO.Cl.[H][H]>[Pd].O>[Cl:2][C:3]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:20]([C:21]2[C:22]([F:31])=[C:23]([F:30])[C:24]([F:29])=[C:25]([F:28])[C:26]=2[F:27])[C:19]2[C:18](=[O:32])[CH2:17][NH:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH3:40])=[O:10]
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCCOc2cccc(Cl)c2Cl)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CN(Cc3ccccc3)CC2=O)N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)OCCOc2cccc(Cl)c2Cl)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CNCC2=O)N1
Reaction time: 72 h

Procedure:
The hydrochloride from above (10 g), 500 ml of methanol, 25 ml of water, 5 ml of concentrated hydrochloric acid and 0.5 g of 10% palladium on carbon were shaken with hydrogen (45 psig initial pressure) for 4 hours. The catalyst was separated and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and shaken with dilute sodium hydroxide solution. The ethyl acetate solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in methanol and saturated with hydrogen chloride. The solution was evaporated to dryness. The residue crystallized on standing with ethyl acetate for 3 days. The solid was treated with boiling ethyl acetate and filtered to obtain the title compound as the hydrochloride, m.p. 228°-231° C. dec.
Reaction SMILES: O(C1C=CC(NC(=O)N[C@@H](CC2C=CC=CC=2)/C=C/C(O)=O)=CC=1)C1C=CC=CC=1.[N:31]1([CH2:36][CH2:37][NH:38][C:39](=[O:68])/[CH:40]=[CH:41]/[C@@H:42]([NH:50][C:51]([NH:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][C:61]3[CH:66]=[CH:65][C:64](F)=[CH:63][CH:62]=3)=[CH:56][CH:55]=2)=[O:52])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)CCC[CH2:32]1.Cl.O(C1C=CC(N=C=O)=CC=1)C1C=CC=CC=1>C(Cl)Cl.O1CCOCC1.C1COCC1>[CH3:32][NH:31][CH2:36][CH2:37][NH:38][C:39](=[O:68])/[CH:40]=[CH:41]/[C@@H:42]([NH:50][C:51]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:56][CH:55]=1)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)NCCN1CCCC1
Agent: Cl
Agent: O=C(O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccccc2)cc1
Agent: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
(E)-(S)-4-[3-(4-Phenoxy-phenyl)-ureido]-5-phenyl-pent-2-enoic acid. To a solution of (E)-(S)-4-tert-butoxycarbonylamino-5-phenyl-pent-2-enoic acid (Example 11, step A) (2.12 g, 7.26 mmol) in CH2Cl2 (73 mL) was added 4 M HCl in 1,4-dioxane (25 mL), and the resulting solution was stirred at rt for 15 min. The solvent was removed. To a solution of the resulting residue and TEA (0.74 g, 7.26 mmol) in THF (73 mL) cooled to 0° C., was added 4-phenoxy phenyl isocyanate (1.53 g, 7.26 mmol), and the mixture was stirred for 30 min. The solution was brought to rt and was stirred for an additional 3 h. The solvent was removed, and the resulting yellow oil was purified by column chromatography on silica gel using a gradient of 0–35% (MeOH (10% acetic acid)/CH2Cl2). The purified product was recrystallized from CH2Cl2 and was washed with hexanes to afford 1.45 g (50%) of the desired product as a grey solid. Rf=0.47 (5% MeOH (1% NH4OH)/CH2Cl2). MS (electrospray): mass calculated for C24H22N2O4, 402.16; m/z found, 403.1 [M+H]+, 425.1 [M+Na]+, 827.3 [2M+Na]+. 1H NMR (400 MHz, DMSO-d6): 12.34 (br s, 1H), 8.51 (s, 1H), 7.40–7.20 (m, 9H), 7.08–7.05 (m, 1H), 6.93–6.91 (m, 4H), 6.86 (d, J=5.0 Hz, 1H), 6.35 (d, J=8.5 Hz, 1H), 5.77 (dd, J=15.6, 1.6 Hz, 1H), 4.70–4.61 (m, 1H), 2.93 (dd, J=13.7, 6.1 Hz, 1H), 2.84 (dd, J=13.7, 7.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[O:5][C:6]([CH3:16])([CH3:15])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O>[N:22]([C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([CH3:16])([CH3:15])[O:5][C:4](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:3]=2[C:1]#[N:2])=[CH:9][CH:10]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a 200-mL round bottom flask with stirbar was added 2-[3-cyano-4-(4-fluoro-phenyl)-5,5-dimethyl-5H-furan-2-ylidene]-malononitrile (0.20 g, 0.716 mmol) and DMSO (8 mL). The mixture was stirred at room temperature, then sodium azide (0.08 g, 1.23 mmol) was added to it and the reaction continued to react at room temperature. After 2 h, the reaction mixture was completely homogeneous. The product mixture was poured into ice-water (300 mL) and stirred 0.5 h. The yellow precipitate was filtered out through suction filtration. The solid was recrystallized from 1-propanol to give the final product as a yellow solid having a UV spectra as set forth in FIG. 25; (0.19 g, 88% yield). IR (neat): 2924, 2228, 2113, 1567, 1533, 1366, 1279, 1188, 1111, 841 cm−1. 1H NMR (400 MHz, DMSO): δ 7.94 (ddd, J=9.2, 2.8, 2.0 Hz, 2H), 7.40 (ddd, J=9.2, 2.8, 2.0 Hz, 2H), 1.78 (s, 6H); 13C NMR (100 MHz, DMSO): δ 177.1, 176.6, 145.0, 130.6, 123.4, 120.3, 112.3, 111.4, 111.3, 101.6, 100.3, 55.2, 24.9. UV-Vis (CH2Cl2): λmax=384 nm, ε=2.9×104 L·mol−1·cm−1.
Reaction SMILES: [CH2:1]([Li])CCC.[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]([CH2:27][CH3:28])[CH2:24][CH2:23][C:22]2=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]([CH2:27][CH3:28])[CH2:24][CH2:23][C:22]2=[CH2:1]
Reactant: CCN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCN(CC)c2c(CSc3nc4ccccc4[nH]3)cccc21
Temperature: -40 °C

Procedure:
To a suspension of methyl triphenylphosphonium bromide (2.65 g)in tetrahydrofuran (50 ml) was added dropwise n-butyllithium (2.2 ml) in a nitrogen flow with stirring at -40° C. After raising the temperature to -20° C., a solution of 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (500 mg) in tetrahydrofuran (5 ml) was added dropwise. The temperature was raised gradually to room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (3:1)] and recrystallized from diethyl ether-dichloromethane to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-methylene-1,2,3,4-tetrahydroquinoline (390 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH2:12][CH3:13])[N:8]([C:30]3[CH:31]=[N:32][CH:33]=[C:34]([F:36])[CH:35]=3)[C:7]=2[CH:37]=1>O1CCOCC1.CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH2:12][CH3:13])[N:8]([C:30]3[CH:31]=[N:32][CH:33]=[C:34]([F:36])[CH:35]=3)[C:7]=2[CH:37]=1
Reactant: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
HCl (0.25 mL of a 4M solution in dioxane) was added to a solution of {(S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propyl}-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (96 mg, 0.20 mmol) in MeOH (1 mL) and the reaction mixture stirred at RT for 10 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 359 (76 mg, 94%) as a white solid. LCMS (Method K): RT 3.23 min [M+H]+ 407.1. 1H NMR (CD3OD, 400 MHz): δ 8.59 (1H, s), 8.51 (1H, s), 8.05 (1H, s), 8.03 (1H, br s), 7.95 (1H, d, J=8.4 Hz), 7.65 (1H, dd, J=8.8, 4.6 Hz), 7.07 (1H, ddd, J=9.7, 8.8, 2.6 Hz), 6.88 (1H, dd, J=8.6, 2.6 Hz), 5.54-5.42 (1H, m), 2.26 (1H, dqd, J=14.9, 7.5, 6.4 Hz), 2.12 (1H, dqd, J=14.9, 7.5, 6.4 Hz), 1.01 (3H, t, J=7.5 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>CC(C)=O>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C=NCCCl
Solvent: CC(C)=O
Product: O=C(NCCCl)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2 g of 5-aminoindole in 125 mL of anhydrous acetone is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution was stirred for 16 h at room temperature, cooled at °20° C., and filtered. The solvent is evaporated and the residue was crystallized from methanol and washed with ether to give a brownish solid, yield 30%, mp 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1=NCCc2ccc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2ccc(Cl)cc21

Procedure:
In close analogy to the procedure described above, 7-chloro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH2:33][N:17]1[CH2:18][CH2:19][N:14]([C:12]2[N:11]=[C:10]([NH2:20])[C:9]3[N:8]([N:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:21]=3)[CH:13]=2)[CH2:15][CH2:16]1
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)c(CN2CCN(c3cn4nc(-c5ccco5)nc4c(N)n3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 5-chloro-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxaldehyde (45 mg, 0.21 mmol), sodium triacetoxyborohydride (65 mg, 0.31 mmol) and acetic acid (12 μL, 0.2 mmol). The reaction was stirred at room temperature overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=40:60) to afford 6-[4-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-piperazin-1-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (9 mg, 13%).