Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[O:17][CH3:18].[CH:19](/B(O)O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH3:18][O:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1c(Br)ccc2c1ncn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C=Cc2ccccc2)ccc2c1ncn2C1CCCCO1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
A 1 L three-necked round bottom flask fitted with an overhead stirrer was dried and cooled under a stream of nitrogen then charged with 5-bromo-4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (30 g, 0.096 mol, 1.0 equiv.) in 1,4-dioxane (300 mL) and water (60 mL). The mixture was degassed with nitrogen. To the degassed solution at RT was added sequentially trans-β-styrene boronic acid (14.26 g, 0.096 mol, 1.0 equiv.), Cs2CO3 (62.82 g, 0.19 mol, 2.0 equiv.), Pd(II)Cl2(PPh3)2 (3.38 g, 0.004 mol, 0.05 equiv.) then the reaction was heated with stirring at 100° C. for 6 h. The reaction mixture was quenched with ice cold water (1 L) and extracted with EtOAc (2×1 L). The organic layers were combined, washed with brine solution (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (40-50% EtOAc) to afford 4-methoxy-5-styryl-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (25 g, 77%) as a brown solid.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]2[CH:14]=[C:13]3[O:15][CH2:16][O:17][C:12]3=[CH:11][C:6]=2[S:7][C:8]=1[CH:9]=[O:10].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:4]2[C:5]3[CH:14]=[C:13]4[O:15][CH2:16][O:17][C:12]4=[CH:11][C:6]=3[S:7][C:8]=2[CH:9]=[O:10])=[CH:21][CH:20]=1
Reactant: O=Cc1sc2cc3c(cc2c1Cl)OCO3
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3

Procedure:
1 equivalent of sodium hydride and then 0.094 mol of the product obtained in Step D are added at ambient temperature and under an inert atmosphere to a solution of 0.10 mol of 4-chlorophenol in 250 ml of dimethylformamide. After 12 hours' reaction at 80° C., the reaction mixture is concentrated under reduced pressure. The residue is then diluted with ethyl acetate, washed with water and then with an aqueous solution of NaOH and then of NaCl, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethyl acetate: 98/2) allows the expected product to be isolated.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:3][CH:2]=1.[C-]#N.[Na+]>CS(C)=O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:5][CH:6]=1
Reactant: COc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)nc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(O)cn1
Temperature: 180 °C

Procedure:
To a mixture of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide (200 mg, 0.58 mmol) in DMSO (4.0 ml) was added sodium cyanide (141 mg, 2.89 mmol) and heated to 180° C. for one hour. An additional amount of sodium cyanide (207 mg, 4.22 mmol) was added and the mixture was further heated for another hour until no significant increase in desired product was observed by LC/MS. After cooling reaction to room temperature, the reaction was taken to neutral pH with the careful addition of 1.0 N HCl solution. Organics were extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo to give an oil. Normal phase chromatography (0-100% EtOAc/Hex) afforded 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-hydroxypyridin-2-yl)ethyl]acetamide as an oil. 1H NMR (CDCl3, 400 MHz) δ 9.55 (brs, 1H); 8.07 (m, 1H); 7.50 (m, 4H); 7.41 (m, 2H); 7.28 (m, 3H); 7.00 (m, 2H); 6.82 (d, J=7.20 Hz, 1H); 5.03 (m, 1H); 3.57 (s, 2H); 1.37 (d, J=6.40 Hz, 3H); MS (Electrospray): m/z 333.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]#[N:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH2:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl[7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (30 mg, 0.07 mmol, cf. example 34d) were dissolved in methanol (3 mL). Raney nickel (10 mg) was added and the reaction mixture stirred at room temperature under an atmosphere of hydrogen for 4 h. The catalyst was removed by filtration and the methanol was evaporated in vacuo. Yield: 18 mg (0.041 mmol, 59%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@@H:23]([C@@H:29]([OH:35])[C:30](OCC)=[O:31])[C:24](OCC)=[O:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C1COCC1.C(OCC)(=O)C.[O-][Mo]([O-])(=O)=O>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([CH2:24][OH:25])[C@@H:29]([OH:35])[CH2:30][OH:31])=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)[C@@H](O)C(=O)OCC
Agent: O=[Mo](=O)([O-])[O-]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncnc2c(CN[C@H](CO)[C@@H](O)CO)cn(COCc3ccccc3)c12
Temperature: 25 °C

Procedure:
To a refluxing solution of (2S,3R)-diethyl 2-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-3-hydroxysuccinate (0.6 g, 1.233 mmol) in THF (10 ml) and methanol (0.499 ml, 12.33 mmol) was added lithium borohydride (0.134 g, 6.17 mmol) in portions over about 1 h. Tlc (CH2Cl2-MeOH-cNH3, 9:1:0.1) still showed (uv, ninhydrin or molybdate) sm. More MeOH (0.5 ml) was added and small portions of LiBH4 (total ˜134 mg) added over about 1 h until tlc showed reaction finished. The solvent was evaporated and the residue chromatographed (CH2Cl2-MeOH-cNH3, 95:5:0.5, then 85:15:0.5) to give a colourless gum which soon crystallized (214 mg, 41%). The gum was of sufficient purity to proceed to the next step, but a small quantity was recrystallised by dissolving a portion of the crude (2R,3R)-3-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)butane-1,2,4-triol in MeOH and evaporating the solvent to leave a mobile gum. The gum was dissolved in hot ethyl acetate, cooled to rt and seeded. The colourless solid was filtered off and dried to give clusters of very tiny crystals under the microscope. Mpt 108-109° C. [α]D18 −6.1 (c 0.59, MeOH). 1H NMR (CD3OD, 300 MHz), δ ppm, 8.42 (s, 1H), 7.64 (s, 1H), 7.28-7.16 (m, 5H), 5.75 (s, 2H), 4.50 (s, 2H), 4.10 (s, 3H), 3.83-3.68 (m, 3H), 3.63 (d, 2H, J 5.5 Hz), 3.31 (pentet, 1H, J 1.6 Hz). 13C NMR (CD3OD, 75.5 MHz), δ ppm, 158.0 (C), 150.8 (CH), 150.7 (C), 138.8 (C), 134.2 (CH), 129.3 (CH), 128.8 (CH), 128.6 (CH), 117.0 (C), 116.1 (C), 78.5 (CH2), 72.1 (CH), 71.5 (CH2), 65.6 (CH2), 62.3 (CH), 61.0 (CH2), 54.3 (CH3), 41.6 (CH2). +ESMS Found 403.1980 (M+H)+ C20H27N4O5 requires 403.1981.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].C(NC(C)C)(C)C.C([Li])CCC.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:32][N:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:30](=[O:41])[CH:29]=2)=[CH:24][CH:23]=1.C(I)C.Cl>O1CCCC1>[CH2:1]([C:29]1[C:30](=[O:41])[N:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:32][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(N2CC(c3ccc(F)cc3)=CC2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1=C(c2ccc(F)cc2)CN(c2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide is generated from diisopropylamine (122 mL, 0.87 mol) and n-butyllithium (2.5 M in hexane, 348 mL, 0.87 mol) in tetrahydrofuran (1.5 L) under a nitrogen atmosphere at -60° C., and 4-(4-fluorophenyl)-1,5-dihydro-1-(4-methoxyphenyl)-2H-pyrrol-2-one (235 g, 0.83 mol) is added to this mixture. The mixture is stirred for 30 minutes at -50° C., 1 hr at 0° C., and then re-cooled to -60° C. Ethyl iodide (73 mL, 0.91 mol) is added, and the reaction is allowed to warm slowly to 25° C., and stirred at this temperature for 18 hr. The mixture is poured into 1.5 L of 4 N HCl and stirred for 1 hr. The mixture is then extracted with methylene chloride, and the extracts are dried with magnesium sulfate and evaporated. Recrystallization of the residue from ethanol followed by drying under vacuum at 60° C. for 18 hr gives the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2.O>CN(C=O)C>[Br:8][C:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[C:10]=1[CH3:9]
Reactant: Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)c2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
25 g of NBS in 75 ml of DMF are added to a solution of 34.8 g of 2-methyl-1-(benzenesulfonyl)-7-azaindole in 75 ml of DMF. The mixture is stirred at room temperature for 1 h, poured into water, the precipitate which has precipitated out is separated off, washed with water and dried, giving 42 g of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole, M˜351.22 g/mol, M+H found 351.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:38]([OH:40])=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:37])[NH:19]S(C1C(C)C2CC(C)(C)OC2=C(C)C=1C)(=O)=O)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:38]([OH:40])=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:37])=[O:11]
Reactant: CC1=C2OC(C)(C)CC2C(C)C(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)=C1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Reaction time: 24 h
Yield: 89.5 %

Procedure:
To methylene chloride solution of the compound obtained in Example 115 (2.8 g) was added dropwise trifluoroacetic acid (50 mL) at room temperature, and the mixture was allowed to stir for 24 hours. To the residue obtained by distilling off the solvent under a reduced pressure was added diethylether, and the mixture was stirred for 24 hours at room temperature. The crystals precipitated were filtered, to give the captioned compound (1.4 g, 68%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=O)=O)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].Cl>C(#N)C.[Zn]>[SH:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:13]2
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Product: CC(=O)NC1Cc2ccc(S)cc2C1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A suspension of zinc (22.94 g, 0.35 mol) and 2-acetylamino-indan-5-sulfonyl chloride (93% weight) (29.45 g, 0.10 mol) in acetonitrile (200 mL) in a 1 Liter four-necked round-bottomed flask equipped with a condenser, a thermometer, an addition funnel, and a mechanical stirrer was heated to about 50-60° C. The heating source was removed and to the warm suspension was added concentrated HCl (59.20 g, 0.60 mol) slowly over 1 hour. The addition rate was adjusted to maintain the reaction temperature between about 70-75° C. A gentle gas (H2) evolution was observed throughout the addition of HCl. The reaction was then cooled to about 30-36° C. over 30 minutes while stirring. The reaction mixture was filtered into a 500 mL one-necked round-bottomed flask through a fritted glass funnel to remove the Zn residue. The reaction flask was rinsed with EtOAc (25 mL). The mixture was concentrated on a rotavapor under reduced pressure at about 45-50° C. bath temperature to remove most of the organic solvents. The concentrated aqueous solution was mixed with of EtOAc (150 mL), followed by the addition of H2O (75 mL). After stirring for 15 minutes, the layers were separated. The organic layer was washed four times with H2O (3×75 mL). After separation of layers, the organic layer was concentrated on a rotavapor at 60° C. to ¼ of its original volume (about 40 mL). Most of the precipitated white solid was dissolved by heating to reflux. The mixture was then diluted with MTBE (75 mL). The mixture was stirred at ambient temperature for 18 hours. The solid product was collected by vacuum filtration, washed with MTBE (20 mL), dried under nitrogen for 4 hours, then in a vacuum oven at about 40-45° C. for 24 h. The product was obtained as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C=C/c1cccn1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cn2cccc2/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a solution of crude (E)-ethyl 3-(1-(4-methoxybenzyl)-1H-pyrrol-2-yl)acrylate in ethanol (50 mL) was added NaOH (1 g in 5 mL of H2O). After stirring 4 hr at room temperature, the solution was concentrated and then diluted with H2O (100 mL) and washed with TBME (2×75 mL). The aqueous base layer was the acidified with 1N HCl and extracted with ethyl acetate (100 mL). Then organic layer was dried (MgSO4), filtered and then concentrated to provide 0.92 g (59% for 3 steps) of (E)-3-(1-(4-methoxybenzyl)-1H-pyrrol-2-yl)acrylic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Br-].[N:15]1C=CC=C[C:16]=1[Zn+]>C1COCC1>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)#[N:15]
Reactant: [Zn+]c1ccccn1
Reactant: Brc1cncc(-c2ccccn2)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1cncc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
2-(3-Bromopyridin-5-yl)pyridine (2 g, 10.9 mmol) in THF (10 ml) was added dropwise to a solution of 2-pyridylzincbromide (22 ml of a 0.5M solution in THF, 11 mmol) in THF (10 ml) under a nitrogen atmosphere. Tetrakis (triphenylphosphine)palladium(0) (630 mg, 0.54 mmol) was added and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution then the volatiles were removed by evaporation. The residue was suspended in water then extracted with DCM. The organic extracts were combined, washed with water then filtered through phase separating paper and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (2:1). The purified product was triturated with diethyl ether to give the title compound (0.98 g, 50%) as a white solid. NMR (DMSO): 7.47 (t, 1H), 7.97 (t, 1H), 8.15 (d, 1H), 8.75 (d, 1H), 8.90 (d, 1H), 9.07 (s, 1H), 9.53 (s, 1H); m/z 182 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.C12CCCCC1CCCNN=2>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: C1CCC2CCCNN=C2C1
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
4-[7-(2-Butynyl)-1,3-bis-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (0.63 g) was dissolved in a solvent mixture of tetrahydrofuran (4 ml) and methanol (2 ml), and diazabicyclo[5.4.0]undecene (0.18 ml) was added to the solution. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give 0.29 g of the title compound from the elution fraction of hexane-ethyl acetate (1:5).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3=[N:18][CH2:19][CH2:20][N:10]23)=[CH:5][CH:4]=1>CCOCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[NH:18][CH2:19][CH2:20][N:10]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCN21
Agent: Cl
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1ccccc1C1=NCCN1
Reaction time: 0.5 h

Procedure:
The hydrochloride was prepared by adding a solution of hydrogen chloride in ether to a suspension of 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoindole. After stirring for 30 minutes a crystalline crop was collected and recrystallized from a mixture of chloroform and ether to give white prisms melting at 168°-171° dec. Ultraviolet inflexion (2-propanol) at 220 mμ (ε = 22,000), maxima at 252 mμ (ε = 12,900), 266 mμ (ε = 13,000); infrared absorption (KBr) at 1670 cm-1.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])=[C:1]=[S:3]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N=C=S)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 61 h
Yield: 100 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 5-aminoisophthalic acid (0.30 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 61hours. The obtained reaction mixture was dropwise added to a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, ethyl acetate (5 mL) was added and thoroughly mixed. Then, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to dryness to obtain 5-isothiocyanatoisophthalic acid as a cream-colored solid (0.33 g, yield: 100%, HPLC purity: 88%, HPLC retention time: 2.8min). LC-MS ES-222 (retention time: 3.7 min, condition 1).
Reaction SMILES: CC(C)CCN[C:6]1[CH:13]=[CH:12][C:9](C#N)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].CI>CN(C=O)C>[N+:14]([C:7]1[CH:8]=[CH:9][CH:12]=[CH:13][CH:6]=1)([O-:16])=[O:15]
Reactant: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.00 g (4.29 mmole) of 4-(3-methylbutylamino)-3-nitrobenzonitrile was dissolved in 10 mL of DMF, 0.205 g (5.14 mmoles) of NaH was added, and the mixture was stirred for 10 minutes at room temperature. 0.5 mL (5.14 mmole) of methyl iodide was added and the mixture was stirred overnight at room temperature. When the reaction had ended, the solvent was removed under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The residue was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding a nitrobenzene intermediate. Next, the nitrobenzene intermediate was dissolved in 20 mL of ethanol, 50 percent NH2OH aqueous solution was added, and the mixture was stirred overnight at 50° C. When the reaction had ended, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, yielding 1.46 g of amideoxime intermediate.
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:26][C:24]([F:25])([F:27])[C:21]1[N:20]=[CH:19][C:18]([CH2:17][NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:29][CH2:28][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Reaction time: 48 h
Yield: 83.4 %

Procedure:
A mixture of 6-benzyl-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (7.41 g, 18.6 mmol), methanol (300 mL), and 10% palladium on charcoal (1.0 g) was evacuated and purged with hydrogen 3 times, then hydrogenated (1 atm) at room temperature for 2 days. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo to yield a pale yellow foam (4.8 g). LC-MS: 310.4 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CCN=C=O
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (15 mg, 33 μmol) was dissolved in abs. pyridine (2 ml), and solid sodium sulfate (spatula tip) and ethyl isocyanate (46.6 mg, 655 μmol, 20 eq.) were added. The reaction mixture was then heated in a microwave reactor (2.5 h at 100° C., then 2 h at 110° C. and finally 2 h at 125° C.). After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (7.8 mg, 48% of theory).