Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Product: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
8-Hydroxyquinaldine (5.0 g) and potassium carbonate (13.02 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 6 days. The reaction is then cooled and the resulting solid is partitioned between EtOAc and water. The organic layer is extracted with water (3×). The combined aqueous layers are washed with EtOAc (3×). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, dried and recrystallized from i-PrOH to yield 1.86 g of the title compound as a gold solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([Cu])#[N:11].N.O=O>CN1CCCC1=O.Cl[Cu].O>[NH2:5][C:4]1[C:3]([CH3:9])=[C:2]([CH:8]=[CH:7][CH:6]=1)[C:10]#[N:11]
Reactant: Cc1c(N)cccc1Cl
Reactant: N#C[Cu]
Agent: Cl[Cu]
Agent: N
Agent: O=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(N)cccc1C#N
Temperature: 225 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
283 g (2.0 mol) of 3-chloro-2-methylaniline are dissolved in 250 ml of N-methylpyrrolidone and admixed with 200 g (2.23 mol) of CuCN. The reaction mixture is subsequently stirred under N2 and at 225° C. for six hours. After cooling to 100° C., the reaction mixture is poured into 2.5 l of 25 percent ammonia solution and stirred at 25° C. for one hour. During this time, the atmospheric oxygen oxidizes the Cu(I) nitrile complex of the product to a water-soluble Cu(II) salt, which is evident by the formation of the intensively blue tetramine complex. Some of the CuCl remains undissolved as a white solid and can be easily removed by filtration with suction. The filtrate is extracted with approximately 2 l of methyl tert-butyl ether and then washed with ammonia water and finally three times with water. The organic phase is dried over sodium sulfate and concentrated, affording 255 g (89% yield of crude product) of a dark oil which can be purified by recrystallization from cyclohexane/toluene (5:1).
Reaction SMILES: [Br:1][CH:2]([P:13]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16])P(OC(C)C)(=O)OC(C)C.[H-].[Na+].[Cl:25][C:26]1[CH:33]=[C:32]([F:34])[C:31]([C:35]2[C:39]([Cl:40])=[C:38]([O:41][CH:42]([F:44])[F:43])[N:37]([CH3:45])[N:36]=2)=[CH:30][C:27]=1[CH:28]=O>>[Br:1][C:2]([P:13](=[O:18])([O:14][CH:15]([CH3:16])[CH3:17])[O:19][CH:20]([CH3:21])[CH3:22])=[CH:28][C:27]1[CH:30]=[C:31]([C:35]2[C:39]([Cl:40])=[C:38]([O:41][CH:42]([F:43])[F:44])[N:37]([CH3:45])[N:36]=2)[C:32]([F:34])=[CH:33][C:26]=1[Cl:25]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CC(C)OP(=O)(OC(C)C)C(Br)P(=O)(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)OP(=O)(OC(C)C)C(Br)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Yield: 21.5 %

Procedure:
Following the procedure described in Example 40 and using 3.4 g (8 mmol) of tetraisopropyl bromomethanediphosphonate, 0.2 g (8 mmol) of sodium hydride and 1.6 g (4 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzaldehyde, a crude product is obtained whose silica gel chromatography first revealed 0.5 g of diisopropyl 1-bromo-2-[2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl]vinylphosphonate followed by 0.4 g of diisopropyl 2-[2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl]ethynylphosphonate.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[O:11][C:10]([CH:12]=[C:13](Br)Br)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[O:11][C:10]([C:12]#[CH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2ccc(C=C(Br)Br)o2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a stirred -78° C. solution in THF (200 mL) under argon of 2-[5-(4-fluorophenoxy)-2-furyl]-1,1-dibromoethene (23.1 g, 63.81 mmol), prepared as in step 2, was added n-butyl lithium (51.0 mL, 127.62 mmol, 2.5M in hexanes). The reaction was stirred for 0.5 hours at -78° C. Aqueous ammonium chloride was added to the cold reaction, the ice bath was removed and the reaction mixture allowed to warm to room temperature. The majority of THF was removed in vacuo. The resulting mixture was partitioned between water and ether. The combined ether layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes) to give 6.5 g (50%) of 2-[5-(4-fluorophenoxy)-2-furyl]-ethyne.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.[BH4-].[Na+]>C(O)C>[O:7]=[C:5]1[N:1]([CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: O=Cc1cccnc1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol) at 0° C. and then treated with pyridine-3-carboxaldehyde (1.41 ml, 15 mmol) in ethanol (3 ml). The mixture was stirred at room temperature for 30 minutes and then cooled to 0° C. and treated portion-wise with sodium borohydride (0.189 g, 5 mmol). The mixture was allowed to warm to room temperature with stirring over 4 hrs then after washing with diethyl ether it was acidified to pH5-6 using concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried in vacuo. This material was then taken up in ethanol (50 ml) and refluxed overnight. Fine solids were removed by filtration and then concentration gave 5-oxo-1-(3-pyridinylmethyl)proline (2.04 g) as a white solid which was used without any further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4c(cc(F)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
A mixture of 6-fluoro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.80 g, 1.64 mmol), lithium hydroxide hydrate (690 mg, 16.4 mmol), water (1.0 mL) in methanol (5 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-fluoro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (400 mg, 52%) as a white solid: LC/MS m/e calcd for C29H32FN3O2 (M+H)+: 474.6, observed: 474.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]([CH3:21])([CH3:20])[C:12]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClS([N:32]=[C:33]=O)(=O)=O.CN(C=O)C>C(#N)C>[C:33]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]([CH3:21])([CH3:20])[C:12]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[O:13])[CH:5]=2)[NH:1][CH:2]=1)#[N:32]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a stirred solution of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 101, 25 mg, 0.067 mmol) in anhydrous acetonitrile (1 mL) was added chlorosulfonyl isocyanate (0.007 mL, 0.074 mmol) at 0° C. under argon. The reaction mixture was stirred at 0° C. for 30 min before anhydrous DMF (0.006 mL, 0.074 mmol) was added. After the reaction mixture was stirred at 0° C. for 30 min and at rt for 1 hr, it was concentrated, mixed with saturated aqueous sodium bicarbonate solution (5 mL), and extracted with dichloromethane (10 mL). The dichloromethane extract was dried (Na2SO4) and concentrated. Silica gel flash chromatography gave 3-(3-cyano-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 108, 11 mg, 0.027 mmol, 41% yield) as a white solid. MS found: (M+H)+=401. 1H-NMR (400 MHz, Acetone-d6): δ ppm 11.15 (1 H, s) 10.48 (1H, s) 8.06 (1H, d, J=2.40 Hz) 7.78 (1H, s) 7.46-7.53 (3H, m) 7.39 (1 H, d, J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.28 (2H, t, J=7.38 Hz) 7.18 (1H, t, J=7.38 Hz) 7.04 (1H, d, J=3.56 Hz) 5.04 (1H, s) 1.51 (6H, d, J=2.54 Hz).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12d and 4-bromoanisole.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]#[N:5].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[SH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>O1CCCC1>[C:12]([S:13]/[CH:2]=[CH:3]/[C:4]#[N:5])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#C/C=C/Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#C/C=C/SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of (E)-3-chloroacrylonitrile (0.1 g) in tetrahydrofuran (2 ml) were added triphenylmethanethiol (0.332 g) and triethylamine (0.175 ml) under ice-cooling. The mixture was stirred at ambient temperature for 16 hours and poured into ice-water. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (E)-3-tritylthioacrylonitrile (0.37 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)[C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ccccn3)cc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccccn1)n2Cc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of the compound obtained in Example 5 (4) (2.3 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride (0.5 mg) was added at 0° C. and the mixture was stirred at the same temperature for 15 minutes. p-Fluorobenzyl bromide (2.4 mg) was then added thereto at 0° C. and the mixture was stirred at 15 to 30° C. for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with toluene, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=100:1) to obtain 1.7 mg of the desired product as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@:8]1([CH2:17][N+:18]([O-])=O)[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:15][CH3:16])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@:8]1([CH2:17][NH2:18])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:15][CH3:16])[CH2:12]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC1=C[C@@H]2[C@H](C1)C[C@@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC1=C[C@@H]2[C@H](C1)C[C@]2(CN)CC(=O)OC(C)(C)C
Reaction time: 5.5 h

Procedure:
Tert-butyl[(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (7.0 g, 23.7 mmol) was dissolved in ethanol (60 mL) and water (21 mL). To the solution, iron powder (13.27 g, 237 mmol) and ammonium chloride (628.1 mg, 11.9 mmol) were added, and the mixture was stirred for 5.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (7.02 g, <100%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([NH2:10])=[CH:4][CH:3]=1>C(O)(=O)C.Br>[NH2:10][C:5]1[C:6](=[O:8])[NH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COc1nc(Br)ccc1N
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(Br)[nH]c1=O
Temperature: 120 °C
Yield: 72.3 %

Procedure:
A solution of 6-bromo-2-methoxy-pyridin-3-ylamine (1A) (5.2 g, 25.6 mmol) in acetic acid (50 mL) and HBr (50 mL) is heated to reflux with an oil bath at 120° C. for 1 hour. The reaction solution is cooled to room temperature and concentrated to dryness. The crude product is purified by chromatography (CH2Cl2 95%, MeOH 5%) to give 3-amino-6-bromo-1H-pyridin-2-one (1B) (3.5 g, yield 72%) as brown solid that turns to deep purple. MS (ESI) m/e 189, 191 (M+H+).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14].Cl.Br[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>O1CCCC1.O.CN(C)C=O.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.C(=O)([O-])[O-].[K+].[K+]>[N:21]1[CH:22]=[CH:23][CH:18]=[CH:19][C:20]=1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:15]
Reactant: C=CCCCO
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: OCCCCCc1ccccn1
Yield: 48 %

Procedure:
9-Borabicyclo[3.3.1]nonane (9-BBN) dissolved in 15 ml of tetrahydrofuran (manufactured by Aldrich Co.) was added to 300 mg (3.483 mmol) of 4-pentene-1-ol and allowed to react at 25° C. for 24 hours. Then, 4-bromopyridine hydrochloride (manufactured by Aldrich Co.) dissolved in water/dimethylformamide (DMF) at a ratio of 2:8, tetrakis(triphenylphosphine)palladium (manufactured by Aldrich Co.), and potassium carbonate (manufactured by Aldrich Co.) were added thereto in an equivalent ratio of 1:1.2:0.2 and allowed to react at 70° C. for 6 hours. Then, solvent was removed under reduced pressure, and the residual material was diluted with ethyl acetate and filtered with Celite. The material thus obtained was purified by column chromatography (column: silica (manufactured by Aldrich Co.), solvent: ethyl acetate/hexane) to obtain 203 mg of pyridinepentanol (yield rate: 48%). The reaction scheme is shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:14](O)=[O:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([NH:13][CH:14]=[O:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cnn(-c2ccc(F)cc2)c1
Product: O=CNc1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-(4-fluorophenyl)pyrazol-4-amine (0.59 g, 3.3 mmol) in formic acid (15 mL) was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-100% EtOAc/CH2Cl2 gradient elution) to give N-[1-(4-fluorophenyl)pyrazol-4-yl]formamide (0.490 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([N:1]=[CH:19][N:20]([CH3:22])[CH3:21])=[C:9]([N+:10]([O-:12])=[O:11])[C:8]([CH3:13])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)#[N:5]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1c([N+](=O)[O-])cc(C#N)c(N=CN(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
To a suspension of 2-amino-4-methyl-3,5-dinitrobenzonitrile (5) (3.129 g, 14.1 mmol) in anhydrous toluene is added N,N-dimethylformamide dimethyl acetal (4 mL). The resultant mixture is heated to about 100° C. for about 2.5 hours. The mixture is cooled to ambient temperature and the solvent is removed using a rotary evaporator. The residue is dried to provide crude N′-(6-Cyano-3-methyl-2,4-dinitro-phenyl)-N,N-dimethyl-methanimidamide (8) (3.85 g, 99% Yield) as a red solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH:8](=O)[CH:9]([CH3:11])[CH3:10]>C1C=CC=CC=1.[Ni]>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][N:6]=[CH:8][CH:9]([CH3:11])[CH3:10]
Reactant: CN(C)CCCN
Reactant: CC(C)C=O
Agent: [Ni]
Solvent: c1ccccc1
Product: CC(C)C=NCCCN(C)C

Procedure:
A solution of N,N-dimethyl-N'-isobutylidene-1,3-diaminopropane in benzene is prepared by reacting 92 g of 3-dimethylamino-1-propylamine with 65 g of isobutyraldehyde in 200 ml of benzene by separating off the water of reaction azeotropically. This solution is hydrogenated in an autoclave at 90° C. and 125 atmospheres in the presence of 14 g of Raney nickel. Working up by distillation yields 95.6 g of pure product with a boiling point of 75° C./14 mm Hg.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[OH-].[Na+].CN([CH:20]=[O:21])C>>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:20]=[O:21])=[CH:7]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (1.2 eq) was added slowly to ice-cold DMF and the resulting mixture was stirred at 0° C. for 30 minutes. To this was added a solution of indole A1 (1 eq) in DMF and the mixture continued to stir for 6 hours. The reaction mixture was poured into an ice/water mixture and pH was adjusted to 7 by adding 1N NaOH. The compound was extracted with ethyl acetate (4×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (typical eluents hexanes and ethyl acetate) to afford the desired indole 3-carboxaldehyde D1. The product structure was confirmed by 1H NMR and mass analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH2:16][C:17]1[NH:21][N:20]=[C:19]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][C:18]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[NH:21][N:20]=[C:19]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][C:18]=23)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2n[nH]c(NC(=O)c3nc(Br)c(C(F)(F)F)nc3N)c2C1

Procedure:
A mixture comprising 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2)(0.102 g, 0.357 mmol), tert-butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (0.08 g, 0.357 mmol), HATU (0.136 g, 0.357 mmol) and N-methylmorpholine (0.071 ml, 0.713 mmol) in DMF (5 ml) was stirred at RT for 30 minutes. The reaction mixture was diluted with water (15 ml) and the resulting orange precipitate was filtered under vacuum and washed with water (10 ml). Purification of the resulting solid by chromatography on silica eluting with iso-hexane:EtOAc (gradient of 0 to 100% EtOAc) to afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1]C(N)CC.CN(C)CCCN.CN(C)[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]2[CH:25]=[N:26][C:27]3[N:31]([CH2:32][CH3:33])[N:30]=[CH:29][C:28]=3[C:23]=2[N:22]2[N:34]=[CH:35][N:36]=[C:21]2[N:20]=1>>[CH2:32]([N:31]1[C:27]2[N:26]=[CH:25][C:24]3[C:19]([NH:18][CH:17]([CH3:1])[CH2:16][CH3:15])=[N:20][C:21]4[N:22]([N:34]=[CH:35][N:36]=4)[C:23]=3[C:28]=2[CH:29]=[N:30]1)[CH3:33]
Reactant: CCC(C)N
Reactant: CCn1ncc2c1ncc1c(NCCCN(C)C)nc3ncnn3c12
Agent: CN(C)CCCN
Product: CCC(C)Nc1nc2ncnn2c2c1cnc1c2cnn1CC
Yield: 78 %

Procedure:
By substituting 1-methylpropylamine for the 3-dimethylaminopropylamine in the procedure of Example 1 (c), 8-ethyl-N-(1-methylpropyl)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5-amine is obtained, yield 78%; m.p. 228°-230° (methanol).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[C:16](/[C:21]([O:23][CH3:24])=[O:22])\[CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:24][O:23][C:21](/[C:16](=[CH:15]/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)/[CH2:17][C:18]([O:20][CH3:25])=[O:19])=[O:22]
Reactant: COC(=O)/C(=C/c1ccc(OC)c(OC2CCCC2)c1)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C/C(=C\c1ccc(OC)c(OC2CCCC2)c1)C(=O)OC
Temperature: 25 °C

Procedure:
1.67 g (0.005 mol) of (3E)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-(methoxycarbonyl)-3-butenoic acid are suspended in 8 ml of methylene chloride. 0.36 ml of N,N-DMF (0.005 mol), are added under stirring at room temperature, the solution is cooled to 0° C. and 0.87 ml (0.01 mol) of oxalyl chloride is added.