Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([C:14]([NH:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19][N:18]=2)=O)=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([NH:8][C:9]1[S:10][C:11]([CH2:14][NH:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[NH:19][N:18]=2)=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(-c2ccc(F)cc2)[nH]n1)c1cnc(NCc2ccccc2)s1
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(NCc3cnc(NCc4ccccc4)s3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
BMS was added to a solution of 2-(benzylamino)-N-(5-(4-fluorophenyl)-1H-pyrazol-3-yl)thiazole-5-carboxamide (50 mg, 0.13 mmol) in THF (1 mL). The resulting solution was stirred at RT overnight. The reaction was then quenched with MeOH (0.5 mL) and 1N HCl was added until pH=2. After stirring the reaction mixture at RT for 3 hrs, the organic solvents were evaporated and the aqueous solution was neutralized with a NaHCO3 saturated aqueous solution, extracted with AcOEt, dried with Na2SO4 and concentrated. The crude product was purified by column (0-2% MeOH/AcOEt gradient), yielding N-benzyl-5-((5-(4-fluorophenyl)-1H-pyrazol-3-ylamino)methyl)thiazol-2-amine (59 mg, 98%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[C:10]([F:11])=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]>CS(C)=O>[Br:4][C:5]1[C:10]([F:11])=[C:9]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(Br)c1F
Reaction time: 3 h

Procedure:
NaOMe (9.5 g) was added portion wise to a solution of 2-bromo-3,4-difluoro-1-nitro-benzene (21.0 g) dissolved in DMSO (250 ml) at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hrs and then poured onto water and extracted with ethyl acetate. The organic phase was extracted with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product, 2-bromo-3-fluoro-4-methoxy-1-nitro-benzene was used as such in Step 2 described below. 1H NMR (CDCl3) δ ppm: 7.85 (1H, dd); 6.99 (1H, dd); 3.99 (3H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH3:9].C([Li])CCC.CCCCCC.[CH3:31][CH:32]([CH3:36])[C:33](=[O:35])[CH3:34].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:33]([OH:35])([CH:32]([CH3:36])[CH3:31])[CH3:34])[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(Br)c1
Reactant: CC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 47.2 %

Procedure:
Compound 7 (1.59 g; 4.96 mmol) was dissolved in tetrahydrofuran (25 ml). While the solution was stirred at −75° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 3.2 ml; 4.99 mmol) was added dropwise. The mixture was stirred for 10 minutes, and 3-methyl-2-butanone (2.00 g) in tetrahydrofuran (5 ml) was added dropwise thereto. The mixture was brought to room temperature over 2.5 hours, and saturated aqueous ammonium chloride solution was added dropwise thereto. Water (100 ml) was added to the mixture, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→5:1), to thereby yield 0.76 g of the target compound as yellow oily matter (yield: 47.2%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.Cl>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)c1cccc(O)c1
Reactant: COc1ccccc1B(O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1Oc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 2-(3-hydroxyphenyl)propionitrile (0.118 g, 0.80 mmol), prepared as above described, in dry CH2Cl2 (6 mL were sequentially added, molecular sieves (4 Å), CuOAc (0.145 mg, 0.80 mmol) and pyridine (0.33 mL, 4.0 mmol). After stirring 20 min commercial 2-methoxyphenylboronic acid (0.243 g 1.60 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0° C., 0.5N HCl added and the organic phase washed (3×10 mL) with 0.5N HCl. After drying over Na2SO4 and solvent evaporation under reduced pressure a residue was obtained that, after flash chromatography (eluent mixture n-hexane/EtOAc 9:1), afforded 2-{3-[(2-methoxy)phenoxy)phenyl]propionitrile as pale yellow oil (0.172 g, 0.68 mmol). Yield 85%.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:38]=[CH:37][C:12]2[C:13](=[O:36])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=4[N+:33]([O-])=O)=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1)([O-])=O>C(O)C>[NH2:6][C:9]1[CH:38]=[CH:37][C:12]2[C:13](=[O:36])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][C:24]=4[NH2:33])=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)COc1cc(Nc3ccc(C(F)(F)F)cc3N)ccc1C2=O

Procedure:
In accordance with general method Y, 0.30 g (1.32 mmol) of tin(II) chloride dihydrate is dissolved in 15 ml of ethanol, and 0.095 g (0.20 mmol) of (18) is added. Yield: 0.061 g (76.4%); melting point: 93.9° C.; C21H16F3N3O2 (Mr=399.38); LC 19.06 min
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl.[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(COC)OC>[I:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[NH:3]1
Reactant: OB(O)c1ccccc1
Reactant: COCCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COCCOCN1NC(I)(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 85 °C
Yield: 58.2 %

Procedure:
To a mixture of 3-iodo-1-(2-methoxyethoxymethyl)-5-nitro-1H-indazole (0.50 g, 1.32 mmol), phenyl boronic acid (0.22 g, 1.80 mmol), potassium phosphate (1.26 g, 5.94 mmol) and 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II), complex with dichloromethane (0.15 g, 0.18 mmol) was added dry dimethoxyethane (8.0 ml) and then heated at 85° C. for 18 hours. Ammonium chloride solution (30 ml, saturated aqueous) was added and extracted into ethyl acetate (3×30 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% MeOH in DCM) to afford the title compound as a yellow solid (0.35 g, 81%). 1H NMR (400 MHz, CDCl3) δ 3.37 (3H, s), 3.51–3.53 (2H, m), 3.73–3.75 (2H, m), 5.93 (1H, s), 7.50–7.54 (1H, m), 7.57–7.61 (2H, m), 7.73 (1H, d), 7.98 (2H, dd), 8.37 (1H, dd), 9.00 (1H, s).
Reaction SMILES: I.[NH2:2][C:3](=[N:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[O:12][C:13]([CH2:16][N:17]=[C:18]([NH2:21])SC)=[CH:14][CH:15]=2)[N:10]=1)[NH2:4].[N:22]#[C:23][NH2:24].C(N(CC)CC)C>CN(C)C=O>[NH2:2][C:3](=[N:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[O:12][C:13]([CH2:16][NH:17][C:18]([NH2:21])=[N:24][C:23]#[N:22])=[CH:14][CH:15]=2)[N:10]=1)[NH2:4]
Reactant: CSC(N)=NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: N#CN
Agent: I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CN=C(N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 24.5 %

Procedure:
A solution of 2-(diaminomethyleneamino)-4-[5-(2-methyl-3-isothioureido)methylfuran-2-yl]thiazole hydriodide (1.0 g), cyanamide (120 mg) and triethylamine (1.2 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. for 3 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1, V/V). Recrystallization from 20% methanol afforded 2-(diaminomethyleneamino)-4-[5-(2-cyanoguanidino)methylfuran-2-yl]thiazole (170 mg).
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].[Cu]I>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:34][CH2:35]3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(NC(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.48 g, 0.96 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl piperidin-4-ylcarbamate (0.22 g, 1.05 mmol), copper(I) iodide (0.022 g, 0.11 mmol), potassium carbonate (0.32 g, 2.32 mmol), and L-proline (0.026 g, 0.23 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, additional portions tert-butyl piperidin-4-ylcarbamate (0.048 g, 0.47 mmol), copper(I) iodide (0.018 g, 0.095 mmol), and L-proline (0.022 g, 0.19 mmol) were added. Heating was continued for an additional 4 h. After a total of 20 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (25 mL). The mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water (×2), brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-10% methanol/dichloromethane elute) afforded 0.33 g (60%) of tert-butyl (1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate as an impure solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[C:21]([C:22]2[S:23]C(C3NC=NN=3)=C(C3C=CC=CC=3)[N:26]=2)=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1.Cl[CH:39]([C:45]([O:47]CC)=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(O)C>[OH:47][C:45]1[N:26]=[C:22]([C:21]2[C:13]([CH3:12])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)[S:23][C:39]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: Cc1nn2ccccc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Temperature: 90 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (1.7 g, 7.5 mmol) produced in Example 11-B (v) and diethyl chloromalonate (2.0 g, 11 mmol) in 2-propanol (25 mL) was stirred at 90° C. for 4 hr with heating. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and dried to give ethyl 4-hydroxy-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (1.45 g, 64%) as a yellow solid.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.CON(C)[C:15]([C:17]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[CH:18]=1)=[O:16]>C1COCC1>[O:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:15]([C:17]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[CH:18]=1)=[O:16]
Reactant: CON(C)C(=O)C1=CC2CN(C(=O)OC(C)(C)C)CC2C1
Reactant: Brc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2C=C(C(=O)c3ccco3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 2-bromofuran (0.11 g, 0.74 mmol) in THF (3 mL) at −78° C. was added n-BuLi solution (2.5 M solution in hexanes, 0.30 mL, 0.75 mmol) and the mixture was stirred for 1 h. A solution of N-methoxy-N-methyl-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide (0.20 g, 0.65 mmol) in THF (2 mL) was added, and the mixture was warmed to ambient temperature over 8 h. The reaction was quenched with water (0.2 mL), diluted with of ethyl (20 mL) acetate, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude product was purified on silica gel column chromatography to obtain 0.10 g of 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone and 0.06 g of recovered starting material. A sample of 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone (0.050 g, 0.16 mmol) was dissolved in dichloromethane (3 mL), treated with TFA (2.0 mL), and stirred at ambient temperature for 1 h. The volatiles were evaporated, and the product was vacuum dried to obtain 0.047 g of 2-furanyl(3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone trifluoroacetate (1H NMR (CD3OD, 300 MHz): δ 7.81-7.80 (m, 1H), 7.38-7.36 (m, 1H), 6.91-6.88 (m, 1H), 6.65 (dd, J=3.66, 1.71 Hz), 3.95-3.86 (m, 1H), 3.56-3.40 (m, 3H), 3.27-3.16 (m, 1H), 3.14-3.02 (m, 2H), 2.77-2.68 (m, 1H); MS (m/z): 204 (M+1)). This material exhibited Ki values at rat and human α4β2 of 8 nM and 2 nM respectively and did not pass HTS for α7.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[S:3][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2)s1

Procedure:
To a boiling solution of 2-methyl-5-phenylthiophene (2g) in dry CCl4 (100 ml) was rapidly added N-bromosuccinimide (1.94 g) and dibenzoylperoxide (0.15 g). After heating under reflux for 30 min., the mixture was cooled and filtered. Evaporation in vacuo gave the title compound as an oil (1.5 g).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:16]=[C:15]4[CH:29]=O)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.C([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][OH:26])[CH:16]=[C:15]4[CH2:29][N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNCC3)c2c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide (Example 1f, 0.15 g) in DCE (5 mL) was treated with 1-Boc-piperazine (0.19 g) and titanium(IV) isopropoxide (0.30 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 16 h before adding sodium triacetoxyborohydride (0.28 g). The mixture was stirred at room temperature for 2 h before adding TFA (5 mL). The mixture stirred at room temperature for 2 h and evaporated to dryness. The mixture was quenched with 10% aq ammonia (5 mL) and extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to afford the title compound (0.065 g) as a white solid.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])(CC)C.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:3]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 538A (6.11 g, 17.21 mmol) in THF (150 mL) at −78° C. was treated with sec-butyl lithium (24.6 mL, 34.41 mmol) dropwise via syringe and stirred for 30 minutes at −78° C. The solution was then treated with a saturated ammonium chloride solution (100 mL), allowed to warm to room temperature, diluted with ether and extracted. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the desired product in quantitative yield. MS (ESI(+)) m/e 196 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33](F)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:49]1[CH2:52][CH:51]([N:53]2[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]2)[CH2:50]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:49]4[CH2:52][CH:51]([N:53]5[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]5)[CH2:50]4)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCN(C2CNC2)CC1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: O
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(N4CC(N5CCN(CC)CC5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Yield: 36.8 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-8-((6-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (30.0 mg, 0.0537 mmol) described in Production Example 2-4 and NMP (2.0 mL) was added a mixture (45.0 mg) of 1-(azetidin-3-yl)-4-ethylpiperazine and benzylbenzene described in Production Example 1-3-2 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 8 hours. Water was added to the reaction mixture, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1), and was then further purified by NH silica gel thin-layer chromatography (ethyl acetate). The resultant product was further purified by silica gel thin-layer chromatography (methanol) and was then filtrated using a NH silica gel to give the title compound (14.0 mg, yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([N:17]([CH2:18][CH2:19][O:20][CH3:21])[C:29]([NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:30])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCNc1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(2-methoxy-ethyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 3 days under reflux conditions to give the title compound as brown foam. MS: m/e=427.4 [M+H+].
Reaction SMILES: [C:1](N1C(N)=C(C2C=CN=CC=2)C=N1)(=N)N.[C:16]([N:19]1[C:23]([NH2:24])=[C:22]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[CH:21]=[N:20]1)(=[NH:18])[NH2:17]>>[NH2:18][C:16]1[N:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)=[C:23]2[N:24]=[CH:1][N:17]=1
Reactant: N=C(N)n1ncc(-c2cnccn2)c1N
Reactant: N=C(N)n1ncc(-c2ccncc2)c1N
Product: Nc1ncnc2c(-c3cnccn3)cnn12
Yield: 75 %

Procedure:
By replacing the 1-amidino-4-(4-pyridyl)-5-amino-pyrazole employed in Example 1C with an equivalent quantity of 1-amidino-4-(2-pyrazinyl)-5-aminopyrazole and following substantially the same procedure described in Example 1C there is obtained a 75% yield of 4-amino-8-(2-pyrazinyl)-pyrazolo[1,5-a][1,3,5]triazine. The product separates from boiling dimethylformamide in crystals melting above 360° C.
Reaction SMILES: S(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:10]=[O:11].[C-:16]#[N:17].[Na+]>O>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:10]([OH:11])[C:16]#[N:17]
Reactant: [C-]#N
Reactant: O=Cc1cc(F)cc(F)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: N#CC(O)c1cc(F)cc(F)c1
Yield: 85.7 %

Procedure:
Under stirring, 21 ml of a saturated aqueous solution of sodium bisulfite were added little by little to the mixture of 10.0 g of 3,5-difluorobenzaldehyde, 3.6 g of sodium cyanide and 15 ml of water. Upon the gradual addition, ice pieces were added at the same time to maintain the reaction temperature at 20°-30° C. The reaction mixture was stirred for 10 hours and then extracted with benzene. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, whereby 10.2 g of crude 3,5-difluoromandelonitrile were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:12])[C:8]([Cl:11])([Cl:10])[Cl:9].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=[C:3]1[C:7](=[O:12])[C:8]([Cl:9])([Cl:10])[Cl:11]
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2.12 g (9.34 mmol) of 1-methyl-2-trichloroacetyl-1H-pyrrole are dissolved in 9.5 ml of acetic anhydride and cooled to −20° C., and 0.43 ml (9.34 mmol) of nitric acid is added. The mixture is slowly warmed to RT and stirred at RT for 1 h. The reaction mixture is poured into 95 g of ice and stirred vigorously for 2.5 h (initially oily deposit then crystallization). The precipitate is filtered off with suction, triturated with 20 ml of methanol, filtered and dried under reduced pressure overnight. To remove the regioisomers, which are also formed, the product is triturated with 10 ml of acetic acid/water 1:1 for 2 h, and the solid is filtered off with suction and dried under reduced pressure. This gives a solid.