Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16]CC4C=CC5N(C6CCCCO6)C=NC=5C=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3c(c2)ncn3C2CCCCO2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
To a solution of 32 (406 mg, 0.94 mmol) in MeOH (5 mL) and water (1 mL) was added p-TsOH.H2O (178 mg, 0.94 mmol). The reaction mixture was heated at reflux for 18 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to afford 180 mg (55%) of N2-41H-benzo[d]imidazol-5-yl)-methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (I-13) as white solid.
Reaction SMILES: [CH:1]1([N:5]2[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15](=O)[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>C1C=CC=CC=1>[CH:1]1([N:5]2[C:9]3[N:10]=[C:15]([CH:12]4[CH2:13][CH2:14]4)[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=3[C:7]([CH3:11])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C2CCC2)n1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCC1
Reaction time: 4 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 33 using 1-cyclobutyl-3-methyl-1H-pyrazol-5-amine (400 mg, 2.65 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (487 mg, 2.65 mmol) and benzene (50 mL), wherein the reaction time was 4 h. The final product was collected as 0.556 g (70%). LCMS E-S (M+H)=300.6 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.22 (m, 4 H) 1.47 (t, J=7.07 Hz, 3 H) 1.80-2.01 (m, 2 H) 2.15-2.28 (m, 1 H) 2.38-2.51 (m, 2 H) 2.70 (s, 3 H) 2.82 (td, J=9.85, 2.53 Hz, 2 H) 4.49 (q, J=7.07 Hz, 2 H) 5.32-5.57 (m, 1 H) 7.41 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:34][C:35]1[CH:40]=[N:39][CH:38]=[C:37]([CH2:41][CH3:42])[N:36]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:41]([C:37]1[N:36]=[C:35]([NH:34][C:2]2[CH:7]=[C:6]([CH2:8][O:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=[N:39][CH:38]=1)[CH3:42]
Reactant: CCc1cncc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCc2ccnc(Cl)c2)c2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Temperature: 20 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
Dioxane (125 mL) was added to tert-butyl (4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (Intermediate C) (9.6 g) and the mixture stirred at 20° C. Cesium carbonate (2 eq, 16.3 g) and 2-amino-6-ethylpyrazine (1.5 eq, 4.8 g) were added to the stirred mixture at ° C. Argon was purged through the reaction mixture. Tris(dibenzylideneacetone)dipalladium(0) (0.05 eq, 1.14 g) and racemic BINAP (0.10 eq, 1.56 g) were added to the reaction mixture. The mixture was stirred for an additional 15 min at 20° C. The mixture was heated to 90° C. at a rate of 1.5 K/min then stirred for 12 h at 90° C. The mixture was cooled to 20° C. and stirring continued for an additional 6 h. The heterogeneous mixture was filtered over Celite, and the filter washed with dioxane (twice 5 mL). The filtrate was concentrated in vacuo at 20 mbar and 50° C. The residue was dissolved in ethanol (150 mL). Spontaneous crystallization occurred. The heterogeneous mixture was stirred for 3 h at 22° C. The precipitate was filtered and washed with ethanol (10 mL). The product was dried in vacuo at 50° C. for 20 h to give tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (9.05 g, 76.8%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[C:39]([C:41]([C:43]3[C:51]4[CH:50]=[N:49][CH:48]=[N:47][C:46]=4[N:45]([CH:52]([CH3:54])[CH3:53])[CH:44]=3)=[O:42])[CH:40]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1.O>ClCCl>[CH:24]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[C:39]([C:41]([C:43]3[C:51]4[CH:50]=[N:49][CH:48]=[N:47][C:46]=4[N:45]([CH:52]([CH3:54])[CH3:53])[CH:44]=3)=[O:42])[CH:40]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:23]
Reactant: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(CO)c3)c2)c2cncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C=O)c3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Dess Martin Periodinane (392 mg, 0.93 mmol) was added to a solution of (2-[3-(hydroxymethyl)phenyl]-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide (Preparation 193, 265 mg, 0.62 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 18 hours. Water (10 mL) was added and the aqueous layer extracted with a 95:5 mixture of dichloromethane/methanol (3×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel (gradient of dichloromethane to dichloromethane/methanol (10:1 to 9:1) to afford the title compound as a brown solid in 80% yield, 211 mg.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(F)(F)c1ccc(Sc2ccc(Cl)cc2)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccc2Sc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexane, 6.5 mL, 16.2 mmol) was slowly added to a stirred solution of 1-bromo-2-(4-chlorophenylsulfanyl)-5-(trifluoromethyl)benzene (5.96 g, 16.2 mmol) in dry THF (40 mL) under argon at −78° C. The solution was stirred for 10 min before 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.23 g, 16.2 mmol) was added in one portion. The solution was allowed to warm to rt and then stirred overnight. Saturated aqueous ammonium chloride (80 mL) was added and the solution was extracted with ethyl acetate (80 mL). The organic phase was washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate and the solvent was evaporated off. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8) to produce the target compound as a white foam, yield: 4.53 g (57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[C@@:15]([NH2:19])([S:30](=[O:32])(=[O:31])[N:29]([CH3:34])[CH3:28])[CH:16]([CH3:17])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)[C@@H](N)C(C)C)cc1OC
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)[C@](N)(C(C)C)S(=O)(=O)N(C)C)cc1OC

Procedure:
7.2 g of (S)-2-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide and 4 ml of triethylamine are initially introduced in 120 ml of 1,4-dioxane at room temperature, while stirring. 2.8 ml of N,N-dimethylsulfamoyl chloride are added dropwise in the course of 5 minutes. The reaction mixture is then stirred at room temperature for 20 hours and subsequently introduced into 80 ml of 2N hydrochloric acid. The mixture is extracted twice with 200 ml of ethyl acetate each time. The organic phases are washed once with 80 ml of 2N hydrochloric acid, once with 80 ml of saturated sodium chloride solution, once with 80 ml of 5% sodium bicarbonate solution and once with 80 ml of saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated. (S)-2-(N,N-dimethylsulfamoyl)-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide, which can be purified by recrystallization from ethyl acetate/hexane, is obtained, melting point 97°-99° C.
Reaction SMILES: [F:1][C:2]1[C:19](F)=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:36][CH3:37])(=[O:35])[CH2:30][C:31]([O:33][CH3:34])=[O:32].Cl>CS(C)=O>[F:1][C:2]1[CH:19]=[C:18]([CH:30]([C:29]([O:36][CH3:37])=[O:35])[C:31]([O:33][CH3:34])=[O:32])[C:17]2[C:16](=[O:21])[C:15]3[C:6]([C:5](=[O:22])[C:4]=2[CH:3]=1)=[CH:7][C:8]1[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=3
Reactant: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)cc2c1C(=O)c1cc3ccccc3cc1C2=O

Procedure:
1 g (3.4 mmol) of 2,3-difluoro-naphthacene-5,12-dione, 0.94 g (6.8 mmol) of potassium carbonate, 0.89 g (6.8 mmol) of dimethyl malonate and 20 ml of DMSO are stirred at 50° C. for 22 hours. The mixture is poured onto dilute hydrochloric acid and extracted with THF/toluene. The organic phase is washed with water, dried over sodium sulfate and evaporated. The product is purified by chromatography over silica gel (mobile phase: 1% acetone/99% CH2Cl2); yield 1.25 g (91%); melting point 225°-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[C:20]([O:32][CH3:33])[CH:19]=2)=[C:4]2[N:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:17].C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>C(Cl)Cl>[NH2:17][C:5]1[C:4]2=[C:3]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)=[C:20]([O:32][CH3:33])[CH:19]=3)[C:2]([Cl:1])=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:41](=[O:44])[CH:42]=[CH2:43])[CH2:12]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(-c2c(Cl)c(C3CCCNC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCCC(c2c(Cl)c(-c3ccc(Oc4cccc(Cl)c4)c(OC)c3)c3c(N)ncnn23)C1
Temperature: -10 °C

Procedure:
The compound (27.6 mg, 0.057 mmol) prepared in Example 31 was taken up in 1 mL DCM (dry) under argon and triethylamine (23.8 μl, 0.171 mmole) was added. The reaction was cooled to −10° C. and the acryloyl chloride (4.17 μl, 0.051 mmole) was added via syringe slowly. The reaction quenched with methanol and solvent removed under vacuum. The title compound (10.5 mg) having the following data was isolated by prep-HPLC.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N>O.CO>[NH2:6][C:5]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNc1ccccc1
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.32 g (21 mmol) of phenylhydrazine with a purity of 98% by weight, 10 ml of methanol and 3.0 ml (36 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 10 ml of water was added to the mixture to cool the same up to 10° C., then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower for 30 minutes. Precipitated crystals were collected by filtration, and the crystals were washed with 5 ml of cold water and dried under reduced pressure to obtain 3.19 g of 5-amino-4-nitroso-1-phenylpyrazole (Isolation yield: 63.4%) as an ocherous solid with a purity of 74.9% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18][O:19][C:20]=3[CH3:21])[N:13]=[CH:12]2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1.O>[CH3:21][C:20]1[O:19][N:18]=[C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[C:14]1[N:13]=[CH:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Yield: 99.9 %

Procedure:
To a solution of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid ethyl ester (1.50 g, 4.0 mmol) in THF (20 mL) was added a solution of lithium hydroxide monohydrate (0.5 g, 12 mmol) in water (10 mL). The resulting mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to afford the title compound (1.38 g, 99%) which was obtained as a light yellow solid. MS m/e=346.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@@H:6]([C:17]([O:19]C)=[O:18])[NH:5]1)[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@@H:6]([C:17]([OH:19])=[O:18])[NH:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
A mixture of methyl (1RS,3RS)-cis-1-n-propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (1.3 g), 1N NaOH (5.5 ml) and methanol (8 ml) is stirred at room temperature for 1.5 hours. The mixture is distilled under reduced pressure to remove methanol. The residue is adjusted to pH 4 with 10% HCl, and the precipitated crystals are collected by filtration, washed with water and then dried to give the title compound (1.0 g, 81%) as colorless needles, m.p. 225°-226° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1>[Cu]Br.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:16]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:8]=2)[CH:7]=1
Reactant: N#Cc1cccnc1
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 135 °C
Yield: 52 %

Procedure:
A mixture of 5-bromopyridin-2-amine (2 g, 11.6 mmol), nicotinonitrile (24.1 g, 231 mmol), 1,10-phenanthroline monohydrate (115 mg, 578 μmol) and copper (I) bromide (82.9 mg, 578 μmol) was placed in a 100 ml 2 necked flask and heated to 135° C. Heating was continued while air was bubbled gently through the mixture for 1.5 days. The excess nicotinonitrile was distilled off under reduced pressure and the black residue purified by chromatography (70 g silicagel column using heptane/ethyl acetate 10-100% as eluent). Final evaporation of the solvents afforded 6-bromo-2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine (1.66 g, 52%) as yellow solid. Mp.: 176° C. MS: m/z=275/277 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4c3)c2cc1OC
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (232 mg, 1.06 mmol) in toluene (4.5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.55 mL, 1.10 mmol) at RT followed by 2-(bromomethyl)naphthalene (252 mg, 1.14 mmol) and the mixture was stirred at 110° C. for 15 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) before extraction with CH2Cl2 (50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 210 mg of 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol as a yellow solid. The free base was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.15 M HCl solution in MeOH (8 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford after drying 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol hydrochloride 17 as a yellow solid (230 mg, 55% yield).
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19].C([Li])CCC.CCOCC.[C:31](Cl)(=[O:35])[CH2:32][CH2:33][CH3:34]>O1CCCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][N:3]1[C:2]([C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[C:10]2[C:5]([N:6]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH2:7][CH2:8][CH2:9]2)=[N:4]1
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(C)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(=O)c1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a solution of 3-bromo-2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-b]pyridine (0.053 g, 0.159 mmol) in 1 mL of tetrahydrofuran at −78° C. was added n-butyl lithium (0.12 mL, 0.19 mmol), and the yellow solution was stirred at −78° C. for 10 min. A 1.0 M zinc chloride in ether solution (0.45 mL, 0.45 mmol) was added, the resulting cloudy pale orange solution was stirred at RT for 10 min., then butyryl chloride (0.020 mL, 0.19 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.003 g, 0.003 mmol) were added. The golden yellow solution was stirred for 3 h, then quenched with 1 mL of a saturated aqueous ammonium chloride solution. The mixture was partitioned between 5 mL of water and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered, and concentrated to a yellow oil. Column chromatography (0→20% EtOAc/hexanes) afforded 0.021 g (41%) of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-butan-1-one as a slightly impure pale yellow oil that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(C3CCCCC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C3CCCCC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 54.9 %

Procedure:
A mixture of 2′-amino-6-bromo-2-cyclohexy-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.08 mmol), 3-cyanophenylboronic acid (23 mg, 0.15 mmol), Pd(PPh3)2Cl2 (20 mg), aqueous cesium carbonate solution (2 M, 0.5 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. under microwave for 35 minutes. The reaction mixture was concentrated to give the residue, which was purified by preparative TLC and preparative HPLC to give 3-(2′-amino-2-cyclohexy-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (18.2 mg, 56%). 1H-NMR (MeOD): 1.22-1.39 (m, 4H), 1.69-1.86 (m, 4H), 2.01 (s, 1H), 2.13-2.24 (m, 1H), 2.28-2.46 (m, 1H), 3.12 (s, 1H), 3.27-3.36 (m, 3H), 4.63 (m, 1H), 7.06 (m, 1H), 7.49 (s, 1H), 7.57-7.76 (m, 3H), 7.86 (t, 1H), 7.94 (d, 1H).
Reaction SMILES: [Si:1]([O:8][NH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([S:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]3[C:44](O)=[O:45])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[O:8]([NH:9][C:44]([CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][N:38]1[S:35]([N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)(=[O:37])=[O:36])=[O:45])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: O=C(O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)ONC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
O-(tert-butyldimethylsilyl)hydroxylamine (57 mg, 0.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) were added to a solution of 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (100 mg, 0.26 mmol), [prepared as described above] in methylene chloride (4 ml). The reaction mixture was stirred overnight at RT and then diluted with methylene chloride. The solution was washed with water, 10% citric acid, and brine, and dried over MgSO4. After the organics were removed the residue was chromatographed (SiO2, 20-30% ethyl acetate/hexane) to give N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide as a colorless foam (56%).