Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[CH:32]=[CH:33][C:34]([O:46][CH3:47])=[C:35]3[O:39][C:38]([S:40](=[O:45])(=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:37][C:36]=23)=O)=CC=1)([O-])=O.O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:46][CH3:47])=[C:35]2[O:39][C:38]([S:40](=[O:44])(=[O:45])[N:41]([CH3:43])[CH3:42])=[CH:37][C:36]=12)=[O:28]
Reactant: Cc1cnccc1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(S(=O)(=O)N(C)C)oc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccncc2C)c2cc(S(=O)(=O)N(C)C)oc12
Reaction time: 0.08 h
Yield: 81 %

Procedure:
To a stirred solution of 4-amino-3-methylpyridine (200 mg) in dimethylformamide (8 ml) under an atmosphere of nitrogen at 0° C. was added sodium hexamethyldisilazide (1.0M solution in tetrahydrofuran, 1.9 ml). The reaction mixture was stirred at this temperature for 5 minutes. 2-Dimethylsulfamyl-7-methoxy-benzofuran-4-carboxylic acid 4-nitrophenyl ester (400 mg) was then added and stirring continued for 30 minutes. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3×50 ml) and washed with brine (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with 10% methanol in ethyl acetate afforded the title compound as a white solid (0.3 g).
Reaction SMILES: CS([Cl:5])(=O)=O.C(N(CC)CC)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=2)=[O:24])=[CH:21][CH:20]=1>ClCCl>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH2:33][Cl:5])=[CH:31][CH:30]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(NCCCc1ccc(CO)cc1)c1ccc(-c2ccccn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCc1ccc(CCl)cc1)c1ccc(-c2ccccn2)cc1
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Methanesulfonyl chloride (294 mg) and triethylamine (0.37 ml) were successively added to a solution of 4-[3-(4-pyridine-2-ylbenzoylamino)propyl]benzylalcohol (0.74 g) in dichloromethane (20 ml). The mixture was allowed to stand at ambient temperature for 16 hours. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated to afford crystals. The crystals were washed with a small amount of diisopropyl ether to afford the desired compound (0.68 g).
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][O:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23](=[S:26])[NH:24][NH2:25]>C(O)C>[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]1[S:26][C:2]([CH2:3][CH2:4][O:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:25][N:24]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)NOCCC(=O)c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NOCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A mixture of tert-butyl 3-oxo-3-phenylpropoxycarbamate (1.09 g, 4.10 mmol) and 2,5-difluorobenzothiohydrazide (0.515 g, 2.74 mmol) in ethanol (3 mL) were stirred together at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product as a white solid (0.94 g, 79% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][OH:24])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:6])([F:25])[F:26])[CH:9]=1)(=[O:15])=[O:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCCCC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
Methanesulfonyl chloride (1 eq), dissolved in methylene chloride (2 ml/mmol) was added dropwise to a cooled solution (0° C.) of (1-(3-(trifluoromethyl)phenyl-sulfonyl)piperidin-2-yl)methanol (1.1 eq) in methylene chloride (4 ml/mmol) and triethylamine (2.5 eq). When the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature until, according to thin layer chromatography control, the reaction was complete. Hydrogen chloride solution (0.5 mol/l, 2 ml/mmol) was added, the mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield: 43%
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11]([OH:22])=[N:10][C:8]=2[N:9]=1.I[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH3:26])[C:8]=2[N:9]=1
Reactant: CCCI
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a suspension of NaH (60% in mineral oil, 31 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one from Example 11 (205 mg, 0.67 mmol). The mixture was heated at 50° C. for 1 hour resulting in a clear solution. 1-Iodopropane (100 μL, 1.03 mmol) was added, and the solution was stirred at 50° C. for 10 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The residue was dried and purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate to provide 159 mg (68%) of 2-amino-6-(2,6-dichlorophenyl)-8-propyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 196°-197° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:21][CH2:20]1)=[O:32]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccc(Cl)cc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (74.8 mg, 0.149 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (71.4 mg, 1.7 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated. Water (˜20 mL) was added and the mixture was neutralized with 1.0 N HCl (30 mL). The resulting white precipitate was collected by filtration and dried under high vacuum overnight to provide {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (57.8 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.5 (br. s, 1H), 8.46 (br. s, 1H), 7.90 (dd, J=8.80, 6.50 Hz, 1H), 7.76-7.86 (m, 1H), 7.68 (m, 2H), 7.50 (d, J=8.78 Hz, 1H), 7.40 (dd, J=8.70, 2.30 Hz, 1H), 7.30-7.37 (m, 1H), 4.20-4.32 (m, 2H), 3.68-3.97 (m, 4H), 3.02-3.24 (m, 2H), 2.43 (s, 3H), 2.16-2.40 (m, 2H), 1.61-1.70 (m, 2H). MS cald. for C25H24Cl2FN2O3 [(M+H)+]: 489, obsd. 489.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].Cl[Si](C)(C)C>CN1C(=O)CCC1.C(O)(=O)C>[CH2:19]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NCc3ccccc3)c2)s1
Reaction time: 8 h
Yield: 46.3 %

Procedure:
N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (30 mg, 0.11 mmol), benzaldehyde (0.016 mL, 0.16 mmol) and sodium cyanoborohydride (13 mg, 0.21 mmol) were mixed in NMP (0.9 mL) and acetic acid (0.1 mL). Chlorotrimethylsilane (0.04 mL, 0.32 mmol) was added and the mixture was stirred overnight. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.73 minutes; 19 mg); 1H NMR Spectrum: (DMSOd6) 12.13 (1H, s); 7.60 (1H, d); 7.38-7.30 (4H, m); 7.22 (1H, t); 6.80 (1H, d); 6.67 (1H, s); 4.47 (2H, s); 2.12 (3H, s); 2.03 (3H, s); Mass Spectrum: M+H+ 373 and 375.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:23][C:19]1([C:15]2[N:14]=[C:13]([CH2:12][N:9]3[C:4]4[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:3]=4[N:11]=[N:10]3)[CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Reactant: OB(O)c1ccccc1
Product: Nc1nc(-c2ccccc2)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1

Procedure:
Prepared from 7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and phenylboronic acid by the method described in Example 7 to give the title compound (0.03 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]([NH:63][C:56]2[CH:55]=[C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[C:53]4[C:48]=3[CH:47]=[CH:46][NH:45]4)[CH:62]=[C:61]3[C:57]=2[CH:58]=[N:59][NH:60]3)=[O:11])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 3,6-dichloro-2-pyridinecarboxylic acid (available from Matrix Scientific, 930 mg, 4.8 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1840 mg, 4.8 mmol) were dissolved in DMF (15 ml) and treated with DIPEA (2.53 ml). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (600 mg, 2.4 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5 ml which was added to 2×50 g aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The mixture was concentrated in vacuo and a precipitate occurred, which was collected by filtration to give the title compound (0.55 g) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C:9](=[N:54]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:53]=[CH:52][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:50])[C:25]([N:27]([CH2:36][C:37]3[CH:38]=[C:39]([CH:47]=[CH:48][CH:49]=3)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:26])=[C:20]([Cl:51])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:50])[C:25]([N:27]([CH2:36][C:37]3[CH:38]=[C:39]([CH:47]=[CH:48][CH:49]=3)[C:40]([OH:42])=[O:41])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:20]([Cl:51])[CH:19]=2)=[O:16])=[CH:52][CH:53]=1)[C:9]([NH2:54])=[NH:8]
Reactant: CC(C(=O)N(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OC(=O)c2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)N(CC(=O)O)Cc1cccc(C(=O)O)c1)c1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-{[{2-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]propanoyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (180 mg) in dichloromethane (1.92 mL) was added trifluoroacetic acid (0.646 mL), followed by stirring at room temperature overnight. After completion, the reaction solution was concentrated under reduced pressure, and then to the residue was added acetonitrile (20.0 mL), followed by concentrating under reduced pressure again. This operation was repeated twice, to the residue was added a 50% aqueous acetonitrile solution (5.00 mL), and a 1 M aqueous sodium hydroxide solution (0.208 mL) was added thereto under ice-cooling. After stirring for 1 hour under ice-cooling, the precipitated crystals were collected by filtration, and washed with a 10% aqueous acetonitrile solution and then dried under reduced pressure to obtain 3-{[(2-{4-[(4-carbamimidamidobenzoyl)oxy]-2-chlorophenyl}propanoyl)(carboxymethyl)amino]methyl}benzoic acid (92 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.07 mmol, intermediate 9), tert-butyl 3-bromopropanoate (0.22 mL, 1.29 mmol) and potassium carbonate (0.22 g, 1.61 mmol) were combined in DMF (5 mL) and heated at 100° C. for 24 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×50 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to leave a white solid. This solid was purified using a 25 g silica gel flash column eluted with 10% ethyl acetate/hexanes to give tert-butyl 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate (0.26 g, 41% yield) as a white solid. LCMS retention time=4.841 min and 99% purity, LCMS MH+=595. 1H NMR (CDCl3) δ 7.12-7.46 (m, 8H), 5.41 (s, 2H), 4.29 (t, 2H, J=8 Hz), 3.53 (s, 3H), 2.61 (t, 2H, J=8 Hz), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9](=O)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[CH3:10]
Reactant: Cc1cccc(N)n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cccc(C)n1
Reaction time: 4 h
Yield: 50.5 %

Procedure:
2-Amino-6-methylpyridine (1.00 g, 9.25 mmol) and acetaldehyde (0.52 mL, 9.34 mmol) were stirred together in anhydrous methyl alcohol for 1 hour at room temperature under a nitrogen atmosphere. The mixture was then treated with sodium triacetoxyborohydride (7.84 g, 37.0 mmol) and five drops of acetic acid and all was allowed to continue stirring for 4 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM, and the separated aqueous phase was extracted twice with DCM. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a mobile oil which was purified by flash column chromatography, eluting with 2% MeOH/DCM, to give 2-ethylamino-6-methylpyridine (636 mg, 51%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:3]=1.[C:26](B1OC(C)(C)C(C)(C)O1)([CH3:28])=[CH2:27].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[C:26]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:3]=1)([CH3:28])=[CH2:27]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(OC)c(OCCOC)cc12
Temperature: 180 °C

Procedure:
A mixture of [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (150 mg), isopropenyl boronic acid pinacol ester (70 μl), Na2CO3 (70 mg), Tetrakis(triphenylphosphine)palladium(0) (10 mg), DMF (0.5 ml) and water (0.5 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the reaction mixture was purified by preparative LC-MS to give [1-Isopropenyl-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (120 mg). LC-MS: m/e 369(MH+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([Cl:8])=[CH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Cl:8][C:6](=[CH2:7])[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:20](=[O:21])[C:19]1[CH:18]=[C:17]([CH3:16])[CH:25]=[C:24]([CH3:26])[CH:23]=1
Reactant: C=CCNCC(=C)Cl
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCN(CC(=C)Cl)C(=O)c1cc(C)cc(C)c1
Temperature: 10 °C

Procedure:
A solution was formed by dissolving N-allyl-2-chloroallylamine (0.032 moles) in 40 ml. of benzene. Then, triethylamine (0.032 moles) was added thereto. This solution was then cooled to 10° C. in an ice bath. Then, 3,5-dimethylbenzoylchloride was diluted with 40 ml. of benzene and added to the amine solution. The temperature rose to about 35° C. with triethylamine hydrogen chloride separation. The next day the reaction mixture was washed two times with diluted HCl and then two times with dilute (5% solution) sodium carbonate and dried. The solvent was removed to yield 7.0 grams of product ND30 1.5367.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH2:3]1.[H-].[Na+].I[CH3:22]>CN(C=O)C.O>[F:17][C:15]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N:4]2[CH2:3][C:2]([CH3:18])([CH3:1])[N:6]([CH3:22])[S:5]2(=[O:8])=[O:7])[CH:16]=1
Reactant: CC1(C)CN(c2cc(F)ccc2C#N)S(=O)(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(C)(C)CN(c2cc(F)ccc2C#N)S1(=O)=O
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of 2-(4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-4-fluorobenzonitrile (3.18 g, 11.81 mmol) in DMF (40 mL) was added NaH (0.312 g, 12.99 mmol) and the mixture stirred for 5 min. Iodomethane (1.477 mL, 23.62 mmol) was added and the mixture stirred at 90° C. for 2 h then at room temperature for 16 h. The mixture was diluted with H2O and extracted with ethyl acetate. The organic phase was washed two times with H2O followed by brine, dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (3.35 g, 100% yield). LCMS (M+H) calcd for C12H15FN3O2S: 284.08; found: 284.14. 1H NMR (300 MHz, CDCl3) δ: 7.70-7.61 (2H, m), 7.11-7.05 (1H, m), 3.80 (2H, s), 2.73 (3H, s), 1.42 (6H, s).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:29]([N:31]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1)[CH2:32][CH3:33])[CH3:30]
Reactant: CCNCC
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), diethylamine (47 mg, 0.65 mmol) and acetic acid (39 mg, 0.65 mmol) in dichloromethane (50 mL) was stirred at room temperature for 60 min. Upon cooling the mixture to 0° C., sodium triacetoxyborohydride (69.3 mg, 0.33 mmol) was added. After the addition, the mixture was stirred at room temperature overnight. Dichloromethane was removed under reduced pressure. The crude product was purified by chromatography (silica gel, dichloromethane/Methanol=50:1) to give the title compound (34 mg, yield 36%). LC-MS (ESI) m/z: 425 (M+H)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.10 (t, 6H), 2.64 (q, 4H), 3.70 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.75 (d, J=8.0 Hz, 1H), 7.06-7.09 (m, 2H), 7.13-7.20 (m, 4 H), 7.22-7.29 (m, 4H), 7.54-7.56 (dd, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc(F)c4)cc3c2C1
Yield: 66.8 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.1 μL (0.051 mMol) 3-fluorobenzoyl chloride, 10.8 mg (69%) of the title compound were recovered as a beige solid.