Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Nc1ccncc1
Product: c1ccc2c(Nc3ccncc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and pyridin-4-ylamine to give N3-(1H-pyrazol-3-yl)-N1-pyridin-4-yl-isoquinoline-1,3-diamine. LC-MS m/e 303(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:12]([N:15](C(C)C)CC)([CH3:14])[CH3:13].C(N)(C)C>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH:12]([CH3:14])[CH3:13])=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(F)c(C(=O)O)c1
Solvent: CC#N
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc(N)ccc1F
Yield: 619.6 %

Procedure:
A solution of 5-amino-2-fluorobenzoic acid (300 mg, 1.9 mmol), diisopropylethylamine (1 ml, 5.8 mmol), and isopropylamine (0.3 ml, 3.9 mmol) in acetonitrile was heated to 110° C. in microwave for 45 min. This reaction was repeated 5 times and the crude products combined then concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/dichloromethane (0% to 10% v/v) to afford the title compound as a yellow solid (2.31 g). HPLC retention time 3.93 min. Mass spectrum ES+) m/z 197 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:34]=2[CH2:33][CH2:32]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:42][C:39]2[CH:40]=[CH:41][C:34]3[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:37][CH2:36][C:35]=3[CH:38]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)cc2CC1
Yield: 75 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (84 mg, 0.00021 mol), 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (47 mg, 0.00021 mol), and 10-Camphorsulfonic acid (58 mg, 0.00025 mol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.5 mL satd. sodium bicarbonate, then extracted 2×10 mL DCM, dried over sodium sulfate and conc. onto 1 g Celite. Chromatography (ISCO, Amine-capped SiO2, 14 g, 25-100% EtOAc:Hex) afforded 3-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-morpholin-4-yl-phenoxy)-propionitrile as a light pink solid (91 mg, 74%). MP: 91-96° C., LCMS 578 (M+H); 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.8 Hz), 8.02 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H, J=7.9 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.56 (d, 1H, J=8.8 Hz), 6.50 (s, 1H), 4.28 (t, 2H, J=6.3 Hz), 3.88 (m, 4H), 3.53 (t, 2H, J=6.3 Hz), 3.38 (s, 3H), 3.14 (m, 4H), 2.90 (m, 6H), 2.72 (m, 6H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[CH3:41][O:42][CH2:43][C:44](Cl)=[O:45]>C1COCC1.C(=O)([O-])O.[Na+]>[CH3:32][O:31][C:9]1[C:10]2[C:11](=[O:30])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[S:20][C:8]=1[C:6]([N:5]([CH2:4][CH2:3][NH:2][C:44](=[O:45])[CH2:43][O:42][CH3:41])[CH3:33])=[O:7]
Reactant: COCC(=O)Cl
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCCN(C)C(=O)c1sc2c(c1OC)c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of the compound of Example 103 (100 mg, 0.21 mmol) and triethylamine (46 mg, 0.45 mmol) in THF (10 mL) was added methoxyacetyl chloride (25 mg, 0.23 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (61 mg, 56%) as a white powder.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.C(O)(C)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH:25]([CH3:30])[CH3:26])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(O)cc2C)c1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(OC(C)C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
To a solution of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol (58 mg, 0.176 mmol) in 3 ml of dry THF was added triphenylphosphine (70 mg, 0.264 mmol) and isopropanol (60 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 5 min, diethyl azodicarboxylate (46 mg, 0.264 mmol) was added. The mixture was stirred at room temperature overnight. An additional 20 mg of diethyl azodicarboxylate was added and the mixture was stirred for an additional 4 hours. The mixture was quenched with water and extracted with methylene chloride. The organic layer was dried and concentrated to give an oil. The oil residue was purified through silica gel column chromatography using 1:1 hexane:chloroform to 1:2 hexane: chloroform as eluent to give 38 mg (58%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 6.60 (s, 2H), 6.28 (s, 1H), 4.50 (m, 1H), 4.18 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 2.079s,6H), 1.71 (m, 4H), 1.34 (d, 6H), 0.98 (t, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitrobenzene (24 g) in anhydrous THF (200 mL) was added 1 M vinylmagnesium bromide in THF (328 mL) dropwise at −78° C. slowly, then the mixture was allowed to warm to RT and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated aqueous NH4Cl solution. The organic phase was separated by extraction with EA (3×200 mL). The crude product was purified by column chromatography to afford 7-bromo-5-fluoro-1H-indole (D131) (15 g) as a brown oil.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][C@H:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH3:20])[C:10]2=[O:21])[CH2:6][CH2:5][NH:4]1)#[N:2].[O:22]=[S:23]1(=[O:39])[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25](=[O:33])[N:24]1[CH2:34][CH2:35][CH2:36][CH2:37]Br.[I-].[K+]>>[O:39]=[S:23]1(=[O:22])[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25](=[O:33])[N:24]1[CH2:34][CH2:35][CH2:36][CH2:37][N:4]1[CH2:5][CH2:6][C@@H:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH3:20])[C:10]2=[O:21])[CH2:8][C@@H:3]1[C:1]#[N:2]
Reactant: CCCn1c(=O)n([C@@H]2CCN[C@@H](C#N)C2)c2ccccc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Agent: [I-]
Agent: [K+]
Product: CCCn1c(=O)n([C@@H]2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)[C@@H](C#N)C2)c2ccccc21
Temperature: 80 °C

Procedure:
From (±) cis/trans-2-cyano-4-(3-n-propyl-2-oxo-1-benzimidazolinyl)-piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using a modification of the procedure described in Example 1, Step 4, wherein one equivalent of potassium iodide was added and the reaction was warmed at 80° C. for 24 hours, there was obtained a white solid after chromatographic purification, melting point 159-160° C. The NMR was consistent with structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17]([C:18]([O:20]CC)=[O:19])=[C:13]2[CH:12]=[C:11]([CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17]([C:18]([OH:20])=[O:19])=[C:13]2[CH:12]=[C:11]([CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccccc2)n2nc(C)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of 390 mg (1.13 mmol) of 7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 7A) in 6 ml of 1,4-dioxane was admixed with 4 ml of 2 M sodium hydroxide solution. The mixture was stirred at 100° C. for a further 18 hours. The reaction mixture was cooled under reduced pressure and then concentrated under reduced pressure. The residue was admixed with acetonitrile (10 ml) and water (2 ml), followed by 2 ml of trifluoroacetic acid, which was added dropwise. The resulting precipitate was filtered off and dried under reduced pressure, which gave 262 mg (72% yield, 92% pure) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23]>>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: Cc1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Reactant: NN
Solvent: O
Product: Cc1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
12.0 g of 3-chloro-5,6,7,8-tetrahydro-6-(p-toluoyl)pyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 2 hours. The title compound has a M.P. of 207°-210° (decomp., from 95% ethanol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][C:11]3[N:12]([CH3:13])[C:8]4[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:26]=[CH:25][C:9]=4[N:10]=3)[S:16][C:17]=2[CH:23]=1
Reactant: CCOC(=O)c1ccc2nc(Nc3nc4ccc(Cl)cc4s3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2ccc(C(=O)O)cc21
Yield: 89.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid (1 g) was prepared by following General Procedure E starting from 2-(6-chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester (1.2 g) and 2 N NaOH (5 mL) in methanol:THF (1:1, 20 mL).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=O)=[O:12].[NH2:24][C:25]1[CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:17](=[O:19])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[CH3:23])=[O:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1sc2nccnc2c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1sc2nccnc2c1N
Yield: 9.7 %

Procedure:
A solution of 109 (0.305 mmol, 100 mg), 3-aminobenzotrifluoride (0.305 mmol, 0.038 mL), TBTU (0.457 mmol, 147 mg) and DIPEA (0.914 mmol, 0.150 mL) in NMP (5 ml) stirred overnight at 80° C. The light brown solution was poured into citric acid solution and extracted with ethyl acetate. The combined organic layers were washed with brine and evaporated. The crude compound was purified by HPLC and chromatography (0-5% methanol in CH2Cl2) gave 7-amino-N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 110 (14 mg, 10%). NMR (400 MHz, DMSO-d6) 2.33 (s, 3H), 7.10 (s, 2H), 7.47 (m, 2H), 7.61 (m, 1H), 7.85 (dd, J=7.8 Hz and 1.6 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.80 (d, J=2.3 Hz, 1H), 9.62 (s, 1H), 10.52 (s, 1H). (m/z)=472 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[S:9]([C:12]1[N:16]2[C@:17]([CH3:42])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:32][CH:31]=3)[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)(=[O:11])=[O:10])=O.[NH3:43]>>[Cl:27][C:22]1[CH:21]=[C:20]([N:19]2[C:15]3=[N:14][CH:13]=[C:12]([S:9]([N:6]4[CH2:7][CH2:8][C@H:5]4[C:3]([NH2:43])=[O:2])(=[O:11])=[O:10])[N:16]3[C@:17]([CH3:42])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:32][CH:31]=3)[C:18]2=[O:28])[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: N
Reactant: COC(=O)[C@@H]1CCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Product: C[C@@]1(Cc2ccc(-c3cncnc3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CC[C@H]3C(N)=O)n21
Temperature: 50 °C

Procedure:
(S)-1-[(R)-7-(3,5-Dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-azetidine-2-carboxylic acid methyl ester (0.025 g, 0.04 mmol) was dissolved in 2.0 M methanolic ammonia solution (5 mL) in a sealed tube and heated to 50° C. for 48 h. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The resultant residue was purified by silica gel chromatography to afford 0.018 g of the title compound (612.1, M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[C:13](=[O:19])[C:12]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)=[O:21].C(N(C(C)C)C(C)C)C>O1CCCC1>[C:1]([O:19][C:13]1[CH:14]2[CH2:18][CH:17]([C:11](=[O:10])[C:12]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:21])[CH2:16][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CCC(C2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(OC(=O)c2ccccc2)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., a solution of 0.562 g (0.0004 mol) of benzoyl chloride in 1 ml of tetrahydrofuran is added to a solution of 1.14 g (0.0035 mol) of 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one and 0.517 g (0.004 mol) of ethyidiisopropylamine in 15 ml of tetrahydrofuran. The reaction mixture is stirred at 25° C. for 2 hours, evaporated and purified over silica gel (hexane/ethyl acetate 1:1). This gives 0.9 g (60%) of the title compound in the form of a yellowish resin. 1H NMR (CDCl3, ppm): 7.91-7.87, m, 3H; 7.64, t, J=7.5 Hz, 1 H; 7.5 0-7.40, m, 3H; 3.24, br t, J=4 Hz, 1 H; 3.14, br t, J=4 Hz, 1H; 2.70, s, 3H; 2.47, d, J=13.5 Hz, 1H; 2.40, 2.15, m, 3H; 1.95-1.8, m, 2H.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[CH:13]1([NH:12][C:4]2[N:3]=[C:2]([N:21]3[C:20]([CH3:19])=[CH:24][C:23]([CH3:25])=[N:22]3)[N:10]=[C:9]3[C:5]=2[N:6]([CH3:11])[CH:7]=[N:8]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cn1cnc2nc(Cl)nc(NC3CCCCC3)c21
Product: Cc1cc(C)n(-c2nc(NC3CCCCC3)c3c(ncn3C)n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-7-methyl-7H-purin-6-yl)-cyclohexyl-amine and 3,5-dimethylpyrazole.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:7][CH3:8])[OH:6])([CH3:3])[CH3:2].[C:9](#[N:12])[CH:10]=[CH2:11].C(O)(C)C.[Na]>>[C:9]([CH2:10][CH2:11][P:5]([CH2:7][CH3:8])(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])#[N:12]
Reactant: CCP(O)OC(C)C
Reactant: C=CC#N
Agent: [Na]
Solvent: CC(C)O
Product: CCP(=O)(CCC#N)OC(C)C
Reaction time: 1 h

Procedure:
To 34 g of ethylphosphonous acid-isopropylester and 16.45 ml of acrylonitrile is added with stirring 40 ml of isopropanol containing 0.25 mol of sodium isopropylate. The reaction is exothermic. After 1 hour stirring at 20° the mixture is fractionated. There is obtained isopropyl 2-cyanoethyl(ethyl)phosphinate as a colorless oil, b.p. 102°-104°/10 Pa.
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][C:2]([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)([CH3:21])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccncc1
Yield: 67.9 %

Procedure:
Using the method of Example 68, 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 770 mg, 2.59 mmol) was reacted with isonicotinoyl chloride hydrochloride (1.15 mg, 6.48 mmol). The crude product was purified as described in Example 68 to provide 708 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]isonicotinamide as an off-white solid, mp 148-150° C. MS (APCI) m/z 403 (M+H)+; Anal. Cacld for C23H26N6O: C, 68.63; H, 6.51; N, 20.88. Found: C, 68.30; H, 6.49; N, 20.92.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C.O>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:10][C:8]1[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.281 g) was added to a solution of 5-fluoro-2-methoxyphenol (1.0 g) in DMF (20 ml) and stirred at RT for 30 min. 2-Chloro-1-fluoro-4-nitrobenzene (1.23 g) was added and the mixture stirred at RT for 16 h then diluted with water and extracted with diethylether. The organics were dried and evaporated under reduced pressure, yield 1.95 g.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].O.[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>O1CCCC1>[C:14]([O:13][C:11]([NH:6][C@@H:5]([CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:10])[C:3]([O:2][CH3:1])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.0 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19](Cl)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([N:40]4[CH2:41][CH2:42][CH:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C2CC2)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C5CC5)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-cyclopropyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.26 (s, 1H), 3.87 (t, 1H), 3.75 (m, 2H), 3.56 (m, 1H), 3.49 (m, 1H), 3.36 (m, 2H), 3.24 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 1.85 (m, 1H), 1.67 (m, 2H), 1.44-1.38 (m, 4H), 1.27 (m, 2H), 0.30 (m, 2H), 0.23 (m, 2H). m/z: 458 [M+H]