Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1.ClCCl.[CH2:15](N(CC)CC)[CH3:16]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.CCO>[CH:15]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1)=[CH2:16]
Reactant: COc1cc(Cl)ncc1C#N
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1cc(OC)c(C#N)cn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A 20 mL microwave tube was charged with 6-chloro-4-methoxypyridine-3-carbonitrile (200.0 mg, 1.2 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (97.0 mg, 0.12 mmol), potassium vinyl trifluoroborate (318.0 mg, 2.37 mmol), and triethylamine (0.33 mL, 2.37 mmol), and EtOH (6 mL). The microwave tube was evacuated and filled with nitrogen (two times) and heated to 140° C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The extracts were concentrated and chromatographed over a column of SiO2 (0-30% EtOAc/hexanes as eluent). Evaporation of the solvent yielded the title compound. 1H NMR (500 MHz, DMSO-d6), δ 8.65 (s, 1H), 6.89 (s, 1H), 6.83 (dd, J=10.7 Hz, 1H), 6.42 (d, J=7.3 Hz, 1H), 5.70 (d, J=10.6 Hz, 1H) 4.05 (s, 3H);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[N:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([C:19]([O:1][C:2]2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)c1cc(O)cc(C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C=O)cc(OC(=O)N2CCOCC2)c1
Reaction time: 3 h
Yield: 22.1 %

Procedure:
To a stirring solution of 91.9 mg (0.634 mmol) of 3-hydroxy-5-isopropylbenzaldehyde in 5 mL of CH2Cl2 at r.t. was added 220 μL (1.92 mmol) of 4-morpholinecarbonyl chloride and 0.5 mL (3.59 mmol) of Et3N. After 3 h, sat. NaHCO3 (15 mL) was added, and the aqueous layer was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (20% EtOAc/hexanes) provided 38.8 mg of 3-formyl-5-isopropylphenyl morpholine-4-carboxylate as a yellow oil in 24% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[C:18]4[CH3:24])[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1.[CH:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:25][C:4]1[CH:3]=[C:2]([NH:1][CH2:26][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[CH3:24])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1cc(N)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-amino-2-methylphenyl)-4-(3-methyl-1H-indazol-5-yl)pyrimidin-2(1H)-one (25 mg, 0.06 mmol) in 6 mL dichloroethane were added tert-butyl 4-formylpiperidine-1-carboxylate (76.6 g, 0.36 mmol), NaBH(OAc)3 (76 mg, 0.36 mmol), and 500 μL acetic acid. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous NaHCO3 (15 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl 4-((3-methyl-4-(6-(3-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenylamino)methyl)piperidine-1-carboxylate, which was submitted to the next step without further purification.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[CH2:41]([O:43][NH2:44])[CH3:42]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6](/[C:7](=[N:44]\[O:43][CH2:41][CH3:42])/[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccc(Oc2ccc(CN3CCC(C(=O)c4ccc(Br)cc4)CC3)cc2)cc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCO/N=C(\c1ccc(Br)cc1)C1CCN(Cc2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
To a solution of the compound prepared in Example 5(15) (912 mg) in ethanol (10 mL) were added pyridine (5 mL) and O-ethylhydroxyamine hydrochloride (340 mg) and the solution was refluxed for 3 hours. After finishing the reaction, the reaction solution was concentrated. Water and 2N hydrochloric acid were added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=25:1) and 4N hydrogen chloride/ethyl acetate solution was added to the obtained residue, which was concentrated to give the compound of the present invention (E-form: 409 mg, Z-form: 500 mg) having the following physical data.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:23]#[N:24])=[CH:13][C:11]=2[CH:12]=1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 40 °C
Reaction time: 96 h
Yield: 28 %

Procedure:
The crude product from Example 112D, the mono-(L)-tartaric acid salt of (2R)-2-methylpyrrolidine (306 mg, 1.3 mmol), and Cs2CO3 (652 mg, 2.0 mmol) were stirred in an approximately 0.2 M MeCN solution of (2R)-2-methylpyrrolidine (1.6 mL, 0.3 mmol). The mixture was heated at 40° C. overnight. More Cs2CO3 (326 mg, 1.0 mmol) and acetonitrile (0.5 mL) were added and the reaction was stirred at 40° C. for four days. The mixture was cooled to room temperature, diluted with CH2Cl2, filtered, and concentrated. The residue was chromatographed twice through a short column of silica with a 0 to 5% gradient of MeOH/CH2Cl2 to provide the title compound as an orange-tan gum (28% yield). 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H), 1.39-1.54 (m, 1H), 1.75-1.87 (m, 2H), 1.96-2.09 (m, 1H), 2.27-2.39 (m, 1H), 2.46-2.63 (m, 2H), 2.95-3.15 (m, 2H), 3.20-3.35 (m, 2H), 6.63 (s, 1H), 7.49-7.52 (m, 2H), 7.62 (dd, 1H), 7.67 (ddd, 1H), 7.78 (dd, 1H), 7.90 (ddd, 1H), 7.98 (dd, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]=[C:2]1[N:7]([CH3:16])[C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)OCC(=O)N2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)OCC(=O)N2C
Yield: 92 %

Procedure:
Following the procedure of Example 1, 21.7 g of 3-oxo-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine and 19.88 g of methyl iodide were reacted in 600 ml of acetone in the presence of 19.32 g of solid potassium carbonate. The reaction was carried out, and the product isolated and purified by the procedure of Example 1 to yield 3-oxo-4-methyl-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine; yield=92%; molecular ion by mass spectrum=193.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.OCCCCCCCCCC(O)=O.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51]CC2)CCCCC1>O1CCCC1>[CH3:1][N:45]([C:46]1[CH:51]=[CH:52][CH:53]=[CH:48][N:47]=1)[CH3:39]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)CCCCCCCCCO
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 471 mg of 10-hydroxydecanoic acid, 25 ml of dry tetrahydrofuran, 516 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 332 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:6]([O:17][CH3:18])=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[N+](=[CH2:21])=[N-]>O1CCCC1.CCOCC>[CH3:21][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[C:6]([O:17][CH3:18])=[CH:7][C:8]=1[O:14][CH2:15][CH3:16]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid (13 g, 44 mmol) in tetrahydrofuran was cooled to 5° C. and treated with excess diazomethane in ether solution (prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) and stirred for 10 min. Solvent and excess diazomethane was removed by rotary evaporation. The resulting residue was dissolved in dichloromethane and filtered through a plug of silica gel and evaporated. The solids were triturated with ether/hexane to give 13 g of 5-chlorosulfonyl-2-ethoxy-4-methoxy-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH:6]([NH2:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:15]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH3:2])=[O:16])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CC(N)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid methyl ester hydrochloride (1.50 g, 6.1 mmol) and sodium carbonate (90.65 g, 6.1 mmol) in 40 mL of water was added N-carboethoxyphthalimide (1.34 g, 6.1 mmol) in 12 mL of acetonitrile. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partially concentrated and this mixture was stirred for 72 hours. The resulting slurry was filtered and the solid was washed with copious amount of water. The solid was dried in vactio (30° C., <1 mm) to afford 1.70 g (50%) of methyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder. mp 65-66° C.; 1H NMR (DMSO-d6, 250 MHz) δ7.83-7.91 (m, 4H), 6.88-7.3 (m, 4H), 5-80 (dd, 1H, J=7.5, 2.5), 3.72 (S, 3H), 3.54 (3, 3H), 3.2-3.6 (m, 2H); 13C NMR (DMSO-d6) δ170.7, 167.5, 158.7, 134.6, 131.0, 130.5, 128.3, 123.2, 113.9, 55.0, 51.5, 49.4, 35.4. Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13; Found: C, 66.96; H, 5.00; N, 4.11.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.[CH2:37]([C@H:42]1[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH2:40][CH3:41].O1CCCC1>O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]=[CH:48][C@H:45]2[CH2:46][CH2:47][C@H:42]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44]2)=[CH:13][CH:14]=1
Reactant: c1ccc([P+](CCCc2ccc(OC3CCCCO3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](C=CCCc2ccc(OC3CCCCO3)cc2)CC1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of 4.0 g of [3-(4-[tetrahydro-2-pyranyloxy]phenyl)-1-propyl]triphenylphosphonium bromide, 1.3 g of trans-4-pentylcyclohexanecarboxaldehyde and 50 ml of absolute tetrahydrofuran was treated portionwise with 0.8 g of solid potassium t-butylate. After completion of the addition the reaction mixture was stirred for a further two hours and then poured into 500 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene gave 1.0 g of 1-[tetrahydro-2-pyranyloxy]-4-[4-(trans-4-pentylcyclohexyl)-3-butenyl]benzene (cis/trans mixture).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Ethyl N-(3-chlorobenzyl)indole-2-carboxylate (0.47 g) was dissolved in THF/MeOH (1:1) and sodium hydroxide (2M, 4.5 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo to dryness and the residue dissolved in water. The solution was acidified to pH 3 by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered off, washed with water and dried in vacuo to give the desired end product (0.35 g, 82%), mp 188-189°; NMR δ (CD3SOCD3) 5.85 (s, 2H), 6.90 (d, 1H), 7.1 (m, 2H), 7.3 (m, 4H), 7.55 (d, 1H), 7.70 (d, 1H); M/z (−) 284 (M−H+).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc(F)cc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 4-fluorophenylboronic acid (81 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated to dryness, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 5-(2-(4-fluorophenyl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.17 (d, 1H), 7.02 (d, 1H), 6.8-6.98 (m, 4H), 4.7 (d, 1H), 4.3 (d, 1H), 3.65 (m, 1H), 3.41 (m, 1H), 2.9-3.18 (m, 7H), 2.52-2.77 (m, 2H), 2.45 (s, 3H), 2.21 (m, 2H).
Reaction SMILES: C(O[C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])(C)(C)C.C(OC(=O)[CH2:16][N:17]=[C:18]=[O:19])C.[ClH:21].C(O)C>C(Cl)Cl>[ClH:21].[NH2:10][CH2:9][CH2:8][N:7]1[C:6](=[O:11])[CH2:16][NH:17][C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: NCCN1C(=O)CNC1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(2-Aminoethyl)-carbamic acid tert-butyl ester (14.4 g, 90 mmol) was dissolved in DCM (100 mL) and was treated with a solution of isocyanatoacetic acid ethyl ester (11.6 g. 90 mmol) in DCM (100 mL) added dropwise over 30 min. The resulting solution was stirred for 1 h and concentrated to give a pale gum. Aqueous 5N HCl (250 mL) was added and the mixture stirred until dissolved. The resulting solution was heated at 100° C. for 16 h, concentrated, water (250 mL) was added and the solution again concentrated to give a solid. Ethanol (100 mL) was added and the mixture was again concentrated. Ethanol (150 mL) was added and the mixture stirred for 16 h to give the product as a fine white powder which was collected by filtration. Yield=14.7 g, 91%. MS (M+H)+ 144.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](Cl)=[O:38])[CH:34]=[N:33]1>ClCCl>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[O:38])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: Cn1cc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cnn(C)c2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (53.8 mg, 0.144 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.10 mL, 1.2 mmol) and 1-methyl-1H-pyrazole-4-carbonyl chloride (27.7 mg, 0.192 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into 50 mL dichloromethane, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.1 mg (61%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-1-methyl-1H-pyrazole-4-carboxamide. LCMS (ESI): RT (min)=4.307, M+H=426.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.80 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.01 (d, J=4.9 Hz, 2H), 7.93 (d, J=8.6 Hz, 1H), 7.70 (dd, J=10.3, 4.6 Hz, 3H), 7.30 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 2.25 (s, 3H), 2.19-1.98 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[C:20]([O:22][CH3:23])=[O:21].Cl[CH2:25][C:26]#[N:27].O>CS(C)=O>[C:26]([CH2:25][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[C:20]([O:22][CH3:23])=[O:21])#[N:27]
Reactant: N#CCCl
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1c(OCC#N)c2cc(OC)ccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
A suspension of potassium tert-butoxide (3.2 g, 29 mmol) in 60 mL of dimethyl sulfoxide is treated in portions with methyl 3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylate (5.6 g, 24 mmol; Unangst P. C., et al., J. Heterocyclic Chem., 24:811 (1987)). The mixture is stirred for 15 minutes, and chloroacetonitrile (4.8 mL, 5.7 g, 76 mmol) is added dropwise. The mixture is heated at 80° for 90 minutes, cooled, and added to 800 g of ice and water. The precipitated solid is filtered, washed with 10% methanol-water, and recrystallized from aqueous acetonitrile to give 3.9 g (60%) of product, mp 136°-137° C.
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.[CH3:18][CH:19]([CH3:22])[CH2:20][OH:21]>>[CH2:20]([O:21][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)[CH:19]([CH3:22])[CH3:18]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CC(C)CO
Product: CC(C)COc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methyl-propan-1-ol to give (1-isobutoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 283(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].Cl.Cl.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[CH2:43][NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][C:39]3[NH:38][CH:42]=[CH:41][N:40]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCc2ncc[nH]2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 32.9 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added (1H-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (7 mg, 33%). LC-MS m/z 533 (M+H)+; 1H-NMR (MeOD) δ 1.26 (d, 6H), 2.26 (s, 3H), 4.12 (s, 2H), 4.23 (m, 1H), 4.36 (s, 2H), 6.88 (s, 2H), 7.10 (t, 2H), 7.48 (m, 2H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[N:10]=[C:9]2[CH3:23])[CH:5]=[N:6][CH:7]=1.Cl.[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH3:27])[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[N:10]=[C:9]2[CH3:23])[CH:5]=[N:6][CH:7]=1
Reactant: CNC
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)cn1-c1cncc(F)c1
Agent: Cl
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1-c1cncc(N(C)C)c1

Procedure:
The title compound, MS: m/e=328.4 (M+), was prepared in accordance with the general method of example 27 from 3-[1-(5-fluoro-pyridin-3-yl)-2-methyl-1H-imidazol-4-ylethynyl]-benzonitrile and dimethylamine hydrochloride.