Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.O=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](OCC)=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:12]([OH:13])[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Nc1ccc(Cl)nc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Reaction time: 72 h

Procedure:
To a stirred solution of 6-chloropyridine-2,3-diamine(8-1, Oguchi, et. al. J. Med. Chem. (2000), 43, 3052-3066; 15 g, 105 mmol) in DMF (53 mL) was added ethyl oxo(phenyl)acetate (23 mL, 160 mmol) and DIPEA (37 ml, 210 mmol). After 72 hours, the reaction was concentrated to dryness. The resulting material was suspended in ethyl acetate/water and filtered to give 8-2 as a solid. The organic phase was washed with water, NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated. The crude mixture was suspended in DCM (200 mL) and filtered to give another batch of 8-2 as a solid. MS calculated: 257.7; observed: 258.0.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18]1>O1CCCC1>[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18]1
Reactant: CN1CC[C@H](O)C1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol, 60% in mineral oil) and (S)-1-methylpyrrolidin-3-ol (4.7 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 hours, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10.9 g of the title compound. MS (ESI+) m/z 271 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:21][C:3]1[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(NS(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Then, 0.10 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23) was dissolved in 0.62 ml of pyridine, to which 36 μl of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with 2N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 91 mg (yield, 73%) of 3-[4-chloro-2-fluoro-5-(methanesulfonylamino)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-37; m.p., 168.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][OH:10])[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: O=C(CO)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OCC1(c2ccc(F)cc2)OCCO1
Yield: 71.8 %

Procedure:
The same reaction as in the synthesis of 3a was conducted from 1-(4-fluorophenyl)-2-hydroxyethanone (23.89 g, 155 mmol), ethylene glycol (42 mL, 780 mmol), p-toluenesulfonic acid monohydrate (0.5 g) and benzene (300 mL) and the resulting crude product was purified by a silica gel column chromatography (toluene:ethyl acetate=4:1) to give [2-(4-fluorophenyl)-[1,3]dioxolan-2-yl]methanol (22.05 g, 72%) as an oily product. 1H-NMR (DMSO-d6) δ: 3.51 (d, J=6.3 Hz, 2H), 3.75-3.81 (m, 2H), 3.99-4.07 (m, 2H), 4.94 (t, J=6.3 Hz, 1H), 7.13-7.19 (m, 2H), 7.42-7.47 (m, 2H).
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CC1CCNCC1C(OCC)=O.C(N(CC)CC)C.[CH3:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]>ClCCl>[CH3:35][C@H:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[CH2:38][C@H:37]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCOC(=O)C1CNCCC1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
Di-tert-butyl dicarbonate (3.26 g, 15.20 mmol) was added to a solution of ethyl 4-methylpiperidine-3-carboxylate (2.0 g, 11.68 mmol) and triethylamine (3.9 mL, 28.05 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The mixture partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a mixture of the cis and trans diastereomers of 1-tert-butyl 3-ethyl 4-methylpiperidine-1,3-dicarboxylate (3.0 g). The crude material was purified via column chromatography (5-10% ethyl acetate in petroleum ether) to afford cis-1-tert-butyl 3-ethyl 4-methylpiperidine-1,3-dicarboxylate (2.5 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[CH:23]=[CH:22][S:21][C:19]=2[N:20]=1>C1COCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[CH:23]=[CH:22][S:21][C:19]=2[N:20]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Clc1nc(Cl)c2ccsc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A stirred suspension of NaH (85 mg, 2.12 mmol) in dry THF (12 mL) was added 4-hydroxy-3,5-dimethyl benzonitrile (311 mg, 2.12 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (434 mg, 2.12 mmol) in dry THF (10 mL) and heated at 50° C. for 2 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1) to give the product as a white solid (188 mg, 28%):
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Ethyl 1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylate (0.42 g, 1.0 mmol) was dissolved in methanol (10 mL), and was treated with an aqueous solution of lithium hydroxide (0.048 g, 2.0 mmol) in water (5 mL). The mixture was stirred at 50° C. for 2 h, cooled to RT, neutralized with 1N HCl (2 mL). The volatiles were removed under reduced pressure. The residue was co-evaporated with toluene (3×), and dried to afford the desired product which was directly used in next step. LCMS: (M+H)=397.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[NH2:10].[CH2:11]([N:13]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1)[CH3:12]>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:10]=[C:18]([C:16]1[CH:15]=[N:14][N:13]([CH2:11][CH3:12])[CH:17]=1)[N:8]2[CH3:9]
Reactant: CNc1ncnc(Cl)c1N
Reactant: CCn1cc(C=O)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 103 %

Procedure:
To a solution of 6-chloro-N4-methylpyrimidine-4,5-diamine (300 mg, 1.9 mmol) in anhydrous DMF (8 mL) were added 1-ethyl-1H-pyrazole-4-carbaldehyde (236 mg, 1.9 mmol) and Iron (III) chloride hexahydrate (0.51 g, 1.9 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (20 g). The resulting precipitate was collected by vacuum filtration, and triturated with 10 mL of ethanol at 50° C. for 30 min. The solids were collected by vacuum filtration to give 514 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, 2H), 8.19 (s, 1H), 4.25 (q, 2H), 3.95 (s, 3H), 1.43 (t, 3H); MS (EI) for C11H11ClN6: 263.3 (MH+).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Si:10]([O:2][CH2:1][CH2:3][NH2:4])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
Ethanolamine (2.00 g, 32.7 mmol) was dissolved in DMF (15 mL) followed by addition of imidazole (1.11 g, 16.4 mmol) and tert-butyldimethylsilyl chloride (2.46 g, 16.4 mmol), and then the mixture was stirred at room temperature for 12 hours. Water and an aqueous saturated sodium hydrogencarbonate solution were added to the reaction mixture in that order, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give 2-(tert-butyldimethylsilyloxy)ethylamine (1.59 g; yield 56%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:24])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:24])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: CCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
A solution of 3.0 g. of 1-acetamido-2-nitro-4-n-propylthiobenzene in 30 ml. chloroform is cooled to -15° C. and treated with a solution of 2.5 g. of 40% peracetic acid in 4 ml. methanol. After the addition the temperature is allowed to rise slowly to 20° C whereupon the solution is washed with sodium bisulfite solution and then with sodium bicarbonate solution. The product is isolated by evaporation of the solvent and purified by treatment with ether to afford 1-acetamido2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][S:25][CH2:26][CH2:27][CH2:28][NH2:29]>C(O)C>[CH3:24][S:25][CH2:26][CH2:27][CH2:28][NH:29][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CSCCCN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCCSC)ncc2c(=O)[nH]1
Yield: 56.1 %

Procedure:
In a similar manner to Example 38 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.79 g) and methylthiopropylamine (0.50 g) in ethanol (15 ml) for 40 hours yielded a crude product which was purified by elution from silica with 40-60° petroleum ether:chloroform (gradient elution) to yield the title compound 0.52 g, m.p. 173-4° C. (recrystallized from methanol).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:29]3[CH:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
N,N'-carbonyldiimidazole (1 g) is added to a solution, cooled to +5° C., of 2-dimethylaminophenylacetic acid (1.1 g) in dry dichloromethane (30 cc). The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS, 7aRS)- 7,7-diphenylperhydro-4-isoindolone hydrochloride (2.03 g) and triethylamine (1.68 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 24 hours, then washed with water (3×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 3 cm, height 25 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40:60 by volume) and collecting 125-cc fractions. Fractions 8 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS, 7aRS)-7,7-Diphenyl-2-[2(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (0.9 g) is obtained in the form of white crystals, m.p. 150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccncc4)c3)c2c1
Yield: 4.4 %

Procedure:
Following Example 290, the reaction of 3-(3 aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 4-pyridylacetic acid hydrochloride (0.15 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 12 mg (4% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.5 (dd, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4-7.1 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH3:15])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1.[OH-].[Na+]>CC#N.O>[CH3:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[C:2]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[N:3]=1
Reactant: O=C(O)C1CCNCC1
Reactant: CNc1nc(Cl)nc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-N-methyl-6-phenyl-1,3,5-triazin-2-amine (10.0 g, 45.3 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (60 mL) was cooled (0° C.), and 4-piperidinecarboxylic acid (11.7 g, 90.6 mmol, 2.00 equiv) was added. The pH of the reaction mixture was adjusted to 9-10 by treating with 1 N NaOH. The pH was maintained at 9-10 for 24 hours (product formation monitored by LCMS). The mixture was diluted with water, and filtered to provide the crude product (filtered solid was washed with additional water). The resulting solid was purified by HPLC to afford 9.1 g of the title compound. MS (ES+): m/e 314.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[CH2:10]([O:12][C:13]([C:15]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[CH:8]=[O:9])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: Cn1ncc(Br)c1C=O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4C=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 4-bromo-2-methyl-2H-pyrazole-3-carbaldehyde and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[N:36][C:37]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:38][CH:39]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:34]2[CH:39]=[N:38][C:37]([O:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[N:36][CH:35]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Brc1cnc(OCCN2CCCC2)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cnc(OCCN3CCCC3)nc2)cc1
Yield: 28.2 %

Procedure:
Using an analogous procedure to that described in Method 44, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with 5-bromo-2-(2-pyrrolidin-1-ylethoxy)pyrimidine (Method 64, 136 mg, 0.5 mmol) to give the title compound (71 mg; 28%). Mass Spectrum: M+H+ 504.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1>CCO.O1CCOCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)COc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)COc1cc(C)nc2c(O)cccc12
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a mixture of give 8-(benzyloxy)-2-methylquinolin-4-ol (2.34 g, 8.83 mmol) and potassium carbonate (1.83 g, 13.2 mmol) in anhydrous DMF (50 mL) was added ethyl bromoacetate (1.77 g, 10.6 mmol) with stirring under nitrogen. The mixture was heated at 80° C. for 1 h, cooled, mixed with a saturated aqueous sodium bicarbonate and extracted with EtOAc. Evaporation gave a crude product that was dissolved in dichloromethane and precipitated by the addition of a mixture of Hex/EtOAc (10/1). The precipitate was filtered and dried to give ethyl 2-((8-(benzyloxy)-2-methylquinolin-4-yl)oxy)acetate (2.13 g, 69%). A mixture of ethyl 2-((8-(benzyloxy)-2-methylquinolin-4-yl)oxy)acetate (0.70 g, 1.99 mmol), Pd/C (10%, 0.07 g) in EtOH/dioxane (20 mL/20 mL) was placed under hydrogen atmosphere with stirring overnight. The mixture was filtered and evaporated to give ethyl 2-((8-hydroxy-2-methylquinolin-4-yl)oxy)acetate (0.24 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].Br[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(c1ccc(-c2cc(Cl)ccc2O)cc1Cl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(Cl)c1
Reaction time: 16 h

Procedure:
The product from step c) (180 mg), tert-butyl bromoacetate (0.07 ml), potassium carbonate (0.1 g) and DMF (10 ml) were charged to a flask and stirred for 16 h. Water was added and then washed with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (8:2). The sub-title compound was dissolved in DCM (8 ml) and TFA (2 ml) was added, stirred for 1 h, then concentrated in vacuo. Trituration with a mixture of ether and isohexane gave a solid, which was further purified by reverse phase HPLC to give the title compound. Yield (48 mg)
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+]>O>[CH:18]1([O:24][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCCCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
To dimethylformamide solution (35 ml) containing 2-chloro-5-nitrobenzonitrile (14.1 g) and cyclohexanol (8.5 g) was added sodium hydride (60% content, 3.7 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give 2-cyclohexyloxy-5-nitrobenzonitrile (11.6 g), melting point: 97–98° C.