Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].COC1C(C)=C2C(C(O)=CC(C3SC=C(C(F)(F)F)N=3)=N2)=CC=1>>[Cl:22][C:8]1[C:7]([O:23][CH3:24])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Product: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1Cl
Yield: 70 %

Procedure:
8-Chloro-7-methoxy-2-(4-trifluoromethyl-thiazol-2-yl)-quinolin-4-ol 203d was synthesized from compound 202d as a yellow powder in 70% yield, following the procedure as described for compound 203b. MS (ESI, EI+) m/z=361 (MH+).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1(O)[C:13]#[C:14][CH:15](O)[CH3:16]>O>[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13](=[O:2])[CH:14]=[CH:15][CH3:16]
Reactant: CC(O)C#CC1(O)CCCCC1C
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC=CC(=O)C1=C(C)CCCC1
Reaction time: 0.75 h

Procedure:
20 g of 50 % aqueous sulphuric acid (parts by weight) were added to 20.2 g (0.11 mole) of 2-methyl-1-hydroxy-1-[3-hydroxy-but-1-ynyl]-cyclohexane and the thus obtained mixture was stirred for 45 minutes at 50°. After having added water to the said mixture, it was extracted three times with pentane, and the combined organic extracts were washed, dried (MgSO4) and concentrated. The resulting residue gave, by fractional distillation, a product of b.p. 118°-120°/12 Torr; 10.9 g (60 %). By purification by means of vapour phase chromatography there was obtained 2-methyl-1-[but-2-enoyl]-cyclohex-1-ene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[N:9][CH:8]=1.BrC1C=[N:30]C2C(C=1)=NC=C(OCC1C=CC(F)=C(F)C=1)C=2.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCCOCCOCCOCCOCC1.C(OCC)(=O)CC(OCC)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([NH2:30])=[O:19])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: CCOC(=O)Cc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Reactant: Fc1ccc(COc2cnc3cc(Br)cnc3c2)cc1F
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CCOC(=O)CC(=O)OCC
Product: NC(=O)Cc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Temperature: 115 °C
Yield: 53.8 %

Procedure:
Ethyl 2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetate. 3-Bromo-7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine (3.20 g, 9.11 mmol), Pd2(dba)3 (41.72 mg, 0.05 mmol), tri-tert-butylphosphonium tetrafluoroborate (290.84 mg, 1 mmol), potassium phosphate (5.42 g, 25.52 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (1.2 g, 4.56 mmol), and diethyl malonate (9.17 mL, 60.15 mmol) were added to a microwave vial, which was capped and purged with nitrogen for several minutes then heated to 115° C. for 19 h. The reaction was cooled to ambient temperature then water and EtOAc were added. The layers were separated and the aqueous solution was extracted with EtOAc and DCM. The combined organic layers were washed with brine then dried (Na2SO4). The solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-70%, EtOAc/hexanes) afforded the title compound as a pure beige solid (1.76 g, 53.8%). 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J=18.1, 2.5 Hz, 2H), 8.27 (d, J=1.4 Hz, 1H), 7.68 (d, J=2.6 Hz, 1H), 7.47-7.30 (m, 1H), 7.26-7.17 (m, 2H), 5.20 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.86 (s, 2H), 1.30 (t, J=7.2 Hz, 3H). [M+H]=359.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:13])=[CH2:12].O.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:13])[CH2:12][O:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)c1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: O
Product: CC1(c2cc([N+](=O)[O-])ccc2F)CO1
Temperature: 10 °C
Reaction time: 48 h

Procedure:
1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene (1 eq) was dissolved in dichloromethane and cooled to 10° C. using and ice/salt/water bath under nitrogen. MCPBA (1.5 eq) in dichloromethane was then added dropwise and resulting solution allowed to warm to room temperature and allowed to stir 48 h. Solution was quenched with 10% sodium sulfite, neutralized with saturated solution of sodium bicarbonate, extracted with dichloromethane. Organics were washed with brine, dried with sodium sulfate and concentrated. Crude product was purified with flash chromatography (85% Hex:15% EtoAc) to afford 2-(2-fluoro-5-nitrophenyl)-2-methyloxirane.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>CC(O)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Br:23])=[CH:25][C:26]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Yield: 69.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (8.35 g, 27.8 mmol), (prepared, for example, as described in WO 97/22596, Example 1), and 4-bromo-2-fluoroaniline (5.65 g, 29.7 mmol) in 2-propanol (200 ml) was heated at reflux for 4 hours. The resulting precipitate was collected by filtration, washed with 2-propanol and then ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (9.46 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:10]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:21]=[CH:20]3)[CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C)c1-c1cccc(COc2ccc3[nH]ccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3cccc(-c4c(C)cccc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
5-[(2′,6′-Dimethylbiphenyl-3-yl)methoxy]-1H-indole (0.95 g, 2.90 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and N,N-dimethylformamide (4 mL). The solution was ice-cooled, and sodium hydride (60% in oil, 0.12 g, 3.0 mmol) was added, and the mixture was stirred at the same temperature for 20 min. Then, ethyl bromoacetate (0.36 mL, 3.25 mmol) was added to the solution, and the mixture was allowed to warm to room temperature and stirred for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.0 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[N:22]1[N:23]([C:27]2([C:30](=N)OCC)[CH2:29][CH2:28]2)[N:24]=[CH:25][CH:26]=1.C(N(CC)CC)C.C(O)(=O)C>C(O)C>[N:22]1[N:23]([C:27]2([C:30]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH2:29][CH2:28]2)[N:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2nccn2)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5nccn5)CC4)[nH]c3n2)C1)N1CCCC1
Yield: 2.9 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (0.4 g, 1.36 mmol) in ethanol was added ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropanecarbimidate (600 mg, crude), triethylamine (5 mL) and acetic acid (6 mL). The reaction mixture was heated to reflux for 12 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was dried over sodium sulfate and concentrated. The crude material was purified via preparative TLC to afford the title compound (16 mg). MS (ES+) (M+H) 407.3; LCMS retention time 1.793 min (Method N1).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(O)C(N)Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(O)C(Cc2ccc(C(F)(F)F)cc2)NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.38 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (308 ml, 2.07 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title-compound (574 mg, 91%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[N:38][CH:39]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[N:38][CH:39]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
N-(5-(3-(4-(bis(4-Methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-yl)acetamide (0.0806 g, 0.107 mmol) and trifluoromethanesulfonic acid (0.02 mL, 0.2 mmol) were dissolved into TFA (2 mL). The pale yellow solution was stirred at rt for 30 min. Then the mixture was stirred at 65° C. for overnight. After cooling to rt, solid sodium carbonate was added followed by aq sodium bicarbonate. The resulting greenish solid was collected and the crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30 mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fractions containing product were collected and concentrated to dryness in vacuo. The yellow residue was taken up in aq. sat'd sodium bicarbonate and sonicated. The resulting yellow solid was collected and washed with water and dried in a vacuum oven overnight to give N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-yl)acetamide (0.0361 g, 66% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.90 (s, 1H); 10.35 (s, 1H); 8.74 (d, J=2.54 Hz, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.21-8.28 (m, 2H); 8.02 (d, J=9.00 Hz, 1H); 7.89 (br. s., 1H); 7.74 (br. s., 1H); 3.49 (s, 2H); 3.10 (d, J=4.50 Hz, 4H); 2.86 (s, 3H); 2.44 (s, 3H); 2.07 (s, 3H). 4 protons on the piperazine were buried under the water peak and could not be integrated. m/z (ESI, +ve ion) 513.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.C(N(CC)CC)C.[CH2:24](Br)[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)(Cl)Cl>[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[NH:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Yield: 82.2 %

Procedure:
To a solution comprising 2.3 g of 4-(2-keto-1-benzimidazolinyl)-piperidine, 1.1 g of triethylamine, and 20 ml of chloroform is added 2.2 g of phenacyl bromide, and the reaction is carried out under the same conditions as in Example 1. The same post-treatment as in Example 1 is conducted to obtain 3.2 g of a crude product. Recrystallization of the product from a mixture solution of ethanol and ethyl acetate (2:3 by volume) yields 2.92 g of 1-[2-oxo-2-phenyl-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([CH3:13])=[CH2:12])[N:10]=1)[C:5]([OH:7])=[O:6].[N+](=[CH:16][Si](C)(C)C)=[N-]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([CH3:13])=[CH2:12])[N:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: C=C(C)c1cc(C(=O)O)cc(Cl)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: C=C(C)c1cc(C(=O)OC)cc(Cl)n1

Procedure:
To a solution of 2-chloro-6-isopropenylisonicotinic acid (0.25 g, 1.27 mmol) in dichloromethane (4.7 mL) and methanol (1.6 mL) was added (diazomethyl)(trimethyl)silane (0.63 mL, 1.27 mmol). After the addition, the mixture was concentrated and carried onto the next step. MS 212.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[N:4][N:3]=1>O1CCCC1.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:5]2[N:6]([C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([OH:11])=[O:10])[C:2]([CH3:1])=[N:3][N:4]=2)=[CH:21][CH:20]=1
Reactant: Cc1nnc(-c2ccc([N+](=O)[O-])cc2)n1-c1ccccc1C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(N)cc2)n1-c1ccccc1C(=O)O

Procedure:
was prepared by hydrogenating 270 mg of 2-[3-methyl-5-(4-nitrophenyl)-[1,2,4]triazol-4-yl]benzoic acid in the presence of Pd/C in tetrahydrofuran and purified by column chromatography (silica gel, solvent: 95:5 dichloromethane:methanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[B-](F)(F)(F)[CH2:84][N:85]1[CH2:90][CH2:89][N:88]([CH3:91])[CH2:87][CH2:86]1.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:19]2[N:18]=[C:17]([C:4]3[C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[N:6][CH:7]=[C:2]([CH2:84][N:85]4[CH2:90][CH2:89][N:88]([CH3:91])[CH2:87][CH2:86]4)[CH:3]=3)[N:22]=[C:21]([CH3:23])[N:20]=2)=[CH:27][CH:28]=1
Reactant: CN1CCN(C[B-](F)(F)F)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C
Yield: 88.7 %

Procedure:
A mixture of 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 mg, 0.274 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (X-Phos, 13.06 mg, 0.027 mmol), cesium carbonate (268 mg, 0.822 mmol), potassium 1-methyl-4-trifluoroboratomethylpiperazine (Frontier Scientific Co., 66.3 mg, 0.301 mmol) and palladium acetate (3.08 mg, 0.014 mmol) was purged with argon. The mixture was then treated with THF (1.0 mL) and water (0.1 mL) and heated under microwave irradiation at 140° C. for 30 min. The mixture was filtered through a short path of Celite® (diatomaceous earth), washed with EtOAc (×3), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM to 5% MeOH in DCM) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (161 mg, 0.243 mmol, 89% yield) as a yellow syrup. m/z (ESI, +ve ion) 662.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][CH:21]1[CH2:24][CH:23]([CH2:25][OH:26])[CH2:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:1][S:2]([O:26][CH2:25][CH:23]1[CH2:24][CH:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22]1)(=[O:4])=[O:3]
Reactant: OCC1CC(OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulphonyl chloride (0.16 gm, 1.1 mmol) and triethylamine (0.26 gm, 2.6 mmol) were added to a solution of [3-(benzyloxy)cyclobutyl]methanol (0.25 gm, 1.3 mmol) (step a) in dichloromethane at 0° C. and the reaction mixture was stirred at room temperature for about 2 hours. It was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19]2)=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:19]2[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC(=O)n1c(-c2ccc(F)cc2)c(-c2ccncc2)c2ccc(NC(=O)CNC(=O)OC(C)(C)C)nc21
Temperature: 23 °C

Procedure:
6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (29) (50 mg, 0.108 mmol), isobutyl chloroformate (42 ml, 0.325 mmol) N-methylmorpholine (119 ml, 1.08 mmol), potassium carbonate (74.9 mg, 0.542 mmol), and DMF (4 mL) were warmed at 80° C. for 16 h. After cooling to 23° C., the reaction was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by preparative plate chromatography to afford 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (142). Compound (104) was converted to 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (143) in the manner of example 6: Mass Spectrum (CI) 462 (MH+).
Reaction SMILES: Br.Br[CH:3]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5][C:4]1=O.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)C>[NH2:23][C:21]1[S:22][C:4]2[CH2:5][CH2:6][N:7]([CH2:10][CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][C:3]=2[N:20]=1
Reactant: O=C1CCN(CC#Cc2ccccc2)CCC1Br
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1)CC2

Procedure:
Prepared from 5-bromo-1-(3-phenyl-2-propyn-1-yl)-hexahydro-4H-azepin-4-one hydrobromide by reacting with thiourea in ethanol. Yield: 4% of theory, Melting point: 145°-148° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1.O>O1CCOCC1>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[N:10]=[CH:11][N:12]=[C:13]([NH:26][C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[CH:31][CH:32]=2)[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
To a solution of N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7.0 g, 19.7 mmol) and TEA (5.5 mL, 40 mmol) in dioxane (100 mL) was added tert-butyl 3-aminophenylcarbamate (4.2 g, 20.0 mmol). The reaction mixture was heated to 70° C. for 6 hrs under N2. After the reaction was cooled down to room temperature, water (150 mL) was introduced. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layer was washed with water (150 mL×2) and brine (100 mL×1), dried over Na2SO4 and concentrated to dryness. tert-Butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (9.2 g, 88%) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 527.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH2:22]3)[O:18][N:17]=2)[N:3]=1.Cl>>[NH2:27][CH:24]1[CH2:25][CH2:26][CH:21]([C:19]2[O:18][N:17]=[C:16]([C:4]3[N:5]=[C:6]([N:8]([CH3:15])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[N:20]=2)[CH2:22][CH2:23]1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(NC(=O)OC(C)(C)C)CC3)n2)n1
Agent: Cl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(N)CC3)n2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
To tert-butyl N-[4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)cyclohexyl]carbamate (Example 423, 2.349 g, 5.035 mmol) was added hydrogen chloride solution (4M in 1,4-dioxane, 10 mL, 40 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum, water was added and the aqueous was neutralized to pH7 using saturated aq. sodium bicarbonate. The resultant precipitate was collected by filtration to afford the title compound as a white solid (0.877 g, 48%).