Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.65 g, 1.9 mmol) in acetonitrile (10 mL), was added acetyl chloride (0.13 mL, 1.8 mmol) and N,N-diisopropyl ethylamine (0.70 mL, 4.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a light yellow solid (104 mg, 16% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 3.93 min (99.0%); mp, 293-291° C.; 1HNMR (DMSO-d6)1.92 (s, 3H, CH3), 2.14-2.20 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.73-4.77 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.31-7.76 (m, 3H, Ar), 8.22 (t, J=6 Hz, 1H, CH2NH); 13C NMR (DMSO-d6) δ 20.78, 22.60, 23.26, 30.58, 41.49, 56.48, 117.65, 124.48, 125.42, 133.83, 141.06, 148.44, 154.75, 160.95, 169.32, 169.51, 172.58. LCMS MH=343; Anal Calcd For C17H18N4O4: C, 59.64; H, 5.30; N, 16.37. Found: C, 59.46; H, 5.05; N, 16.24.
Reaction SMILES: [F:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[C:13](=[NH:18])([NH2:17])[CH2:14][CH2:15][CH3:16].C[O-].[Na+]>CO.C(OCC)(=O)C>[F:1][CH:2]([C:3]1[N:17]=[C:13]([CH2:14][CH2:15][CH3:16])[NH:18][C:5](=[O:7])[CH:4]=1)[CH3:11]
Reactant: CCCC(=N)N
Reactant: CCOC(=O)CC(=O)C(C)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1nc(C(C)F)cc(=O)[nH]1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-fluoro-3-oxopentanoate (5.0 g), butanimidamide hydrochloride (4.6 g) and sodium methoxide (28% methanol solution, 16 mL) in methanol (50 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (5.7 g, 100%).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31](OC1C=CC=CC=1)=[O:32])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:43]([NH2:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:51][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:32])(=[O:28])=[O:29])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCN
Reactant: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Yield: 97.6 %

Procedure:
A benzene (10 ml) solution containing 200 mg (0.40 mmol) of 3-benzyloxy-N-[2-[(phenyloxycarbonylamino)sufonyl]phenyl]benzamide produced in Example 45 and 0.15 mol (0.88 mmol) of octylamine was heated under reflux for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel chromatography to obtain 210 mg (yield: 98.0%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].N1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CN(C)C=O>[N:12]1([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
A mixture of 2,4-dinitrobenzonitrile 4.20 g (21.75 mmol) and morpholine 5.7 mL (66.0 mmol) in N,N-dimethylformamide 20 mL was stirred at room temperature for 20 hours. The reaction mixture was poured into water. The precipitate was collected and washed with water to give the title compound 4.20 g as orange solid. Yield 74.5%.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]2[O:8][C:9]([F:12])([F:11])[O:10][C:3]=2[CH:2]=1.Cl.[C:14](Cl)(Cl)=[S:15].ClCCl>O>[N:7]([C:6]1[CH:1]=[CH:2][C:3]2[O:10][C:9]([F:11])([F:12])[O:8][C:4]=2[CH:5]=1)=[C:14]=[S:15]
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: FC1(F)Oc2ccc(N=C=S)cc2O1
Reaction time: 0.5 h

Procedure:
34.6 g of 5-amino-2,2-difluorobenzodioxole were added dropwise to a solution of 90 ml of conc. hydrochloric acid in 350 ml of water. The mixture was stirred for a further 30 minutes and then 27 g of thiophosgene were metered in rapidly. The mixture was stirred at the given temperature for a further 3 hours, the almost colourless suspension was admixed with 150 ml of dichloromethane and the dichloromethane was removed. The crude product was distilled at 45 mbar. 28 g (=89% of theory) were obtained as a colourless to yellowish liquid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:28]=[CH:29][N:30]=[CH:31][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=2)[CH2:23][CH2:24]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (174 uL, 1.0 mmol) and acetyl chloride (43 uL, 0.60 mmol) in DMF (2 mL) at 0° C. and the resulted mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated and the residue was washed with water (sonicated) and the solid was collected by filtration, dried under high vacuumn to give compound 186 (170 mg, 74% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.82 (1H, s), 9.27 (1H, s), 9.01 (1H, s), 8.44 (1 H, d, J=5 Hz), 8.21 (1H, d, J=10 Hz), 8.07 (1H, d, J=2 Hz), 8.04 (1H, d, J=5 Hz), 7.52 (1H, dd, J=10 Hz, J=2 Hz), 5.37 (1H, p, J=10 Hz), 3.61 (4H, q, J=5 Hz), 3.17 (2H, t, J=5 Hz), 3.10 (2H, t, J=5 Hz), (3H, s), 2.40 (2H, m), 2.08 (4H, m), 2.06 (3H, s), 1.78 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 456.1, Calculated 456.2.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](O)=[O:8])[C@H:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C1C[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of (+−)-trans-4-methylene-2-phenylcyclopentanoic acid (26 g, 129 mmol) from Step A in THF (600 mL) under nitrogen at −10° C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) in THF (193 mL, 193 mmol). After 16 h at rt, the excess LAH was quenched by dropwise addition of acetone and the reaction was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (20% ethyl acetate in hexanes) to afford the title product (23.8 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]>CN(C)C=O.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)Nc1cnccn1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Temperature: 4 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A solution of (2-methoxy-5-nitrophenyl)-3-pyrazin-2-yl-urea (Compound 159, Example 3) (16.9 g, 55 mmol) in dimethylformamide (DMF, 320 mL) was shaken under H2 in the presence of palladium on carbon (Pd/C) catalyst (1.6 g, 10% Pd) at 80° C. for 12 h. A second portion of catalyst was added (1.6 g) and shaking was continued for an additional 8 h at the same temperature. The solution was filtered through a pad of celite using an additional 200 mL of DMF. The filtrate was concentrated in vacuo and the residue was triturated with methanol (100 mL). The solid was collected, stirred in boiling methanol, and solids present (1.8 g) were filtered off and discarded. The filtrate was cooled at 4° C. overnight. Solids (1.4 g) were removed by filtration and the filtrate was concentrated in vacuo to a tan solid (2.6 g). The crude solid product was triturated with THF (200 mL), collected by filtration, and dried in vacuo to afford the product as a tan solid (1.85 g, 13%). 1H NMR (300 Mhz, d6 DMSO) δ: 10.10 (s, 1H), 9.94 (br s, 1H), 8.89 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.58 (s, 1H), 7.75 (d, 1H), 6.21 (d, 1H), 4.70 (s, 2H), 3.76 (s, 3H). 13C. NMR (75 Mhz, d6-DMSO) δ: 151.4, 149.4, 142.6, 140.9, 139.8, 137.2, 135.2, 128.7, 112.8, 107.7, 106.0, 56.8.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.Cl.[F:28][C:29]([F:38])([F:37])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([C:16]4[CH:19]=[C:20]([C:23]([N:34]5[CH2:33][CH2:32][N:31]([CH2:30][C:29]([F:37])([F:38])[F:28])[CH2:36][CH2:35]5)=[O:25])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12]3)[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: FC(F)(F)CN1CCNCC1
Agent: Cl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)N3CCN(CC(F)(F)F)CC3)ccc1OCC2

Procedure:
Following the procedure for 116, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride to give 124 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1 Hz, 1H); 7.95 (s, 1H); 7.35 (dd, J=8.3, 2.1 Hz, 1H); 7.23 (d, J=8.3 Hz, 1H); 6.88 (s, 1H); 5.73-5.60 (m, 1H); 4.58 (t, J=5.8 Hz, 2H); 3.94-3.44 (br m, 4H); 3.20 (t, J=5.8 Hz, 2H); 3.04 (q, J=9.4 Hz, 2H); 2.74 (br s, 4H); 1.58 (d, J=6.6 Hz, 6H). LCMS: RT=10.93 min, M+H+=490
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.O>[CH3:17][S:18]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:20])=[O:19]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (23 g, 0.099 mol) and TEA (42 mL 0.298 mol) in dry dichloromethane (400 mL) maintained at 0° C. under nitrogen atmosphere, was added methanesulfonylchloride (12.6 g, 0.109 mol) over a period of 20 min. The reaction mixture was stirred at room temperature for 6 h and diluted with water. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtrated and concentrated. The crude product was recrystallized from petrol ether:EtOAc (9:1) to afford the title compound as a solid (27 g, 87% yield). TLC: Rf=0.75 (Chloroform:MeOH; 9:1). 1H NMR (CDCl3, 300 MHz) δ: 2.82 (3H, s), 3.32 (4H, m), 3.79 (4H, m), 6.68) (1H, d, J=9 Hz), 7.68 (1H, d, J=9 Hz), 8.42 (1H, s).
Reaction SMILES: [CH2:1]([S:19][C:20]([CH3:30])([CH3:29])[C:21]([CH2:23][C:24]([O:26]CC)=O)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:31][O:32][C:33]1[C:34]([NH2:39])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:24](=[O:26])[CH2:23][C:21](=[O:22])[C:20]([S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:29])[CH3:30]
Reactant: COc1ccccc1N
Reactant: CCCCCCCCCCCCCCCCCCSC(C)(C)C(=O)CC(=O)OCC
Product: CCCCCCCCCCCCCCCCCCSC(C)(C)C(=O)CC(=O)Nc1ccccc1OC
Yield: 83 %

Procedure:
A mixture of 8.0 g of ethyl (2-n-octadecylthio-2-methylpropionyl)acetate obtained in Step 1 above and 3.2 g of o-anisidine was stirred in an oil bath at 140° C for 3 hours under a reduced pressure of 60 mmHg, and then the excess o-anisidine was removed under a reduced pressure of 1mmHg. The reaction mixture was recrystallized from ethanol to obtain 7.9 g (yield 83%) of Coupler (4) having a melting point of 59° to 61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10](S(C)(=O)=O)=[N:9][C:8]=2[CH2:7]1.[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].CCN(CC)CC.Cl>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([NH:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[N:9][C:8]=2[CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc(CN2Cc3nc(S(C)(=O)=O)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2Cc3nc(NCCNC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 6-(2,4-dimethoxybenzyl)-2-(methylsulfonyl)-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one (0.07 g, 0.149 mmol), tert-butyl 2-aminoethylcarbamate (0.024 g, 0.149 mmol), and Et3N (0.104 mL, 0.747 mmol) in DMA (2 mL) was heated in a sealed tube at 90° C. for 4 h. The reaction mixture was poured slowly onto ice and its pH adjusted to about 7 through addition of 1 N HCl, resulting in precipitation of a tan solid. The solid was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound as a tan brown solid (55 mg, 67%). [M+H] calc'd for C29H36N6O5, 549; found, 549.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>ClCCCl>[C:2]1([CH2:1][NH:8][C:9]2[N:14]=[C:13]([NH:15][C:35]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)=[O:36])[C:12]([C:16]3[NH:17][N:18]=[N:19][N:20]=3)=[CH:11][N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a solution of N2-Benzyl-5-(1H-tetrazol-5-yl)pyrimidine-2,4-diamine (27 mg, 0.1 mmol) in 1 mL of DCE, DIPEA (0.3 mmol, 3.0 eq.) was added followed by thiophene-2-carbonyl chloride (0.15 mmol, 1.5 eq.). The reaction was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated down in vacuo, and the residue redissolved in ethylacetate. This organic solution was extracted several times with water, dried with magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give 4.8 mg of the desired compound. 1H-NMR (400 MHz, d6-DMSO): δ 9.07 (t, 1H), 7.81 (dd, 1H), 7.77 (dd, 1H), 7.36-7.29 (m, 4H), 7.28-7.23 (m, 1H), 7.16 (t, 1H), 4.45 (d, 2H). MS (EI) for C17H14N8OS: 379 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30]N1C(=O)CCC1=O>ClCCl>[Cl:30][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCCCc1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCCc1ccncc1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
3-(4-Pyridyl)-1-propanol (2.68 g, 19.3724 mmol) was dissolved in dichloromethane (100 ml), triphenylphosphine (5.6 g. 21.3096 mmol) was added, and then N-chlorosuccinimide (2.6 g, 19.3724 mmol) was gradually added while cooling on ice prior to stirring overnight. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid. Upon neutralization with saturated bicarbonate water, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2,375 g, 15.2605 mmol, 78.77%) as a yellowish-brown oil. This was used without further purification for the following reaction.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].Br[CH:11]([CH3:15])[C:12](Br)=[O:13].C(N(CC)CC)C>CC(C)=O>[CH3:15][CH:11]1[O:4][C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[O:1][C:12]1=[O:13]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCC(O)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCC1OC(=O)C(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
2.5 g 2-hydroxyhexanoic acid (18.9 mmol) and 2.1 mL 2-bromopropionyl bromide (19.7 mmol) were stirred at 75° C. under nitrogen for 12 h. 150 mL acetone and 5.3 mL anhydrous triethylamine (38 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 300 mL ethyl acetate:hexane mixture (1:2). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.05 (q, 1H), 4.90 (dd, 1H), 1.9-2.15 (br m, 2H), 1.68 (d), 1.65 (d), (3H, of 2 diastereoisomers), 1.3-1.6 (br m, 4H), 0.93 (t, 3H). 13C NMR (500 MHz, CDCl3): δ 167.54, 166.93, 166.25, 165.85, 75.79, 72.50, 72.24, 31.61, 29.70, 26.69, 26.42, 22.19, 21.97, 17.52, 15.81, 13.72, 13.66. ELEM. ANAL. Calcd. for C9H14O4: C, 58.06; H, 7.53. Found: C, 57.62; H, 7.60. Yield: 40%.
Reaction SMILES: [CH:1]1([S:4]([C:7]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[N:13]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])OC4C=CC=CC=4)=[CH:25][CH:24]=3)[N:11]=2)([CH3:9])[CH3:8])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(S(C[C:46]2C=C(N3CCOC[C@@H]3C)N=C(C3C=CC(NC(=O)OC4C=CC=CC=4)=CC=3)[N:47]=2)(=O)=O)CC1>>[CH:1]1([S:4]([C:7]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[N:13]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:47][CH3:46])=[O:38])=[CH:25][CH:24]=3)[N:11]=2)([CH3:8])[CH3:9])(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)cc(C(C)(C)S(=O)(=O)C3CC3)n2)cc1

Procedure:
The following compounds were made in an analogous fashion from either phenyl N-[4-[4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[S:4].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:1][NH:2][C:3]([O:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])=[S:4]
Reactant: CNC(=S)OC[C@@H]1Cc2ccccc2CN1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CNC(=S)OC[C@@H]1Cc2ccccc2CN1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
(S)-3-(N-Methyl-thiocarbamoyloxymethyl) -1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.94 mmol) dissolved in 20 mL dichloromethane was combined with PhNCO (1.0 g) and stirred for 24 h at rt. The reaction mixture was evaporated and the crude product was purified by column-chromatography (SiO2, hexanes:EtOAc=3:2) to provide the product as white solid (1.7 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](OC)=[O:10])[N:4]=1.O.[NH2:16][NH2:17]>CCO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:16][NH2:17])=[O:10])[N:4]=1
Reactant: COC(=O)c1nccc(C(F)(F)F)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nccc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of methyl 4-(trifluoromethyl)pyrimidine-2-carboxylate (500 mg, 2.4 mmol) in EtOH (12 mL) was added hydrazine monohydrate (0.24 mL, 4.9 mmol). After 1 h, the reaction was concentrated to afford the desired product as a white solid (426 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=5.0 Hz, 1H), 9.05 (s, 1H), 7.83 (d, J=5.0 Hz, 1H), 4.25 (br s, 2H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[H-].[Na+].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].C([Li])CCC>C1COCC1>[OH:25][C:24]1[CH2:26][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH3:18])[O:19][C:22](=[O:27])[CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 using 16.9 g (60.9 mmol) of 4-(4-tert-butyldimethylsilyloxyphenyl)-2-butanone (prepared in Example R), 7.32 g (183 mmol) of 60% NaH dispersion in mineral oil, 21.2 g (183 mmol) of methyl acetoacetate, 114 mL (1.64 M, 183 mmol) of n-butyllithium and 360 mL of THF. The reaction mixture was quenched with 0.1N HCl and the product was extracted into EtOAc. The organic layer was dried (MgSO4) and the solvents were evaporated.