Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:23])[O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.Cl[CH2:25][CH:26]=O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:23])[O:5][C:6]1[C:7]([NH:19][C:20]2[S:21][CH:25]=[CH:26][N:22]=2)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: O=CCCl
Reactant: COCC(C)Oc1cc(Oc2ccccc2)cnc1NC(N)=S
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1Nc1nccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
[3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiourea (0.2 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.0 eq., 55% in water) is added and stirred three hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine (“A28”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 46%. HPLC (method C): 1.80 min; LC-MS (method A): 1.72 min, 358.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 7.739 (d, 1H, J=2.3 Hz), 7.477 (d, 1H, J=3.9 Hz), 7.421-7.369 (m, 3H), 7.142-7.087 (m, 2H), 7.025 (d, 2H, J=8 Hz), 5.408 (br, 1H), 4.737-4.696 (m, 1H), 3.639 (dd, 1H, J=6.5 Hz, J=10.6 Hz), 3.505 (dd, 1H, J=3.6 Hz, J=10.6 Hz), 3.3 (S, 3H), 1.268 (D, 3H, J=6.4 Hz).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=CCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.63 mL (4.6 mmol) of triethylamine was added and dissolved in a suspension of 0.73 g (4.2 mmol) of ascorbic acid in acetonitrile (9 mL). After the above crude product of (4,8,12-trimethyltridec-3-enyl)tosylate was added at room temperature, the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20].O[CH2:23][C@H:24]1[O:28][C:27](=O)[N:26]([C:30]2[CH:39]=[C:38]3[C:33]([CH:34]=[C:35]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:50])([F:49])[F:48])[NH:36][C:37]3=[O:40])=[CH:32][CH:31]=2)[CH2:25]1.C[O:52]CCOCCOCCOCCOCCO>>[O:52]=[C:18]([O:17][CH2:16][CH:15]([CH2:23][C@@H:24]1[O:28][CH2:27][N:26]([C:30]2[CH:39]=[C:38]3[C:33]([CH:34]=[C:35]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:48])([F:50])[F:49])[NH:36][C:37]3=[O:40])=[CH:32][CH:31]=2)[CH2:25]1)[O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:19]([O-:21])=[O:20].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: COCCOCCOCCOCCOCCO
Agent: COCCOCCOCCOCCOCCOCC(=O)O
Product: COCCOCCOCCOCCOC(COC(=O)C(=O)[O-])C[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)CO1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using [2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]acetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14. However, [2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]acetic acid was synthesized by a method similar to that of Step A of Example 4-39 using pentaethylene glycol monomethyl ether instead of pentaethylene glycol monobenzyl ether.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.[OH-].[K+].CS(O[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=O)=O>CO>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:2]1
Reactant: CS(=O)(=O)OCC1CCCC1
Reactant: Sc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1nc(SCC2CCCC2)n[nH]1
Yield: 95.8 %

Procedure:
1,2,4-Triazole-3-thiol (49.0 g; 0.484 mol) and 86% potassium hydroxide (32.0 g; 0.484 mol) were dissolved in methanol (500 ml) and refluxed for 1 h. The solution was then evaporated to dryness, and the residue redissolved in methanol (500 ml). Cyclopentylmethyl methanesulfonate (86.0 g; 0.484 mol) was added, the solution stirred under reflux for 8 h, and at room temperature overnight. The solution was evaporated and the residue dissolved in ether (500 ml) and water (1 1). The aqueous layer was separated and extracted with another portion of ether (500 ml). The ether solutions were combined, washed with saturated brine (500 ml), dried (MgSO4), filtered and evaporated, to afford cyclopentylmethyl 1,2,4-triazol-3-yl sulfide (85.0 g; 96%) as a waxy, white solid. NMR - d(CDCl3 ; 60 MHz) 1.0-2.4 (10H, m), 3.2 (2H, d, J=7 Hz), 8.1 (1H, s) and 13.4 (1H, br s).
Reaction SMILES: S1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:3][CH2:2]1.O[O:17][S:18]([O-:20])=O.[K+]>CO.O>[O:17]=[S:18]1(=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)SCCC2n1ccnc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCC(n2ccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-thiochroman-4-yl-1H-imidazole, which can be prepared as described in Example 16, (130 mg, 0.60 mmol) in methanol (3 mL) at 0° C. is added dropwise a solution of Oxone® (excess) in water (3 mL). The reaction mixture is stirred overnight at room temperature. The reaction is then concentrated an the resulting residue is purified by silica gel flash chromatography (0:1 to 1:19 methanol-dichloromethane), to afford 1-(1,1-dioxo-thiochroman-4-yl)-1H-imidazole; MS: (ESI) m/z 249.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 2.83-3.13 (m, 2 H), 3.42-3.65 (m, 1 H), 3.64-3.82 (m, 1 H), 6.18 (t, J=7.1 Hz, 1 H), 7.14 (d, J=7.6 Hz, 1 H), 7.49-7.78 (m, 4 H), 8.02 (d, J=8.0 Hz, 1 H), 9.06 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]C)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 7 h
Yield: 46.4 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) and sodium bicarbonate (1.8 g) in water (40 ml) was stirred at 40° to 45° C. for 7 hours. The reaction mixture was adjusted to pH 5.0 with acetic acid. This solution was subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20" (20 ml) and eluted with water. The eluate was acidified to pH 2.2 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g), which was identified by comparing the physico-chemical data with those of the object compound in Example 90.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30]>C1COCC1.CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:29]([CH3:30])[CH3:28])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CNC
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), and dimethylamine (1.24 ml of a 2M solution in THF, 2.48 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by trituration with methanol to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)4-(indol-5-yloxy)-6-methoxyquinazoline (265 mg, 63%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH2:1])[CH2:8][CH2:7]1)=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
50 g (0.318 moles) of trans-4-(aminomethyl)- cyclohexane carboxylic acid, 61.7 g (0.324 moles) p-toluenesulfonic acid, 250 mL (2.4 moles) benzyl alcohol and 250 mL toluene were combined and stirred. The mixture was refluxed for 24 hours and the liberated water was removed azeotropically by means of a Dean-Stark apparatus. A clear solution was obtained after 5 hours of refluxing. The solution was allowed to cool to room temperature. and the product crystallized. The mixture was vacuum filtered, washed with ether and dried in a vacuum oven to give 128.12 g (96% yield.). Reference: Greenstein, Jesse P.; Winitz, Milton. Chemistry of the Amino Acids. vol. 2, (1986), 942. 1H NMR (CD3OD) δ 1.05 (m, 2H), 1.43 (m, 2H), 1.59 (m, 1H), 1.85 (m, 2H), 2.03 (m, 2H), 2.33 (m, 1H), 2.35 (s, 3H), 2.75 (d, 2H), 5.09 (s, 2H), 7.23 (d, 2H), 7.32 (m, 5H), 7.69 (d, 2H). M.P. 154°-156° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][O:23][C:22]1[CH:21]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(OCCO)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OCCO)c1
Yield: 48.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2-(3-aminophenoxy)ethanol in place of the 2,4-difluoroaniline. 180 mg of N-[3-(2-hydroxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>O1CCCC1.C(Cl)Cl>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([NH:1][C:32]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[O:33])[CH:7]=[CH:6][CH:5]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc(-c2cccc(NC(=O)Nc3ccccc3F)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
6-[4-(3-Aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (64 mg) in anhydrous tetrahydrofuran (10 mL) was added to 2-fluorophenyl isocyanate (34 mg) and stirred under an inert atmosphere at ambient temperature for 1 hr. The mixture was diluted with DCM (5 mL) then purified by chromatography on silica eluting with a gradient of 0-50% EtOAc/DCM, then 0-50% MeOH (containing 1% concentrated aqueous amnmonia)/DCM to give the title compound as a solid (76 mg, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([CH:18]2[CH2:20][CH2:19]2)=[C:15]([Cl:17])[CH:16]=1)[C:5]#[N:6].[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:17][C:15]1[CH:16]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[C:28]2[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[N:13][C:14]=1[CH:18]1[CH2:20][CH2:19]1
Reactant: COc1ncccc1B(O)O
Reactant: N#Cc1ccc(Oc2cnc(C3CC3)c(Cl)c2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 75 °C
Yield: 92.3 %

Procedure:
3-bromo-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)benzonitrile (Preparation 38, 485 mg, 1.37 mmol), 2-methoxypyridin-3-ylboronic acid (233 mg, 1.53 mmol) and cesium carbonate were suspended in dioxane (6 mL) and water (3 mL). The suspension was degassed 20 minutes with nitrogen then tetrakis-triphenylphosphinepalladium (80 mg, 0.07 mmol) were added and the reaction mixture was heated overnight at 75° C. The solution was concentrated in vacuo to a quarter of the volume then diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the title compound as a foam (478 mg, 91%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20])[C:14]([NH2:16])=[O:15]>CC(C)=O>[Cl:21][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[C:19]=1[CH3:20])[C:14]([NH2:16])=[O:15]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1c(N)cc(C(N)=O)cc1Cl
Solvent: CC(C)=O
Product: Cc1c(Cl)cc(C(N)=O)cc1Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Cyanuric chloride (65.0 mg, 0.35 mmol) was added to an acetone solution (5 mL) of 3-amino-5-chloro-4-methyl-benzamide (65.0 mg, 0.35 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. Ice was added to the mixture and subsequent filtration yielded of 3-chloro-5-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-4-methyl-benzamide (101.0 mg, 87%) as white solid. MS (m/z) calced for C11H8N5O (MH+), 331: found, 331.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[F-].[K+].[F:12][C:13]([F:17])([F:16])[CH2:14]I.O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:13]([F:17])([F:16])[F:12])=[C:4]([F:9])[CH:3]=1
Reactant: FC(F)(F)CI
Reactant: Oc1ccc(Cl)cc1F
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 4-Chloro-2-fluoro-phenol (521, 5.0 g, 0.034 mol) in methanol (50.0 mL) was added potassium fluoride (2.2 g, 0.038 mol). The solvent was removed. The resulting salt was added to N,N-dimethylformaldehyde (25 mL), followed by adding 1,1,1-trifluoro-2-iodo-ethane (8.60 g, 40.9 mmol). The reaction was stirred at 50° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give colorless oil (522, 2.0 g, 26%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C@H:32]5[CH2:37][O:36][CH2:35][CH2:34][NH:33]5)=[CH:28][CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH2:38]([O:45][CH2:46][CH:47]=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO.C([BH3-])#N.[Na+]>[CH2:38]([O:45][CH2:46][CH2:47][N:33]1[CH2:34][CH2:35][O:36][CH2:37][C@@H:32]1[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:22]2[N:23]=[CH:24][C:19]3[CH:18]=[CH:17][N:16]([C:4]4[CH:3]=[C:2]([F:1])[C:7]([CH2:8][N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[C:6]([F:15])[CH:5]=4)[C:20]=3[N:21]=2)=[CH:27][CH:28]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=CCOCc1ccccc1
Reactant: Fc1cc(-n2ccc3cnc(Nc4ccc([C@H]5COCCN5)cc4)nc32)cc(F)c1CN1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1cc(-n2ccc3cnc(Nc4ccc([C@H]5COCCN5CCOCc5ccccc5)cc4)nc32)cc(F)c1CN1CCOCC1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-((S)-4-morpholin-3-yl-phenyl)-amine (Example 511) with benzyloxyacetaldehyde in methanol and sodium cyanoborohydride at 60° C. HPLC: tR=0.78 min (Method G); MS-ES: (M+H)+=641
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:34])=[O:32]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(=O)(=O)C(F)(F)F)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added Tf2O (203 mg, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 1.5 h then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 to 1:1 hexanes:EtOAc) to yield a colorless oil (312 mg, 82% yield). 1H NMR (CDCl3, 300 MHz): δ 9.39 (brs, 2H), 7.54 (d, J=3.0 Hz, 1H), 7.26 (m, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.08 (brs, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.27 (m, 2H), 1.50 (s, 9H), 1.39 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 160.7, 154.9, 154.3, 133.2, 132.8, 128.1, 113.2, 112.0, 84.7, 79.3, 65.8, 46.7, 40.7, 32.4, 28.5, 28.2; 19F NMR (CDCl3, 282 MHz): δ-75.5 (s).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)=[CH:17][C:16]=3[CH3:31])=[C:11]([CH3:32])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.C>CN(C=O)C.[Pt]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:33]=[CH:34][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:10][C:11]=3[CH3:32])=[C:16]([CH3:31])[CH:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1-c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccc(N)cc2)ccc1-c1ccc(Oc2ccc(N)cc2)cc1C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
4,4'-Bis(4-nitrophenoxy)-2,2'-dimethylbiphenyl (80 g) was dissolved in 350 ml of DMF and added carefully to a hydrogenation bottle containing 8 gm of 5% Pt/C. The solution was subjected to hydrogenation at 100° C. for 3 hours. Then 100 ml of water and 3 g of decolorizing charcoal were added and heated for 5 min. The solution was then filtered through a Celite pad and 1000 ml of water was added. The reaction mixture became a mixture of fluffy solid and a sticky resin and was stirred for 1 hour to give a tan colored solid. The solid was removed by filtration, crushed with a mortar and pestel and then stirred with 1000 ml of water for 1 hour. The solid was collected by filtration and dried to afford 59.2 g (85%) of the product mp=140° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][CH2:19]3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[Br:28]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:28][C:18]1[CH2:19][C:20]2[C:16]([CH:17]=1)=[C:15]([C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[CH:23]=[CH:22][CH:21]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=CC3)cc(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A cold solution (5° C.) of compound 5 (49 g, 161 mmol, 1 equiv), dimethyl sulfoxide (500 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (43 g, 241 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and the mixture extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in toluene (500 mL) and p-toluenesulfonic acid (6.2 g, 32.6 mmol, 0.2 equiv) was added. The mixture was refluxed for 20 hours while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg) eluting with heptanes to give compound 6 (41 g, 66% yield) as a white solid.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:21]=[CH:20][CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:29])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:29][CH:9]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:21]=[CH:20][CH:19]=3)[C:15]=2[CH2:16][CH2:17][NH:8]1
Reactant: [H][H]
Reactant: CC1c2ncnc(-c3ccnn3C3CCCCO3)c2CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1NCCc2c(-c3ccnn3C3CCCCO3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To the product of Example 112, step f (356 mg, 0.91 mmol) in EtOH (9 mL) was added a catalytic amount of 10% Pd/C Degussa type followed by a balloon of hydrogen gas. The mixture was stirred at room temperature overnight. The balloon was refilled with hydrogen gas and an additional spatula tip of 10% Pd/C was added. After an additional 24 h and the reaction was complete. The catalyst was removed by filtration and the liquid was concentrated in vacuo to afford the desired product (268 mg, 98%). MS (ESI) mass calcd. C16H21N5O, 299.2. m/z found 300.2 [M+H]+.