Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][C@@:18]([CH3:24])([C@@H:21]([OH:23])C)[CH2:19][OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1C2C=C(C=O)C3C(=CC=CC=3)C=2C=CC=1.NC(C)(COC)CO>>[ClH:1].[CH3:25][O:20][CH2:19][C:18]([CH3:24])([NH:17][CH2:16][C:13]1[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:15]=3[CH:14]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:21][OH:23]
Reactant: C[C@H](O)[C@@](C)(CO)NCc1cc2ccccc2c2ccccc12
Reactant: O=Cc1cc2ccccc2c2ccccc12
Agent: COCC(C)(N)CO
Agent: Cl
Product: COCC(C)(CO)NCc1cc2ccccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 7G, phenanthrene-9-carbaldehyde (Aldrich) and 2-amino-3-methoxy-2-methyl-1-propanol (9C) gave 3-methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanol hydrochloride mp 211°-213° (dec), (EtOH/Et2O), (C,H,Cl,N).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[O:25][CH3:26])[CH2:14][CH2:13]1)#[N:2].NC1C=CC=CC=1N(C(C1CCCCC1)=O)CCN1CCN([C:51]2C=CC=C[C:52]=2[O:57]C)CC1>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:52](=[O:57])[CH3:51])=[CH:20][C:19]=2[O:25][CH3:26])[CH2:16][CH2:17]1)#[N:2]
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C#N)CC1
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Product: COc1cc(NC(C)=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C#N)CC1
Temperature: 22.5 °C
Reaction time: 17 h

Procedure:
The title compound was synthesized according to the procedure reported in example 28 but substituting the compound of example 79 for the compound of example 27 and stirring at 20-25° C. for 17 h. The usual work-up afforded the title compound. Yield: 49%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>O>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH:20]=[O:21])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CN1CCOc2ccccc21
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCOc2cc(C=O)ccc21
Reaction time: 1.25 h
Yield: 76 %

Procedure:
4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine dissolved in 200 ul DMF under Argon. POCl3 was added under Argon. The reaction was heated and a closed vial at 90° C. for 75 min. 1 ml of NaAc in water was added and stirred while a brown oil was formed. The oil was extracted with DCM. The organic layer was washed with brine, dried and evaporated to dryness, affording 0.18 g (76%) of 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde as colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH2:13][OH:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.ClCCl>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:14][CH2:13][CH2:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=3)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: OCCc1cc2ccc(Br)cc2cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cc3ccc(Br)cc3cn2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The product from Example 52E (0.51 g, 2.0 mmol), tosyl chloride (0.68 g, 3.6 mmol), triethylamine (0.55 g, 5.4 mmol), and DMAP (25 mg, 0.2 mmol) were combined in dichloromethane (20 mL) and stirred at room temperature for 6 hours. The mixture was treated with water (0.5 mL), stirred for 2 hours, and then treated with additional water (15 mL). The organic layer was separated, washed with aqueous sodium chloride solution (10 mL, 10%), evaporated in vacuo, and the residue was azeotroped with heptane (15 mL) to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48](Cl)=[O:49])=[CH:43][CH:42]=1>O>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]3[C:17](=[O:18])[C:16](=[O:19])[C:15]=3[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)=[O:49])=[CH:43][CH:42]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCCNc1c(N[C@@H](Cc2ccc(N)cc2)C(=O)O)c(=O)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1c(N[C@@H](Cc2ccc(NC(=O)Oc3ccc(OC)cc3)cc2)C(=O)O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 1.1 %

Procedure:
To the derivatised resin (5), (120 mg) was added 1,4-dioxan (4.5 ml), DIPEA (0.2 ml, 1.2 mmol), water (0.5 ml) and 4-methoxyphenylchloroformate (0.2 ml, 0.6 mmol). The solution was agitated for 12 h at RT then filtered and washed thoroughly with DCM. The resin was treated with 60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (2 mg).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2O[CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[CH3:14][Si](C=[N+]=[N-])(C)C.CI.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:33][OH:34]>C(Cl)Cl.C(OCC)(=O)C>[CH3:33][O:34][C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][C:6]=1[O:1][C:2](=[CH2:3])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(O)C1COc2ccccc2O1
Reactant: CO
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(Oc1ccccc1OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (1.0 g, 5.6 mmol) in methylene chloride (10 mL) and methanol (10 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane) until yellow color persisted, and the reaction was stirred at room temperature for 15 min. The reaction mixture was concentrated to dryness and azeotroped with toluene. The residue was dissolved in anhydrous tetrahydrofuran (20 mL), and was added methyl iodide (1.8 mL, 28 mmol) and potassium hexamethyldisilazide (0.5 M in toluene, 17 mL, 8.5 mmol) at −78° C. The reaction was allowed to warm to room temperature over 4 h, diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (100 mL) and water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.07 (ddd, 1H), 6.97 (dd, 1H), 6.94 (dd, 1H), 6.85 (ddd, 1H), 5.52 (d, 1H), 4.64 (d, 1H), 3.86 (s, 3H), 3.83 (s, 3H). LC-MS: m/e 231 (M+Na)+ (2.6 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C@:15]([C:28]#[N:29])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni].O>[C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C@:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH2:28][N:29]=2)=[CH:9][C:8]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Alternatively, the title compound can be obtained by carrying out the following experiment: To a vigorously stirred solution of 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (150 mg) in ethanol (9 mL) was added Raney Nickel (1.44 g, 50% suspension in water, previously washed with dry ethanol) and the reaction was stirred at room temperature under hydrogen (1 atm) for 2 hours then under arong overnight. Then the solution was filtered over celite, and the resulting filtrate was concentrated in vacuo to give the title compound (138 mg) as a pale yellow oil. The crude product was purified by flash chromatography (15% dichloromethane in ethyl acetate) to afford 4-[(R)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid tert-butyl ester as a pale yellow oil (0.070 g). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 5.93 minutes (major enantiomer), 8.57 minutes (minor enantiomer).
Reaction SMILES: [N:1](OC(C)(C)C)=O.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([NH:24][CH2:25][C@H:26]([OH:28])[CH3:27])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO.C([O-])(=O)C.[NH4+]>O1CCCC1.[Zn].C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:19]([C:20]([NH2:1])=[N:21][N:24]2[CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:22][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)ON=O
Reactant: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Tert-butyl nitrite (759 mL, 6.38 mol) was added to a stirred solution of (R)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (1), prepared according to the methods described in WO 02/98861 A1 and WO 02/98862 A1 (1.20 kg, 4.25 mol) in 12 L of tetrahydrofuran under an atmosphere of nitrogen. After 1 h, the solution was cooled to 15° C., and 2.6 L of methanol was added followed by 10 L of saturated aqueous ammonium acetate solution. Zinc dust (1.1 kg, 17 mol) was added over 1.5 h, keeping the reaction temperature below 40° C. Ethyl acetate (10 L) was added, and the liquid phase was decanted from the solid residue and combined with that from one additional run on the same scale. The combined liquid phases were partitioned between ethyl acetate and brine. The organic solution was dried (Na2SO4), treated with decolorizing charcoal, filtered and concentrated in vacuo to afford 1976 g (78%) of 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10][Br:11])=[CH:4][CH:3]=1.[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1CCCCC1>[Br-:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10][P+:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCCCC1
Product: Cn1nnnc1C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A slurry of 3,3-bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene (1.95 g, 0.005 mole) [prepared in Example 15, Step D] and triphenylphosphine (1.3 g, 0.005 mole) in cyclohexane (25 mL) was heated to reflux. The reaction mixture became a clear solution after 30 minutes and a white precipitate appeared after 1 hour. The mixture was heated for an additional 8 hours, cooled to ambient temperature and the solid was collected by filtration and washed with diethyl ether. This white powder was dried in vacuum at 50° C. to give 3.0 g (92%) of the title compound; m.p.=254°-255° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:10][CH2:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1cc(C)nc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CCl)cc(F)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 13.6 %

Procedure:
2-Fluoro-4,6-dimethyl-pyridine (4.25 g, 34 mmol) was refluxed with N-chlorosuccinimide (4.99 g, 37.4 mmol) and benzoyl peroxide (822 mg, 3.4 mmol) in carbon tetrachloride (70 ml). After 3.5 hr., the mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:30)) to afford 740 mg (13%) of 4-chloromethyl-2-fluoro-6-methyl-pyridine as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 2.51 (3H, s), 4.51 (2H, s), 6.77 (1H, s), 7.05 (1H, s).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1C=CN=C1)=[S:2].N1CC[O:16][CH2:15]C1>C1COCC1>[N:8]1([C:1](=[S:2])[NH2:3])[CH2:12][CH2:11][O:16][CH2:15][CH2:9]1
Reactant: C1COCCN1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.1 %

Procedure:
To a stirred solution of 1,1′-thiocarbonyldiimidazole (10.0 g, 56.1 mmol) in THF (150 mL) was added morpholine (4.2 g, 4.2 mL, 48.7 mmol). The reaction mixture was then stirred for 72 h at r.t. before it was concentrated in vacuo to 30 mL and NH3 (60.0 mL, 2.0M in MeOH) was added. The reaction mixture was stirred at r.t. in a sealed flask for 18 h, filtered and the resultant solid washed with Et2O to give the title compound (2.0 g, 28%) as a white solid that was used without further purification. δH (DMSO-d6) 7.46 (2H, br. s), 3.82-3.61 (4H, m), 3.60-3.53 (4H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:38][CH2:39]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCC(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 4-(2,4-difluorophenyl)piperidine (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as an eluent to give 7-(2-(4-(2,4-difluorophenyl)piperidin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=463.98). 1H NMR (DMSO-d6, 400 MHz), δ 1.68 (m, 4H), 2.12 (m, 2H), 2.55 (m, 1H), 2.73 (t, 2H, J=6.0 Hz), 3.04 (m, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 7.09 (m, 1H), 7.18 (m, 2H), 7.26 (m, 1H), 7.33 (m, 1H), 7.49 (br s, 2H, NH2), 7.91 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethylamine (46 mg, 0.17 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (44 mg, 0.18 mmol) and DIPEA (86 μL, 0.50 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 60 h. After cooling to RT, the resulting mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 260 as a pale yellow solid (48 mg, 73%). LCMS (Method K): RT 3.04 min [M+H]+ 393.02. 1H NMR (DMSO-d6, 400 MHz): δ 8.63 (1H, s), 8.56 (1H, s), 8.14-8.05 (2H, m), 8.03-7.93 (2H, m), 7.72 (1H, dd, J=8.80, 4.85 Hz), 7.12 (1H, ddd, J=9.86, 8.79, 2.51 Hz), 7.05 (1H, dd, J=8.96, 2.48 Hz), 5.60 (1H, s), 1.65 (3H, d, J=6.80 Hz)
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:9]=1[N:10]([CH3:12])[CH3:11]>>[ClH:3].[Cl:5][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17][Cl:3])=[CH:13][C:9]=1[N:10]([CH3:12])[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1cc(CO)ccc1CO
Agent: Cl
Product: CN(C)c1cc(CCl)ccc1CCl
Yield: 77 %

Procedure:
Thionyl chloride (35 ml) was added to 2 grams (0.00919 mol) of 2,5-bis(hydroxymethyl)-N,N-dimethylaniline hydrochloride, VIII. The 2,5-bis(hydroxymethyl)-N,N-dimethylaniline hydrochloride (VIII) went into solution immediately, accompanied by evolution of heat and gas. The reaction was stirred for several minutes. The volatiles were removed under reduced pressure to yield 2.38 g of crystalline residue, compound IX. The solid IX was dissolved in a minimum amount of hot acetonitrile; the solution was filtered, and an equivalent amount of ethyl acetate added and the solution cooled. Yield 77%. Elemental analysis: calcd for C10H14Cl3N: C, 47.18; H, 5.54: Cl, 41.78,; N, 5.50. Found: C,47.04; H, 5.54; N, 5.34
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][C@H:35]1[CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH:35]([OH:34])[CH2:36][CH:37]5[C:40]([OH:42])=[O:41])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: OC1CCNC1
Product: O=C(O)C1CC(O)CN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with trans-4-hydroxy-L-proline. A yellow solid 131 was obtained (0.017 g, 33%). 1H-NMR(CDCl3,400 MHz)62.42–2.51 (m, 1H),3.66–3.72(m, 1H), 3.85–3.91 (m, 1H), 4.00–4.06 (m, 1H), 4.28–4.34 (m, 4H), 4.64–4.69 (m, 1H), 4.89–4.95 (m, 1H), 6.81 (s, 1H), 6.92–6.96 (m, 2H), 7.03 (dd, J=1.8 Hz, 8.4 Hz, 1H), 7.06–7.10 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.92–7.96 (m, 1H); MS (APCI) m/z 519 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=[C:4]([CH:14]=O)[CH:3]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].O.CCOC(C)=O>C1COCC1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH3:16][C:17]([S@:20](/[N:22]=[CH:14]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1)=[O:21])([CH3:19])[CH3:18]
Reactant: Cc1cc(C=O)ncc1OCC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A mixture of 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde (1.6 g, 7.3 mmol, Step-5), (R)-2-methylpropane-2-sulfinamide (1.33 g, 11.0 mmol), and titanium tetraethoxide (2.50 g, 11.0 mmol) in THF (30 mL) is refluxed with stirring for 2 hours. After cooling to 0° C., water (30 mL) and EtOAc (80 mL) are added to the mixture, and this is filtered through a pad of Celite. The filtrate is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.14 g (48% yield) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)=[O:22])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CCCC3=O)cc1
Yield: 92 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with p-anisoyl chloride (90 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (135 mg, 0.46 mmol, 92% yield) as a white powder after purification by flash chromatography on silica gel (eluent: EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].O>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cccnc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-pyridinol (5 g) in THF (100 ml) at 0° was added sodium hydride (1 g, 80% suspension in oil). The mixture was stirred under nitrogen for 30 min and methyl bromoacetate (3.26 ml) was added dropwise. The mixture was then heated under reflux for 2 h, poured into water (300 ml) and extracted with ethyl acetate (2×250 ml). The combined organic extracts were dried and concentrated to give a solid which was triturated with ether to give the title compound as a white solid (4.5 g), m.p. 63°-64° C.