Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:22][C:9]2[C:10]([C:17]([O:19][CH2:20]C)=[O:18])=[CH:11][NH:12][CH2:13][C:14]([CH3:16])([CH3:15])[C:8]=2[CH:7]=1)=[O:5])C.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](Cl)=[O:28]>>[CH3:1][O:3][C:4]([C:6]1[NH:22][C:9]2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:12]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([F:33])=[C:24]([F:23])[CH:25]=3)[CH2:13][C:14]([CH3:16])([CH3:15])[C:8]=2[CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=O)C1=CNCC(C)(C)c2cc(C(=O)OCC)[nH]c21
Product: COC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2cc(C(=O)OC)[nH]c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid diethyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 11.11 (1H, s), 7.83 (1H, s), 7.48 (1H, m), 7.36 (1H, m), 6.87 (1H, d), 4.33 (2H, q), 4.24 (2H, q), 3.89 (2H, s), 1.36 (3H, t), 1.33 (6H, s), 1.22 (3H, t). MS (ES): 447 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=S(=O)(Cl)c1cccnc1
Yield: 91.9 %

Procedure:
3-Pyridylsulfonic acid (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole), suspended in 150 mL toluene and heated to reflux overnight. The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 30.7 g (92%) of 23-10 as a yellow oil, which was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:6]5[CH2:5][CH2:4][O:3][C:2]5=[O:1])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:31]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(CN2CCOC2=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCOC3=O)cc2)CC1
Yield: 42.3 %

Procedure:
Using 4-(2-oxooxazolidin-3-ylmethyl)benzoic acid (133 mg) described in Preparation Example 62 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (107 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][OH:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)c1cc(Br)ccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[5-Bromo-2-(hydroxymethyl)phenyl]propan-2-ol (1.1 g, 4.4 mmol) and imidazole (0.78 g, 12 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.86 g, 5.7 mmol) was added, followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with hexane, and subsequently the extract was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to afford the title compound (1.1 g, 3.1 mmol) as a colorless oil (yield 70%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]5[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=5)=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCc1ccc(-n2c(-c3ccc(C4CCCCC4)cc3)nc3cccnc32)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1
Yield: 42.6 %

Procedure:
4-[2-(4-Cyclohexylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.37 g, 0.93 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.377 g, 0.93 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.317 g, 0.396 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:6]([CH3:26])=[N:7][C:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[N:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:6]([CH3:26])=[N:7][C:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)=[N:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nc(Cc2ccc(N)cc2)nc1N1CCCC1
Reaction time: 1 h

Procedure:
To a solution of methyl[4-methyl-2-(4-nitrobenzyl)-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate (0.074 g, 0.20 mmol) in anhydrous THF (2 mL) was added Pd/C (10% Pd, 0.050 g) and the resulting black suspension was stirred under an atmosphere of hydrogen. After 1 hour; the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give methyl[2-(4-aminobenzyl)-4-methyl-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)C.Cl.[NH2:20][OH:21]>C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=[N:20][OH:21])[CH2:11][CH2:10]1
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: ON=C1CCC(c2ccc(O)cc2O)CC1
Yield: 98.7 %

Procedure:
To a round bottomed flask, equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (100 mg, 0.49 mmol), anhydrous ethanol (5 ml), triethylamine (102 ml) and hydroxylamine hydrochloride (51 mg, 0.73 mmol). The reaction mixture was heated under reflux for 3 hr, then evaporated in vacuo. The resulting solid was purified by flash column chromatography, (SiO2, ethyl acetate/petroleum ether, 35:65, v/v), furnishing the title compound as short white needles (107 mg, 100%). δH (CD3OD) 1.44-1.61 (2H, m), 1.81-1.88 (1H, m), 1.94-2.00 (2H, m), 2.19-2.27 (1H, m), 2.43 (1H, d), 3.04-3.10 (1H, m), 3.38 (1H, m), 6.22-6.25 (1H, m), 6.28 (1H, d), 6.84-6.86 (1H, m); m/z (EI−) 220.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13]>>[C:1]1([CH:7]([O:13][CH2:12][C:11]([F:15])([F:14])[F:10])[CH2:9][OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC(F)(F)F
Reactant: c1ccc([C@H]2CO2)cc1
Product: OCC(OCC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
Into a 25-mL round-bottom flask was placed (2S)-2-phenyloxirane (1 g, 8.32 mmol, 1.00 equiv), 2,2,2-trifluoroethan-1-ol (5 mL) and bis[(trifluoromethane)sulfonyloxy]alumanyl trifluoromethanesulfonate (197 mg, 0.42 mmol, 0.05 equiv). The resulting solution was stirred for 2 h at room temperature. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 410 mg (22%) of 2-phenyl-2-(2,2,2-trifluoroethoxy)ethan-1-ol as a colorless oil.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].S(=O)(=O)(O)[OH:11].[N+]([O-])([O-])=O.[Na+].[Cl-].[Na+]>O>[OH:11][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](O)C(=O)O

Procedure:
L-Leu-OH (10.0 g) was dissolved in water (150 ml) containing concentrated sulfuric acid (3.2 ml) at 0° C. To the solution was added dropwise a solution of sodium nitrate (7.9 g) in water (50 ml) over 1 hour. The mixture was saturated with sodium chloride and extracted with ethyl acetate (500 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual solid was triturated with hexane to give (2S)-2-hydroxy-4-methylvaleric acid (6.51 g).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[CH:12][C:7]=2[C:6](=[O:24])[NH:5][CH2:4][C:3]1=[O:25].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C=O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:12][C:7]=2[C:6](=[O:24])[N:5]([CH2:30][C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:4][C:3]1=[O:25]
Reactant: ClCc1ncccn1
Reactant: CN1C(=O)CNC(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(Cc2ncccn2)C(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Reaction time: 0.83 h
Yield: 7.7 %

Procedure:
1-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (22.9 mg, 0.065 mmol) and NaH (15.6 mg, 0.650 mmol, 10.0 equiv.) were placed in a 0.5-2 mL Smith process vial. To the vial was added DMF (0.5 mL) followed by 2-(chloromethyl)pyrimidine hydrochloride (53.9 mg, 0.327 mmol, 5 equiv.) was added at room temperature. After stirring for 50 min, reaction was quenched with AcOH. Resulting mixture was filtered and purified via preparative reverse phase HPLC to give the title compound (2.2 mg) as a clear yellow film.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[CH:8][C:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:18]([Cl:17])=[O:20])=[CH:16][CH:15]=1)=[O:12]
Reactant: CCCCCNc1ccc(C(=O)OC)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Cl)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Yield: 275.2 %

Procedure:
A solution of methyl 4-pentylaminobenzoate (43) (200 mg, 0.91 mmole) in 5 mL of THF was treated with 95 mg of triphosgene (0.35 eq.), stirred at reflux for three hours, then poured onto 50 mL ice-water and extracted with three portions of 50 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 250 mg of 4-methoxycarbonylphenyl-pentyl-carbamoyl chloride (45) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([NH2:11])[N:3]=1.Cl.[CH3:13]O>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[CH:5]=[C:4]([NH2:11])[N:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)nc(N)n1
Agent: Cl
Product: COC(=O)c1cc(N)nc(N)n1
Yield: 100 %

Procedure:
2,6-diamino pyrimidine-4-carboxylic acid (G. D. Davies, F. Baiocchi, R. K. Robins and C. C. Cheng, J. Org Chem 26 (1961) 2755-2759) was esterified with HCl/MeOH using the procedure of Preparation 4, step (a) in 100% yield. 1HNMR δ(DMSO) 3.90(3H,s), 6.72 (1H,s), 8.57 (broad), 8.93 (broad).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]3[N:16]=[CH:17][C:18](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1)#[CH:21]>>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([C:20]#[C:21][C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][OH:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[CH:23][CH:24]=1
Reactant: OCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from [5-(4-chloro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-7-yl]-methanol (example C.14 step 2) (193 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (111 mg, 59%). MS (ISP) 376.4 [(M+H)+]; mp 215-217° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:19]=[C:18]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:17]=[C:18]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH:19]=[C:20]([C:22]#[CH:23])[CH:21]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CN2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(CN2CCCC2)cc(C(Nc2ccc(C#N)cc2)C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.6 %

Procedure:
130 mg of the ethyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilanylethynyl-phenyl)-acetate described in Example 156.4 were dissolved in 2 ml of THF and treated at 0° C. with 0.43 ml of a 1 molar solution of tetrabutylammonium fluoride in THF. After 5 hrs. at 0° C. water was added to the reaction mixture and an intermediate was extracted with ethyl acetate. This intermediate was treated at 0° C. in 5 ml of MeOH with 31 mg of sodium cyanoborohydride. Then, the pH was adjusted to 6 with methanolic HCl and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then made basic with methanolic KHCO3 and, after removal of the solvent in a vacuum, the residue was purified by column chromatography (CH2Cl2/methanol). There were obtained 27 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-ethynyl-5-pyrrolidin-1-ylmethyl-phenyl)-acetate as a light yellow solid; MS: 374 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15]>>[OH:16][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCCCO
Product: O=Cc1ccccc1C#CCCCCO
Yield: 59.4 %

Procedure:
Using the procedure of example 5 and starting with 11.1 g (60 mmol) of 2-bromobenzaldehyde and 7.62 g (77 mol) of 5-hexyn-1-ol, 2-(6-hydroxy-1-hexynyl)benzaldehyde was obtained in 59.4% yield, as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].[CH3:38][NH:39][CH3:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:39]([CH3:40])[CH3:38])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(CN(C)C)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (0.102 g, 0.203 mmol) and dimethylamine (0.044 g, 2M 0.507 mL, 1.01 mmol) in dichloroethane (3 mL), acetic acid (0.073 g, 1.021 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.129 g, 0.609 mmol) was added at 0° C. and reaction stirred for 4 h at room temperature. On completion, solvent was removed under reduced pressure and water was added, extraction was carried out using 10% MeOH/DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure giving crude material which was purified by column chromatography to afford the title compound (0.08 g, 75%). LCMS: 532.30 (M+1)+; HPLC: 97.53% (@254 nm) (Rt; 3.878; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (d, 1H, J=1.2 Hz), 8.20 (t, 1H, J=4.8 Hz), 8.02 (d, 1H, J=6.4 Hz), 7.49 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 5.87 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.81-3.84 (m, 2H), 3.56 (s, 2H), 3.22-3.24 (m, 2H), 3.02-3.12 (m, 3H), 2.25 (s, 3H), 2.21 (s, 6H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.50-1.56 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: CCc1ccc(Br)cc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
To a mixture of lead tetraacetate (13.7 g, 31.00 mmol) and mercuric diacetate (0.47 g, 1.50 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (42 ml). This mixture is warmed to 40° C., and 5-bromo-2-ethylphenylboronic acid (6.50 g, 28.00 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is then allowed to cool to room temperature, followed by further cooling to 0° C. then addition of powdered anhydrous potassium carbonate (3.22 g) with rapid stirring for 5 minutes then filtration. The filtrate is concentrated to half its volume, followed by the addition of hexanes to induce precipitation. This mixture is further concentrated, the solvent decanted, and the solid washed with hexanes to afford 5-bromo-2-ethylphenyllead triacetate (10.69 g) as a sandy coloured solid.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([OH:20])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:11]=[C:10]([O:9][CH3:3])[CH:19]=[C:18]([OH:20])[CH:17]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc(O)cc(OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl iodide (6.44 mL, 104 mmol), K2CO3 (28.8 g, 208.15 mmol), and methyl 3,5-dihydroxybenzoate (17.5 g, 64 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.51 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J=4.80, 2.27 Hz, 2 H) 6.63 (t, J=2.27 Hz, 1 H) 5.36 (s, 1H) 3.92 (s, 3 H) 3.83 (s, 3 H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[C:10](=[O:18])[NH:9]1)=O)(C)(C)C.[CH:19]1([C:22]2[CH:23]=[C:24]([NH:27][C:28]3[N:33]=[C:32](Cl)[N:31]=[C:30]([Cl:35])[N:29]=3)[NH:25][N:26]=2)[CH2:21][CH2:20]1>C(O)CCC>[Cl:35][C:30]1[N:29]=[C:28]([NH:27][C:24]2[NH:25][N:26]=[C:22]([CH:19]3[CH2:21][CH2:20]3)[CH:23]=2)[N:33]=[C:32]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([C:10](=[O:18])[NH:9][NH:8]3)=[CH:12][CH:13]=2)[N:31]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(Nc3nc(Cl)nc(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (69 mg, 0.277 mmol) and (5-Cyclopropyl-2H-pyrazol-3-yl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine (50 mg, 0.184 mmol) were taken into 1 ml of n-butanol and stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and the resulting white solid residue dissolved in dichloromethane-trifluoro acetic acid (1:1 mixture, 2 ml. After 3 hours, the solvent was evaporated in vacuo and the crude product purified by prep HPLC to afford 15 mg of the desired product as a white solid (16.4% yield). H-NMR(DMSO-d6, 500 mHz) δ 11.11(m, 1H), 10.41(s, 1H), 10.29(s, 1H), 7.11–7.82(m, 3H), 6.04(s, 1H), 1.84(m, 1H), 0.89(m, 2H), 0.60(m, 2H). MS (ES+): m/e=384.0 (M+H), 382.0 (M−H); LC/Method A/3.891 min, 98.0% purity by area %.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O.O>[F:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(-c2ncccn2)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(F)cc1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a room temperature solution of 2-(3,5-difluoro-phenyl)-pyrimidine (1.2 g, 6.24 mmole) in H2SO4 (3 mL) was added 90% HNO3 (0.375 mL, 9.37 mmoles) over 10 seconds via syringe. The resulting mixture was stirred at room temperature for 1 hour then poured into ice. The resulting heterogeneous mixture was then diluted with water, warmed to room temperature, and filtered. The solids were washed with water and dried in vacuo to afford the title compound (1.53 g, 100%) as a tan solid. 1H NMR (dmso-d6, 500 MHz): 8.92 (d, 2H); 8.67 (m, 1H); 7.94 (m, 1H); 7.65 (dd, 1H).
Reaction SMILES: [H][H].[N+]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]#[N:18])([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[CH:16]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=[CH:15][C:6]=2[NH:18][CH:17]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2c(c1)ccc1[nH]ccc12

Procedure:
At ambient temperature and under 4 bars of hydrogen, hydrogenate 33 g of (2-nitro-1-naphthyl)acetonitrile (0.155 mol) dissolved in 630 ml of ethanol containing 10% water and 6.3 ml of pure acetic acid, using 19 g of 10% palladium-on-carbon. After absorption has ceased, filter off the catalyst, concentrate the solvent in vacuo and then take up the residue in 250 ml of dichloromethane; wash the organic phase with 100 ml of 0.1N potassium hydroxide solution and then dry the organic phase over magnesium sulphate, filter and concentrate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl>>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][CH:2]1[CH2:3][O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH2:7]1
Reactant: COc1ccccc1CCl
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COC1COC(c2ccccc2)OC1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
5-Hydroxy-2-phenyl-1,3-dioxane (8.4 g, 0.05 mole) was reacted with sodium hydride and 2-methoxybenzyl chloride (7.8 g, 0.05 mol) according to the method of Example 2, except that the mixture was heated at 100° C for 12 hours, to give 11.7 g of yellow oil. The oil was distilled under 1 × 10-5 mm to give 4.6 g of product, which distilled at a pot temperature of 180°-190° C. VPC analysis of the product showed it to contain 72% cis-5-(2methoxybenzyloxy)-2-phenyl-1,3-dioxane.