Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>>[C:35]([Si:32]([CH3:34])([CH3:33])[O:31][CH2:30][CH2:29][N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Yield: 500 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a colorless oil (500%).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=O.[NH2:27][C:28]([NH2:30])=[O:29].Cl>CCO>[O:29]=[C:28]1[NH:30][CH:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:27]1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(C(=O)O)cc2)N1
Temperature: 85 °C
Reaction time: 72 h
Yield: 1.6 %

Procedure:
To a solution of 1,2-diphenylethanone (392 mg, 2.0 mmol), 4-formylbenzoic acid (274 mg, 1.8 mmol) and urea (324 mg, 5.4 mmol) in EtOH (40 mL) was added concentrated HCl (0.17 mL). The mixture was stirred at 85° C. for 3 days. The volatiles were removed under reduced pressure and standard aqueous/EtOAc workup procedure was followed. Purification by inverse-phase column to afford Compound 90 as a tan powder (11 mg, 2%). 1H NMR (MeOH-d4 500 MHz TMS): δ 7.99 (d, J=7.0 Hz, 2H), 7.47 (d, J=7.0 Hz, 2H), 7.25 (s, 5H), 7.03 (s, 3H), 6.85 (s, 2H), 5.40 (s, 1H); MS (ESI): m/z 371.0 [M+1]+.
Reaction SMILES: C=O.[C:3](O)(=O)C.[C:7]([BH3-])#[N:8].[Na+].N[C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[C:16]3[NH:23][CH:24]=[CH:25][C:15]=3[C:14]=2[CH:13]=1.[CH2:26]([C:28]([O-:30])=[O:29])[CH3:27]>C(O)C>[CH3:3][N:8]([CH3:7])[C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[C:16]3[NH:23][CH:24]=[CH:25][C:15]=3[C:14]=2[CH:13]=1.[CH2:26]([C:28]([O-:30])=[O:29])[CH3:27]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: C=O
Agent: CCC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 4.8 %

Procedure:
33 μL (0.41 mmol) of a 37% aqueous solution of formaldehyde, 20 μL (0.35 mmol) of acetic acid and 26 mg (0.41 mmol) of sodium cyanoborohydride are added to 100 mg (0.37 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) suspended in 1.2 ml of ethanol. The mixture is stirred for 6 hours at room temperature then 33 μL (0.41 mmol) of a 37% aqueous solution of formaldehyde, 20 μL (0.35 mmol) of acetic acid and 7 mg (0.11 mmol) of sodium cyanoborohydride are added again. The reaction mixture is stirred overnight at room temperature. The solvents are evaporated and the residue obtained is purified by preparative LCMS to give 5 mg (5%) of 8-dimethylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([CH2:12]O)[CH:11]=2)[C:5]([CH3:8])=[CH:6][N:7]=1.S(Cl)([Cl:16])=O>>[ClH:16].[Cl:16][CH2:12][C:10]1[CH:11]=[C:3]2[C:2]([CH3:1])=[N:7][CH:6]=[C:5]([CH3:8])[N:4]2[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncc(C)n2nc(CO)cc12
Product: Cc1ncc(C)n2nc(CCl)cc12
Product: Cl
Yield: 100 %

Procedure:
A solution of (4,7-dimethylpyrazolo[1,5-a]pyrazin-2-yl)methanol (41 mg, 0.23 mmol) in thionyl chloride (2 mL) was stirred at room temperature for 5 min. The mixture was concentrated to dryness to give 53 mg (100% yield) of the title compound as a yellow solid. ESI MS: m/z 196.1 [M+H]+.
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4](=[O:18])[NH:3]1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28]C(=N)N.FC(F)(F)C1C=CC(C2C=CC(CN)=CC=2)=CC=1.CC(N1CCC(=O)CC1)(C)C(OC)=O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][C:2]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4](=[O:18])[N:3]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2cccnc21
Reactant: N=C(N)CCc1ccc(F)cc1F
Agent: COC(=O)C(C)(C)N1CCC(=O)CC1
Agent: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CCOC(=O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Temperature: 25 °C

Procedure:
A mixture of ethyl (2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)acetate (WO 02/30911, Intermediate B52) (40.8 g, 1.2 equiv) and 3-(2,4-difluorophenyl)propanimidamide (made by methods analogous to those described for the 2,3-difluoro isomer, Intermediates A1 to A3 of WO 02/30911) (30.0 g, 1 equiv) was fused in a 150° C. oil bath for 25 min, then cooled quickly to room temperature in a water bath. Chromatography (silica, crude product loaded in DCM and eluted with 50-100% ethyl acetate in hexane) gave the desired product (43.56 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[ClH:12].O1CCOCC1.C(=O)([O-])[O-].[NH4+:23].[NH4+]>C(O)C>[ClH:12].[C:6]([C:5]1[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[NH:23])[NH2:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-methoxy-4-hydroxybenzonitrile (2.0 g, 13.4 mmol) were added ethanol (3 mL) and 4N hydrochloric acid/1,4-dioxane (27 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (50 mL). Ammonium carbonate (6.4 g, 67 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added and the mixture was freeze-dried to give the title compound (1.82 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:21]Br.N>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[C:5]([Br:21])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1nccc(NCC2(CO)CCC2)n1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Br)c(NCC2(CO)CCC2)n1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To 2-amino-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (0.21 g, 1.0 mmol) was added acetic acid (3 ml) and the mixture was heated to 110° C. Sodium acetate 3 hydrate (0.18 g) was added and bromine (60 μl) dissolved in acetic acid (0.5 ml) was dropwise added at 70° C. After cooling, water was added to the reaction mixture and the mixture was neutralized with aqueous ammonia under ice-cooling, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was recrystallized from acetone to give colorless prism crystals (0.21 g, 72.4%), m.p. 156-158° C. (acetone).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[ClH:1].[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH:34][C:2]3[C:3]4[CH:11]=[C:10]([C:12]5[O:13][C:14]([CH3:17])=[N:15][N:16]=5)[N:9]=[CH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:31][CH:32]=2)[CH:27]=[N:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1
Product: Cc1nnc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Product: Cl

Procedure:
4-Chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl) pyrido[3,4-d]pyrimidine (0.02 g) was reacted with 1-benzylindazol-5-ylamine according to Procedure A to give the title compound as a yellow solid; δH [2H6]DMSO 11.50(1H,s), 9.55(1H,s), 9.43(1H,s), 8.95(1H,s), 8.34(2H,m),7.91(1H,d) 7.83(1H,dd),7.40(5H,m), 5.80(2H,s), 2.75 (3H,s); m/z (M+1+) 435.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)(=[O:25])=[O:24])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cc(OC)cc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
To a mixed solution of ethyl 7-amino-5-methoxy-1H-indole-2-carboxylate (0.40 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.38 g) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85-35:65), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (370 mg, yield 57%) as colorless needle crystals. melting point 158-159° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([CH3:20])[CH:13]=1.[SH:21][C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24]>C(#N)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[S:21][C:22]([CH3:27])([CH3:26])[C:23](=[O:24])[NH:9][C:7]3[N:6]([CH3:10])[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[C:8]2=3)=[C:14]([CH3:20])[CH:13]=1
Reactant: Cn1nc(C2CC2)cc1N
Reactant: CC(C)(S)C(=O)O
Reactant: Cc1cc(Cl)ccc1C=O
Solvent: CC#N
Product: Cc1cc(Cl)ccc1C1SC(C)(C)C(=O)Nc2c1c(C1CC1)nn2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
A mixture of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (3 g, 22 mmol, Fluorochem), 4-chloro-2-methylbenzaldehyde (3.1 g, 22 mmol, Fluorochem), and 2-mercapto-2-methylpropanoic acid (3.5 g, 33 mmol, Chemwish) was heated, in a sealed microwave vessel, for about 60 min, at about 80° C. Subsequently, the reaction mixture was heated, for about 24 h, at about 150° C. After cooling to rt, acetonitrile (20 mL) was added and the reaction mixture was stirred for about 2 h, at about 40° C. After cooling to about 0° C., the precipitated solid was collected by filtration and washed with acetonitrile (2 mL) to afford 4-(4-chloro-2-methyl-phenyl)-3-cyclopropyl-1,6,6-trimethyl-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one as white solid (1.25 g, 3.3 mmol, 15%). 1H-NMR (CDCl3, Bruker 400 MHz) δ 0.30-0.39 (1H, s); 0.46-0.67 (3H, m); 0.83-0.93 (1H, m); 1.50 (3H, s); 1.66 (3H, s); 2.48 (3H, s); 3.75 (3H, s); 5.58 (1H, s); 7.09 (1H, dd, J=8.5, 2.5 Hz); 7.14 (1H, d, J=2.5 Hz); 7.21 (1H, d, J=8.5 Hz); H, m); 8.65 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[C:23](=[O:26])([O-])[O-:24].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([N:20]3[CH:21]=[C:14]4[C:5]([CH:4]=[C:17]5[O:26][CH2:23][O:24][C:16]5=[CH:15]4)=[CH:6]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C2c3c(C)c(-n4cc5cc6c(cc5c4)OCO6)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (799.8 mg, 2.73 mmol) in tetrahydrofuran (30 ml) were added 5,6-bis(chloromethyl)-1,3-benzodioxazole (603.8 mg, 2.76 mmol), sodium carbonate (877.8 mg, 8.28 mmol), and tetrabutylammonium iodide (506.8 mg, 1.37 mmol) and the mixture was refluxed with heating for 23 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with isopropyl ether. The combined extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain 136.8 mg (11% yield) of the title compound. Melting point: 236-242° C. (Ethyl acetate)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:17].C[Si]([C:22]#[N:23])(C)C>CO>[NH2:17][CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:22]#[N:23]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: N
Reactant: C[Si](C)(C)C#N
Solvent: CO
Product: N#CC(N)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a stirred solution of 3-benzyloxybenzaldehyde (2.12 g, 10 mmol) in a 7N ammonia solution in methanol (50 mL) at 0° C. was added trimethylsilyl cyanide (1.11 mL, 15 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min, warmed to 45° C. for 18 h and concentrated to dryness. The crude material was purified by silica gel column chromatography, eluting with 0-100% dichloromethane/10% methanol in dichloromethane, to afford the title compound (1.26 g, 53%) as a thick orange oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[C:23]([F:32])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1>>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[C:23]([F:32])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:35][CH:36]=1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(C)(CO)O3)cc1F
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and 2-amino-5-methyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.57 (dd, J=8.46, 1.89 Hz, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.13 (s, 1 H) 7.10 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.71 (dd, J=10.61, 2.27 Hz, 1 H) 3.70-3.77 (m, 1 H) 3.57-3.66 (m, 1 H) 3.19 (d, J=16.67 Hz, 1 H) 3.13 (s, 3 H) 2.98 (d, J=1.52 Hz, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.31 (s, 3H) 1.46 (s, 3 H); LCMS for C26H26FN3O5 m/z 480.00 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16].O>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOCC1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of tetrahydro-4H-pyran-4-ol (408 mg, 102 mmol) and pyridine (632 mg, 19.1 mmol) in 15 mL of CH2Cl2 was added p-nitrophenyl chloroformate (968 mg, 102 mmol). The mixture was stirred at rt for 30 h. Water was added and the organic layer was separated, and washed with 5% aq. citric acid. The organic layer was treated with an aq. solution of ammonia (NH4OH/H2O: ¼ v/v) for 15 min. The organic layer was separated, washed with aq. sodium bicarbonate and brine. After the solvent was removed, the desire product was isolated as a solid. 1H NMR (CD3Cl, 400 MHz) δ 1.80 (m, 2H), 2.00 (m, 2H), 3.52 (m, 2H), 3.92 (m, 2H), 4.88 (m, 1H), 7.32 (d, J=7 Hz, 2H), 8.21 (d, J=7 Hz, 2H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][CH:19]([CH3:21])[CH2:20][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: CC(C)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCC(C)C
Reaction time: 0.33 h

Procedure:
In 250 ml three necked flask, equipped with reflux condenser, mechanical stirrer, 30.4 g (200 mmol) of vanillin, 28 g (200 mmol) of dry K2CO3 and 150 ml of abs. dimethylformamide are placed in the flow of argon. The mixture is stirred for 20 min in argon condition, then 34.3 g (250 mmol) of isobutyl bromide is added. The mixture is refluxed with stirring in argon condition for 20 h at 90÷100° C., and concentrated in vacuum at 50÷80° C. to dryness. Then 200 ml of water is added to the residue, the mixture is extracted with (4×100 ml) of dichloromethane. The combined organic fraction is washed with 7% NaOH solution, dried over magnesium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (15 g of brown oil)-crude 4-(2-methylpropyloxy)-3-methoxybenzaldehyde is used on the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:37]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C:4]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:1][CH2:2][OH:37])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (obtained as described in Example 111) in THF-H2O (1:1, 20 mL) were added NaIO4 (1.0148 g, 4.74 mmol, 5 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.1708 g, 0.0167 mmol, 0.018 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and NaBH4 (0.200 g) was added. After the mixture was stirred for 1 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][C@H:38]1[CH2:40][O:39]1>C(O)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:37][C@@H:38]([OH:39])[CH3:40])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: C[C@H]1CO1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.032 mmol, from Example 67, Step 1) and triethylamine (18 μL, 0.13 mmol) in ethanol (0.53 mL) was added (S)-(−)-methyloxirane (6.8 μL, 0.097 mmol). The resulting mixture was heated at 90° C. for 3 h, then purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The enantiomers were separated on a Phenomenex Lux Cellulose C-4 column (5 μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, to give two enantiomers. First peak (2.7 mg, 18%) retention time 8.9 min; LCMS calculated for C21H27ClFN6O2 (M+H)+: m/z=449.2; Found: 449.1. 1H NMR (DMSO-d6, 500 MHz) δ 8.11 (1H, s), 7.42 (1H, d, J=8.5 Hz), 7.25 (2H, br s), 6.21 (1H, q, J=7.5 Hz), 4.28 (1H, d, J=4.0 Hz), 3.82 (3H, m), 3.62 (3H, s), 3.55 (1H, m), 3.05 (1H, m), 2.97 (1H, m), 2.55 (3H, s), 2.28 (2H, m), 1.70 (2H, d, J=7.5 Hz), 1.00 (3H, d, J=6.0 Hz) ppm. Second peak retention time 10.0 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][N:3]=1.[Br:21]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([Br:21])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(N)c2)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(N)ncc2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A flask was charged with ethyl 3-(2-aminopyridin-4-yloxy)-4-chlorobenzoate (5.50 g, 18.8 mmol) and acetic acid (50 mL), and bromine (0.943 ml, 18.4 mmol) was added. The reaction was stirred at ambient temperature for 30 minutes and then concentrated. The residue was purified by silica gel column chromatography, eluting with 20%-35% ethyl acetate in hexanes to give the desired product (4.20 g, 58.9% yield) as light yellow solid.