Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26]C[CH2:28][CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN3[C@H](C[O:52]CC3=O)C2)C1.C([BH3-])#N.[Na+]>C(O)C.CO.[Cl-].[Zn+2].[Cl-]>[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C@H:21]([CH2:28][O:52][CH2:26][C:25]3=[O:29])[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8]
Reactant: O=C1COC[C@@H]2CN(C3CNC3)CCN12
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCN3C(=O)COC[C@@H]3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 100 mg, 0.22 mmol) and (9aS)-8-azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (see Method 12; ˜0.20 mmol) in ethanol (20 mL) was added a solution of sodium cyano borohydride (125 mg, 2.0 mmol) and zinc chloride (135 mg, 0.99 mmol) in methanol (10 mL). The reaction mixture was stirred at RT for 10 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in a mixture of acetonitrile (10 mL), acetic acid (100 mg) and water (20 mL). The product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate. The proper fractions were combined and concentrated on a rotavapor. The aqueous residue was extracted with ethyl acetate and the organic solution was dried over Na2SO4. The solvent was removed by evaporation. There was obtained 80 mg (55%) of the title compound. 1H NMR (400 MHz, CDCl3): 0.9-3.8 (cm, 21.5H), 3.9 (d, 1H), 4.1-4.2 (qt, 2H), 4.4 (b, 0.5H), 4.5-4.6 (d, 1H), 6.6-7.5 (cm, 6H), 7.8 (s, 1H); LCMS: m/z 642 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].[OH:24]O.[OH-].[Na+].O>CS(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]([NH2:6])=[O:24]
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound (158a) (0.100 g) was dissolved in DMSO (1.2 mL). A hydrogen peroxide solution (30 wt %) (0.053 mL) and a 4 mol % aqueous sodium hydroxide solution (0.233 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (158b) (0.090 g).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[NH:25][C:26]([NH:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)=[C:27]([F:32])[C:28](=[N:30][NH2:31])[N:29]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.CCOCC>[Cl:23][C:24]1[N:29]=[C:28]([NH:30][NH:31][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:32])=[C:26]([NH:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[N:25]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: NN=c1nc(Cl)[nH]c(NC2CCC2)c1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCC2)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To a stirred solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.282 g, 0.92 mmol), 2-chloro-6-(cyclobutylamino)-5-fluoro-4(1H)-pyrimidinone hydrazone (0.225 g), HOAt (0.132 g, 0.97 mmol) and NMM (0.53 mL, 4.85 mmol) in DMF (5 mL) was added EDC (0.186 g, 0.97 mmol) and the reaction was stirred overnight. The mixture was diluted with ether, washed with water, and the aqueous layer was back extracted with ether. The organics were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by RP-HPLC to provide [(2R)-3-{2-[2-chloro-6-(cyclobutylamino)-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a brown oil (0.055 g). LCMS: (M+H)+=519.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]([C:25]([O:27]CC)=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:24]([C:25]([OH:27])=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CC)S(C)(=O)=O)c(OCc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Temperature: 45 °C

Procedure:
Ethyl 5-(benzyloxy)-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.15 g, 0.29 mmol, 1 eq) was dissolved in ethanol. Then sodium hydroxide (0.035 g, 1.17 mmol, 3 eq) was added, followed by the addition of water (1 ml). The reaction was warmed to 45° C. for 14 h. The solution was concentrated and diluted with water and the pH of the reaction was brought to 3 using Conc.HCl. The solid precipitated was filtered and dried under vacuum. Yield: 0.12 g (86%). 1HNMR (400 MHz, DMSO-d6): δ 1.06-1.10 (t, J=7.14 Hz, 3H), 3.01 (s, 3H), 3.62 (m, 2H), 5.34 (s, 2H), 7.27 (t, J=8.9 Hz, 2H), 7.32-7.46 (m, 4H), 7.56 (d, J=7.0 Hz, 2H), 7.63 (s, 1H), 7.80 (t, J=4.77 Hz, 2H), 8.98 (s, 1H). LCMS: (ES+) m/z=484.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 53.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), (R)-3-pyrrolidinol (47 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl) phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 6 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 14a (90 mg, yield 53%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH3:12][CH:13]1[O:17][CH2:16][CH:15]([CH2:18]Cl)[O:14]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[CH3:12][CH:13]1[O:17][CH2:16][CH:15]([CH2:18][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])[O:14]1.[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1OCC(CCl)O1
Agent: CC(C)(C)c1ccccc1N
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Product: CC1OCC(CNc2ccccc2C(C)(C)C)O1

Procedure:
2-t-Butylaniline (0.3 mole), 2-methyl-5-chloromethyl-1,3-dioxolane (0.3 mole), potassium carbonate (0.3 mole) and tetraethylammonium chloride (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of 48 hours. After this time the mixture is filtered to yield the desired product N-2-methyl-1,3-dioxolan-5-ylmethyl)-2-t-butylaniline.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[O:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:27]5[O:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(C(F)(F)F)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)o4)cc3=O)cc21
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg) and (5-(trifluoromethyl)-2-furyl)methanol (462 mg) in THF (40 ml) were added tributylphosphine (1.06 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.08 g) at 60° C., and the mixture was stirred for 3 h. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). Then the resulting solid was recrystallized from EtOH-hexane to give the title compound (313 mg) as an off-white solid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH:13]1([C:19]2[C:27]3[C:22](=[CH:23][C:24](C(O)=O)=[CH:25][CH:26]=3)[N:21]([CH3:31])[C:20]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH2:39][C:40]([N:42]([CH3:54])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][N:48]([CH3:53])[S:49](=[O:52])(=[O:51])[NH2:50])=[O:41])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[CH:13]1([C:19]2[C:27]3[C:22](=[CH:23][C:24]([C:1]([N:8]4[CH:12]=[CH:11][N:10]=[CH:9]4)=[O:2])=[CH:25][CH:26]=3)[N:21]([CH3:31])[C:20]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH2:39][C:40]([N:42]([CH3:54])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][N:48]([CH3:53])[S:49](=[O:52])(=[O:51])[NH2:50])=[O:41])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Solvent: CC#N
Product: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)n3ccnc3)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Carbonyldiimidazole (405 mg, 2.50 mmol) was added to a stirred solution of intermediate 8 (300 mg, 0.50 mmol) in dry acetonitrile (CH3CN) (25 mL). The reaction mixture was stirred at room temperature for 1 h, upon which complete conversion was observed. The resulting solution was evaporated and the residue was purified by silica flash chromatography (gradient AcOEt/CH3CN 1:0 to 0:1) to yield 315 mg (97%) of 2-{2-[3-cyclohexyl-6-(1H-imidazol-1-ylcarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}-N-methyl-N-(2-{2-[methyl(sulfamoyl)amino]ethoxy}ethyl)acetamide 9 as a white powder: m/z=651 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:17][S:18]C(=O)C)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C>O.N>[OH:4][CH2:5][CH:6]([CH2:17][SH:18])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)OCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CO)CS
Reaction time: 1 h

Procedure:
1-[2-acetoxymethyl-3-(acetylthio)propanoyl]-L-proline (1.5 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonia (12 ml.) under a blanket of argon. After one hour, the reaction mixture is concentrated to ca. dryness, diluted with water and the solution applied to a column of cation exchange resin (Dowex 50) in the hydrogen cycle. The water eluate is concentrated to small volume and freeze dried to yield 1-(2-hydroxymethyl-3-mercaptopropanoyl)-L-proline.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@H:23]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH:21]([O:44][Si](C(C)(C)C)(C)C)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@H:23]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:22][CH:21]([OH:44])[CH2:20]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(O[Si](C)(C)C(C)(C)C)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=C1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a suspension of Example 19G (1.05 g, 1.43 mmol)) in ethanol (8 mL) was added concentrated HCl (104 μL, 1.28 mmol) in ethanol (2 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction was poured into 1M NaHCO3 (35 mL) and extracted with tert-butyl methyl ether ( 3×35 mL). The combined organics were washed with brine (35 mL), dried over Na2SO4 and concentrated in vacuo to an oil. The crude material was purified by silica gel chromatography (5% ethyl acetate/hexane) then dried in vacuo at room temperature for one week to afford the titled compound (0.74 g, 83%) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (s, 9 H) 1.02 (s, 9 H) 1.60-1.85 (m, 4 H) 2.46 (s, 1 H) 3.96-4.06 (m, 1 H) 4.63 (dd, J=6.79, 4.05 Hz, 1 H) 4.74 (t, J=5.35 Hz, 1 H) 4.85 (s, 1 H) 4.91 (s, 1 H) 7.27-7.45 (m, 12 H) 7.56-7.67 (m, 8 H); 13C NMR (100 MHz, CDCl3) δ 19.5, 19.6, 27.2, 27.3, 44.6, 67.0, 70.4, 107.9, 127.21, 127.24, 127.3, 129.33, 129.35, 129.5, 132.6, 133.2, 133.4, 133.9, 135.44, 135.48, 135.54, 135.6, 149.9; HRMS (ESI) [MNa+] calcd for C39H48O3Si2 643.3034, found 643.3022; Anal. calcd for C39H48O3Si2: C 75.43, H 7.79. Found: C 75.50, H 7.97.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].C1COCC1.[OH:12][CH2:13][CH2:14][C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20].C(Br)C=C>O>[CH2:3]([O:12][CH2:13][CH2:14][C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20])[CH:2]=[CH2:1]
Reactant: Cc1ncsc1CCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCCc1scnc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
An oven-dried 100 mL round bottom flask was charged with t-BuOK (20.8 mmol), dry THF (25 mL), purged with argon and cooled to 0° C. in an ice bath. 5-(2-Hydroxyethyl)-4-methylthiazole (16 mmol) was then added dropwise to the solution and the reaction stirred at 0° C. for 1 h under argon. Allyl bromide (20.8 mmol) was added dropwise, and the solution was warmed to R.T. and allowed to stir for 20 h under argon. Deionized water (4 mL) was then added and the reaction stirred for 10 min. All liquid were then removed in vacuo and the residue redissolved in ethyl acetate (50 mL). The organic phase was washed three times with water (20 mL), dried over Na2SO4, filtered over Celite, and then concentrated in vacuo to yield a yellow oil (96%). 1HNMR (400 MHz, CDCl3): δ=8.52 (s, 1H), 5.89 (m, 1H), 5.23 (dd, 1H, 3JHHtrans=17.4 Hz, 2JHHgems=1.8 Hz), 5.13 (dd, 1H, 3JHHcis=10.3 Hz, 2JHHgems=1.6 Hz), 3.96 (dt, 2H, 3JHH=5.7 Hz, 4JHH=1.4 Hz), 3.57 (t, 2H, 3JHH=6.9 Hz), 2.99 (t, 2H, 3JHH=6.9 Hz), 2.37 (s, 3H) ppm. 13CNMR (400 MHz, CDCl3): δ=149.6, 149.2, 134.5, 127.9, 17.0, 71.9, 70.0, 27.0, 14.9 ppm. HRMS-ESI: Calculated [M+H]+: 184.0791. found: 184.0787.
Reaction SMILES: C[O:2][C:3](=[O:5])[O-].[CH3:6][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[C:3]([O-:2])(=[O:5])[CH3:6].[CH3:6][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[O-]
Agent: C[n+]1ccccc1
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
By following the same procedure as Example 6 except that 10.0 g of N-methylpyridinium methyl carbonate obtained in the 1st step of Example 4 and 3.1 g of acetic acid were used, 8.7 g (yield of 75.4% of pyridine) of N-methylpyridinium acetate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:12])[C:9]([OH:11])=[O:10])=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][C:9](=[O:11])[C:8]([CH3:12])([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(C(C)(NC(=O)c2cccc(Cl)c2)C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C2(C)N=C(c3cccc(Cl)c3)OC2=O)cc1
Yield: 80.3 %

Procedure:
3.17 g (0.01M) of 2-(m-chlorobenzamido)-2-(p-tolyl)propionic acid was dissolved in 30 ml of acetic anhydride and the resulting solution was heated for 1 hr with reflux. The reaction solution was cooled and distilled out acetic anhydride in vacuo. The residue was subjected to chromatography, to give 2.4 g of the object compound, pure oily compound: 80 % Yield.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCC[C@H]1CO)(OCC1C=CC=CC=1)=O>>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O

Procedure:
(S)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (S)-N-Boc prolinol (Fluka) according to the conditions described by M. G. B. Drew et al., J. Chem. Soc. Perkin 1, 1998, 1627, for the oxidation of CBZ-prolinol.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:18])=[N:5][C:6]([O:16][CH3:17])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:8]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[C:6]([O:16][CH3:17])=[N:5][C:4]([CH3:18])=[C:3]([CH2:2][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: c1nc[nH]n1
Reactant: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1nc(C)c(Cn2cncn2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3-(chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine (Intermediate 8, 87 mg, 0.31 mmol), in acetone (12 mL), was added 1H-1,2,4-triazole (32 mg, 0.46 mmol), and cesium carbonate (150 mg, 0.63 mmol). The reaction mixture stirred at room temperature for 2 h, then filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 0-100%, EtOAc/hexanes) afforded the title compound (82.4 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 7.45-7.37 (m, 2H), 7.37-7.29 (m, 2H), 5.34 (s, 2H), 3.98 (s, 3H), 2.52 (s, 3H). [M+H]=315.22.
Reaction SMILES: CC1(C)OCC(C2C=CC3C(=CC=C(OC4C=CC(OC5C=CC=CC=5)=CC=4)C=3)C=2)(N)CO1.[CH2:34]([O:41][C:42]1[CH:69]=[CH:68][C:45]([O:46][C:47]2[CH:48]=[C:49]3[C:54](=[CH:55][CH:56]=2)[CH:53]=[C:52]([C:57]2([N+:65]([O-])=O)[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59][CH2:58]2)[CH:51]=[CH:50]3)=[CH:44][CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][C:42]1[CH:69]=[CH:68][C:45]([O:46][C:47]2[CH:48]=[C:49]3[C:54](=[CH:55][CH:56]=2)[CH:53]=[C:52]([C:57]2([NH2:65])[CH2:58][O:59][C:60]([CH3:64])([CH3:63])[O:61][CH2:62]2)[CH:51]=[CH:50]3)=[CH:44][CH:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1(C)OCC(c2ccc3cc(Oc4ccc(OCc5ccccc5)cc4)ccc3c2)([N+](=O)[O-])CO1
Agent: CC1(C)OCC(N)(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)CO1
Product: CC1(C)OCC(N)(c2ccc3cc(Oc4ccc(OCc5ccccc5)cc4)ccc3c2)CO1
Yield: 81 %

Procedure:
5-(6-(4-(benzyloxy)phenoxy)naphthalen-2-yl)-2,2-dimethyl-1,3-dioxan-5-amine was synthesized as per 2,2-dimethyl-5-(6-(4-phenoxyphenoxy)naphthalen-2-yl)-1,3-dioxan-5-amine (Example 344) in 81% yield using 5-(6-(4-(benzyloxy)phenoxy)naphthalen-2-yl)-2,2-dimethyl-5-nitro-1,3-dioxane as starting material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:19][O:18][CH2:17][CH2:16][N:15]3[C:26](=[O:29])[C:27]=2[OH:28])=[O:11])=[C:4]([N:30]2[CH:34]=[N:33][C:32]([CH2:35][OH:36])=[N:31]2)[CH:3]=1.[CH2:37](N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:19][O:18][CH2:17][CH2:16][N:15]3[C:26](=[O:29])[C:27]=2[OH:28])=[O:11])=[C:4]([N:30]2[CH:34]=[N:33][C:32]([CH2:35][O:36][CH3:37])=[N:31]2)[CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1-n1cnc(CO)n1)c1nc2n(c(=O)c1O)CCOCC21CCOCC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COCc1ncn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2O)CCOCC32CCOCC2)n1
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
N-((4-fluoro-2-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)phenyl)methyl)-3′-hydroxy-4′-oxo-2,3,5,6,6′,7′-hexahydro-4′H-spiro[pyran-4,10′-pyrimido[1,2-d][1,4]oxazepine]-2′-carboxamide (190 mg, 0.32 mmol) was dissolved in 3 mL CH2Cl2 under N2 and treated with 100 mg triethylamine followed by mesylchloride (46 mg, 0.4 mmol) in 0.5 mL CH2Cl2. This was stirred for 30 min and then washed with dilute HCl. The crude product was purified by column chromatography on silica, eluted with EtOAc to give 170 mg of a clear gum. This was dissolved in 30 mL MeOH and heated at 70° C. in a sealed flask for 18 hrs and then concentrated. The residue was stirred with 5 mL TFA for 30 min and concentrated. The residue gave 45 mg of white crystals from 95%-EtOH. (Yield=34%) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.50 (s, 3H) 3.55-4.13 (m, 14H) 4.50 (d, J=5.80 Hz, 2H) 4.63 (s, 2H) 7.06-7.28 (m, 2H) 7.69 (dd, J=8.55, 5.80 Hz, 1H) 8.36 (t, J=6.87 Hz, 1H) 8.40 (s, 1H) 12.10 (s, 1H); HRMS (M+H) calcd for C24H27FN6O6: 515.2054; found: 515.2032.