Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CO[CH2:26][CH2:27]OC.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:30]1([C:2]2[C:14]([C:15]([CH3:17])([CH3:18])[CH3:16])=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([C:27]5[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=5)=[C:9]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCOC
Reactant: CC(C)(C)c1cc2c(cc1Br)Cc1cc(Br)c(C(C)(C)C)cc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, 8.15 g (18.7 mmol) of 2,7-dibromo-3,6-di-tert-butylfluorene, 1.08 g (0.93 mmol) of Pd(PPh3), and 120 mL of dry 1,2-dimethoxyethane were put into a 300-mL three-necked flask and then stirred at room temperature for 20 minutes. To this solution, 20 mL of a solution of 5.01 g (41.1 mmol) of phenylboronic acid in ethanol was added, the resulting solution was stirred at room temperature for 20 minutes, and then 37.4 mL (74.8 mmol) of an aqueous solution of 2.0-M sodium carbonate was added thereto. Then, the product was heated for 18 hours under reflux, left to stand to cool, and quenched with dilute hydrochloric acid in an ice bath. Ether was added thereto, the soluble part in ether was extracted, and the organic layer was washed twice with an aqueous solution of saturated sodium hydrogen carbonate, further twice with water, and further twice with a saturated salt solution and then dehydrated with magnesium sulfate. The solvent was distilled off, and then the obtained solid was separated by column chromatography to obtain an objective (amount: 4.36 g and yield: 54%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=O)(C)(C)C.S(Cl)([Cl:26])=O.[CH3:28]O>>[ClH:26].[F:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:10]2[C@H:11]([C:14]([O:16][CH3:28])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)[C@H](c2ccc(F)cc2)C1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@H]1CCNC[C@H]1c1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(3R*,4R*)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid (2.00 g, 6.19 mmol, prepared according to the procedure disclosed in WO 02/068387) in MeOH (20 ml) was treated dropwise with thionyl chloride (0.497 ml, 6.80 mmol) at rt. The mixture was stirred at rt for 12 h and then concentrated to afford the title compound. HPLC/MS: 238.0 (M+1); Rt=0.29 min.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=[N:9][C:8]=2[NH2:18])[CH3:3].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=[N:9][C:8]=2[NH2:18])([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 2-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine (Example 36) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-isopropylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.69 (d, 1H), 8.49 (d, 1H), 8.25 (dd, 1H), 7.65 (dd, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 6.02 (bs, 2H), 3.15 (septet, 1H), 1.37 (d, 6H). LRMS [M+H]=238.2.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.O[N:33]1[C:37]2C=CC=[CH:41][C:36]=2N=N1.Cl.C(/N=N/CCCN(C)C)C.N1CCC1>C(Cl)Cl.CO>[N:33]1([C:28](=[O:30])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][C@@H:16]3[CH2:17][C@@H:15]3[CH:12]3[CH2:13][CH2:14][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:8]=4)[CH2:10][CH2:11]3)=[CH:22][CH:23]=2)[CH2:41][CH2:36][CH2:37]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)n1
Agent: C1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(4-(2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetic acid (100 mg, 0.242 mmol), 1-hydroxybenzotriazole hydrate (55 mg, 0.363 mmol), and (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (70.0 mg, 0.363 mmol) were dissolved in CH2Cl2 (4 ml). The mixture was stirred at RT for 5 min. and azetidine (21 mg, 0.363 mmol) was added. The mixture was stirred at RT overnight and loaded directly on Preparative TLC that was developed with 5% MeOH in DCM. The desired product (Rf=0.35 @ 5% MeOH in DCM) was collected to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.20 (d, 2H), 6.90 (d, 2H), 4.05-4.15 (m, 8H), 3.41 (s, 2H), 3.05 (m, 2H), 2.96 (m, 1H), 2.26 (m, 2H), 2.18 (m, 1H), 1.95 (m, 2H), 1.50 (m, 3H), 1.35 (d, 6H), 0.95-1.05 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 453 (M+H)+, GPR119 Human EC50: 1.8 nM.
Reaction SMILES: [C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>C(O)C>[C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(c1ccccc1)O2
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To tert-butyl 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (0.98 g, 2.93 mmol) and NaHCO3 (0.99 g, 11.73 mmol) in ethanol at room temperature was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.82 g, 545 μL, 3.52 mmol) and the reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was cooled, the solid precipitate was removed by filtration and the solvent was removed in vacuo. The residue was taken up in DCM and washed sequentially with 1:1 NaOH(1N): NaHCO3 and then brine. The organics were separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.15 g, 95%). ESI-MS m/z calc. 414.2. Found 415.3 (M+1)+; Retention time: 2.46 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.44-7.26 (m, 5H), 4.81 (dd, J=10.5, 2.6 Hz, 1H), 3.73 (s, 2H), 3.31 (s, 1H), 3.09 (s, 1H), 2.98 (m, 3H), 2.74 (dd, J=11.0, 1.5 Hz, 1H), 2.51 (d, J=14.1 Hz, 1H), 2.40-2.29 (m, 2H), 1.58 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]12[CH2:3][CH2:4][C:5]([C:10]([O:12][CH3:18])=[O:11])([CH2:8][CH2:9]1)[CH2:6][CH2:7]2
Reactant: CO
Reactant: O=C(O)C12CCC(O)(CC1)CC2
Agent: O=S(=O)(O)O
Product: COC(=O)C12CCC(O)(CC1)CC2
Yield: 96 %

Procedure:
To a solution of 4-hydroxybicyclo[2.2.2]octane-1-carboxylic acid (14 g, 82.4 mmol) in methanol (300 mL) was added concentrated sulfuric acid (1 mL). The mixture was refluxed for 10 h and then concentrated. The reside was dissolved in water (100 mL) and the mixture was extracted with ethyl acetate (200 mL×2). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution (100 mL), brine (100 mL) and dried over sodium sulfate. Concentration gave the title compound (14.5 g, yield 96%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (s, 3H), 1.96-1.89 (m, 6H), 1.69-1.64 (m. 6H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.[CH3:12][C:13]([CH3:15])=[O:14]>O>[CH3:1][C@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3]/[CH:4]=[CH:12]/[C:13](=[O:14])[CH3:15]
Reactant: CC(C)=CCC[C@@H](C)CC=O
Reactant: CC(C)=O
Solvent: O
Product: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 4.25 h

Procedure:
To a solution of 25 g (R)-3,7-dimethyl-6-octenal [(R)-citronellal] (chemical purity according to gas chromatography 98.3-98.5%; enantiomeric purity 97-97.6% ee) in 70 ml acetone and 170 ml of water there was added 9.8 g of barium hydroxyde-octahydrate and the mixture was stirred under argon a 68°-69° C. during 4.25 hours. Thereafter, the reaction mixture was cooled to room temperature and extracted two times with 500 ml of n-hexane. The organic phases were combined, washed with 100 ml of water and with 50 ml of 5% aqueous acetic acid, dried over sodium sulfate and concentrated. The so obtained (3E,6R)-6,10-dimethyl-3,9-undecadiene-2-one was 92% chemically pure according to gas chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]([OH:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[CH3:32][C:33](OC(C)=O)=[O:34].[CH3:39][CH2:40][O:41]C(C)=O>>[C:33]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]([OH:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:40](=[O:41])[CH3:39])(=[O:34])[CH3:32]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C(CCCCSCCCCC(C(=O)O)c1ccccc1O)c1ccccc1O
Product: CC(=O)Oc1ccccc1C(CCCCSCCCCC(C(=O)O)c1ccccc1OC(C)=O)C(=O)O

Procedure:
2-Acetoxyphenyl-5-carboxypentyl sulfide (140) was prepared by the acetylation of 135 with Ac2O (FIG. 2Q). The title compound was obtained as a white solid (0.82 g, 87%) upon purification by chromatography on silica gel (EtOAc:hexanes, 20:80, then 40:60). 1H NMR (CDCl3) δ7.35-7.38 (m, 1 H, ArH), 7.19-7.23 (m, 2 H, ArH), 7.03-7.06 (m, 1 H, ArH), 2.85-2.89 (t, 2 H, J=7.1 Hz, CH2), 2.33-2.38 (t merged with a s, 5 H, J=7.2 Hz, CH2 and CH3), 1.60-1.70 (m, 4 H, CH2), 1.44-1.52 (m, 2 H, CH2).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])=[CH2:3].[CH3:10][C:11](=[CH:13][CH2:14][CH2:15][C:16](=[CH:18][CH:19]=O)[CH3:17])[CH3:12]>[O-2].[Zn+2].O>[CH3:3][C:2]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH:8]=[CH:19][CH:18]=[C:16]([CH3:17])[CH2:15][CH2:14][CH:13]=[C:11]([CH3:12])[CH3:10])=[CH2:1]
Reactant: C=C(C)CCCC(C)=O
Reactant: CC(C)=CCCC(C)=CC=O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: C=C(C)CCCC(=O)C=CC=C(C)CCC=C(C)C
Temperature: 160 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of 150 parts of 2-methyl-1-hepten-6-one and 50 parts of citral is heated with 20 parts of zinc oxide in a round flask while stirring for 4 hours at 160° C and atmospheric pressure. Water thus formed is removed by distillation. The fractionation which follows gives 61 parts of 2,10,14-trimethylpentadeca-1,7,9,13-tetraen-6-one having a boiling point of 118° to 120° C at 10116 4 mm. The yield is 88% of theory based on citral, at a conversion of 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][C:23]1[CH:32]=[CH:31][C:26](C(OC)=O)=[CH:25][CH:24]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:26]2[CH:31]=[CH:32][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(3-chlorophenyl)acetic acid (10 g, 58.6 mmol) in THF (58 ml) was added 117 mL of a 1M solution of sodium bis-(trimethylsilyl) amide in THF slowly over 1 h at −78° C. After being stirred at −78° C. for 40 min, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in THF (35 ml) was added over a period of 10 min. The reaction was stirred at −78° C. for 3 h, then allowed to warm to 25° C., and stirred an additional 2 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution and most of the THF was removed under reduced pressure. The residue was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The product was recrystallized from ether/pentane to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]=[CH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:32]([C:35]1[O:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(OCC)(=O)C>[N+:32]([C:35]1[O:39][C:38]([C:40]([O:24][C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([CH:13]=[N:12][NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH:15]=3)[CH:20]=2)=[O:41])=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(NN=Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NN=Cc1ccc2cc(OC(=O)c3ccc([N+](=O)[O-])o3)ccc2c1)OCc1ccccc1

Procedure:
To a solution of 3.2 g of 6-(benzyloxycarbonylaminoiminomethyl)-2-naphthol in 40 ml of ethyl acetate, was added 1.2 g of triethylamine. To the resulting solution, while cooling in ice and stirring, was added 5-nitrofuran-2-carboxylic acid chloride. Thereafter the mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed with water to obtain 4.4 g of 6-(benzyloxycarbonylaminoiminomethyl)-2-naphthyl 5-nitrofuran-2-carboxylate, m.p.: 109°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.C[N:19]1CCOCC1.C(Cl)(=O)OCC(C)C.N[CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:35]1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:1].[CH2:40]([N:36]1[CH2:37][CH2:38][CH:39]([NH:19][C:15]([C:4]2[C:5]3[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=3[CH:14]=[C:2]([Cl:1])[CH:3]=2)=[O:17])[CH2:34][CH2:35]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NC1CCCN(Cc2ccccc2)C1
Reactant: CN1CCOCC1
Reactant: CC1Oc2c(C(=O)O)cc(Cl)cc2N(C)C1=O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1Oc2c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc(Cl)cc2N(C)C1=O
Product: Cl

Procedure:
A solution of 4.0 g of 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 80 ml of tetrahydrofuran is cooled to below 0° C. and 3.17 g of N-methylmorpholine is added under stirring thereto. Further, 2.35 g of isobutyl chlorocarbonate is added and the mixture is stirred at the same temperature for an hour. To the resultant mixture is added 3.28 g of 3-amino-1-benzylpiperidine and the mixture stirred for 4 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ethanol followed by treating with ethanolic hydrochloric acid to give N-(1-benzyl-4-piperidyl)-6-chloro-3,4-dihydro-2,4-dimethyl- 3-oxo-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 214° C. with decomposition.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C1C(=O)N([Cl:21])C(=O)C1.O>CN(C=O)C>[Cl:21][C:13]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cc2c(OC)cccn2n1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn2cccc(OC)c2c1Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 92.1 %

Procedure:
The compound of Example 49 (2.07 g) was dissolved in DMF (60 mL). To this solution, NCS (1.88 g) was added and the mixture was stirred at room temperature for 5.5 hours. Subsequently, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=3:1) afforded the title compound as a gray powder (2.28 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][CH2:27]O)[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.N12CCCN=C1CCCCC2>C(Cl)(Cl)Cl>[O:31]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH:26]=[CH2:27])[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:7]1
Reactant: O=C1O[C@@H](Cn2cc(CCO)nn2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Yield: 73.9 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 51) (142 mg, 0.31 mmol) was suspended in dry chloroform (15 ml), thionylchloride (37 mg, 0.93 mmol) was added and the resulting mixture was refluxed for 12 hours. The solvent and eccess of thionylchloride was removed under vacuum and the residue was dissolved in acetonitrile (15 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (71 mg, 0.47 mmol) was added and the resulting mixture was refluxed for 12 hours. The solvent was removed under vacuum and the residure was purified by flash chromatography on silica gel with 1.5% methanol in dichloromethane to give the title product (100 mg).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:3][S:4][CH3:5].[CH2:18](O)C.C[I:22].[Al]>>[I-:22].[CH2:10]([O:9][C:8]([NH:7][C:2]([CH3:1])([CH3:6])[CH2:3][S+:4]([CH3:18])[CH3:5])=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CSCC(C)(C)NC(=O)OCc1ccccc1
Reactant: CI
Reactant: CCO
Agent: [Al]
Product: C[S+](C)CC(C)(C)NC(=O)OCc1ccccc1
Product: [I-]
Reaction time: 72 h

Procedure:
To a 15 mL pressure tube was added a solution of benzyl 2-methyl-1-(methylthio)propan-2-ylcarbamate in absolute ethanol (0.5 mL, 6.8 M) (1.00 g, 3.9 mmol) and methyl iodide (1.23 mL, 5 equiv, 19.7 mmol). The reaction mixture was covered with aluminum foil and left to stir for 3 days. The light yellow suspension was filtered and washed with diethyl ether (20 mL). The mother liquor was concentrated to a deep yellow solid. This solid was recrystallized from isopropyl alcohol and diethyl ether and combined with the first crop of product 1.29 g (83.6%). 1H NMR (D2O, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI−) for C14H22NO2S+ (268.1); Found: 268 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[N+](C1C=CC([O:28][C:29](=O)[NH:30][C@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=CC=1)([O-])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:37]([Si:34]([CH3:36])([CH3:35])[O:33][CH2:32][C@H:31]([NH:30][C:29](=[O:28])[N:10]([CH2:9][C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)[CH3:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1ccc(N(Cc2cnc(Cl)nc2Cl)C(=O)N[C@H](C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)amine (620 mg, 2.19 mmol) (from Example 38c supra), (R)-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamic acid 4-nitro-phenyl ester (778 mg, 2.19 mmol) (from Example 38b supra) and triethylamine (0.93 mL, 6.6 mmol) (Allied Signal) in toluene (20 mL) was heated at reflux for 48 hours. The reaction mixture was quenched at room temperature with 1 N aqueous hydrochloric acid then extracted with ethyl acetate. The combined organic layers were successively washed with 1 N aqueous sodium hydroxide solution and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give (R)-3-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-1-(2,4-dichloro-pyrimidin-5-yl-methyl)-1-(4-ethyl-phenyl)-urea. (Yield 383 mg, 36%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][N:12]1[N:16]=[C:15]([CH3:17])[O:14][C:13]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][N:12]([NH:16][C:15](=[O:14])[CH3:17])[C:13](=[O:18])[NH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(CC(=O)COCc2ccccc2)c(=O)o1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NN1CC(COCc2ccccc2)=NNC1=O
Temperature: 75 °C

Procedure:
To a solution of 3-(3-benzyloxy-2-oxo-propyl)-5-methyl-1,3,4-oxadiazol-2-one (36.4 g, 139 mmol) in isopropanol (140 mL) was added hydrazine hydrate (62 wt % in water, 11.8 mL, 152 mmol) in at room temperature in one portion. The mixture was heated to 75° C. for 24 h. The volatiles were removed under reduced pressure, and the remaining brown oil was purified by flash chromatography (7% MeOH/dichloromethane) to furnish the desired product as a yellowish solid. 1H NMR (400 MHz, CDCl3) 2.04 (s, 3H), 4.12 (s, 2H), 4.23 (s, 2H), 4.54 (s, 2H), 7.24-7.44 (m, 5H), 8.25 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21](Cl)=[CH:20][N:19]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:34].[K+].C(P(C(C)(C)C)C1(C(C)C)CC(C(C)C)=CC(C(C)C)=C1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:34][C:21]3=[CH:20][N:19]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[CH:17]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(-c3ccc(S(C)(=O)=O)cc3F)ncc2Cl)CC1
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C(C)(C)C)C(C)(C)C)C1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 110 °C

Procedure:
A mixture of 4-[5-chloro-2-(2-fluoro-4-methanesulfonyl-phenyl)-pyridin-4-ylethynyl]-piperidine-1-carboxylic acid tert-butyl ester (208 mg), potassium hydroxide (70 mg), Pd2(dibenzylidenactone)3*CHCl3 complex (10 mg), and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (14 mg) in a mixture of 1,4-dioxane (4 mL) and water (2 mL) is heated under an argon atmosphere in an oil bath at 110° C. for 1 h. The reaction mixture is mixed with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1) to give the title compound. LC (method 7): tR=1.41 min; Mass spectrum (ESI+): m/z=475 [M+H]+.