Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=[O:2].[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=2)[N:8]=[C:7]([CH3:26])[CH:6]=1>O1CCOCC1>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:18][CH2:17]3)[CH:13]=2)[N:8]=[C:7]([CH:26]=[O:2])[CH:6]=1
Reactant: Cc1cc(Br)c2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(Br)c3c2)CC1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
To a suspension of Selenium dioxide (0.333 g, 3.00 mmol) in 1,4-Dioxane (8.0 mL) was added a solution of 4-Bromo-6-(4-tert-butyl-cyclohexyloxy)-2-methyl-quinoline (0.469 g, 1.25 mmol) in 1,4-Dioxane (4.0 mL). The mixture was sealed and was heated at 50° C. in an oil bath. After 4 d, the reaction was filtered through Celite and washed with dioxane. The solvent was evaporated and the residue was purified on silica gel column using 0-25% ethyl acetate in hexanes as eluent. Isolated was the product (Rf=0.68 in 3:1 hexanes/ethyl acetate) in 362 mg yield, 74%. ESI (M+H+): 390.10/392.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH:26]=[CH:27][CH:28]=3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.88 g, 4.54 mmol) in acetonitrile (20 mL) was added cesium carbonate (4.43 g, 13.61 mmol) and tert-butyl 3-(bromomethyl)phenylcarbamate (1.298 g, 4.54 mmol). The reaction was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The aqueous phase was extracted with CHCl3. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by (0-100% ethyl acetate:hexanes) to afford the title compound (1.06 g, 2.65 mmol, 59% yield) as a colorless oil. LCMS, [M+H]+=400.3.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C([O:8][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=2[F:26])=[C:15]([CH3:27])[N:14]2[N:28]=[CH:29][CH:30]=[C:13]2[N:12]=1)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:2]([O:4][NH:5][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=2[F:26])=[C:15]([CH3:27])[N:14]2[N:28]=[CH:29][CH:30]=[C:13]2[N:12]=1)=[O:8])[CH3:3]
Reactant: CCOC(=O)c1nc2ccnn2c(C)c1Nc1ccc(SC)cc1F
Reactant: CCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCONC(=O)c1nc2ccnn2c(C)c1Nc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
O-Ethyl-hydroxylamine HCl salt (2.50 equivalents) is added to a solution of 6-(2-fluoro-4-methylsulfanyl-phenylamino)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethyl ester (1.00 equivalent) in THF. The solution is cooled to 0° C. and lithium bis(trimethylsilyl)amide (6.00 equivalents, 1.0 M solution in hexanes) is added dropwise. The reaction mixture is warmed to room temperature. After stirring for 1 hour, the reaction is quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer is re-extracted with EtOAc. The combined organic extracts is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].Cl.[CH:21](=[NH:30])OCC1C=CC=CC=1.[OH-].[Na+].Cl>>[CH:21]([N:17]1[CH2:18][CH2:19][CH:15]([C:7]2[CH2:6][C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:16]1)=[NH:30]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNC3)C[C@H]12
Reactant: N=COCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCN(C=N)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(pyrrolidin-3-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (250 mg) was added benzyl formimidate hydrochloride (0.48 g) at 0° C. while adjusting pH to 8.5 with 30% aqueous sodium hydroxide solution. After 30 minutes at the same temperature, the solution was adjusted to pH 6.5 with 1N hydrochloric acid, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) eluting with 3% aqueous isopropyl alcohol. The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-(1-formimidoylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (120 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([OH:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:23])[C:7]=2[F:24])[CH2:3][CH2:2]1.O[CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:28][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:26])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:23])[C:7]=2[F:24])[CH2:2][CH2:3]1
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-ol (1.37 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.07 g) and triphenylphosphine (1.61 g) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3.23 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.18 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1)(=[O:24])=[O:23]
Reactant: OCc1cc(-c2ccccn2)no1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2ccccn2)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-hydroxymethyl-isoxazol-3-yl)-pyridine (4.0 gm), and triethylamine (6.5 ml) in dichloromethane (40 ml) was added methanesulfonyl chloride (2.8 ml) at 0° C. The reaction mixture was stirred at 0° C. over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (40 ml×2). Combined organic layer was washed with aqueous sodium bicarbonate solution followed by water and evaporated under vacuum to provide the title compound in 5.1 gm quantity (84%) as a semisolid, which was used without purification for the next reaction.
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N#N.[ClH:13]>C1CCCCC1>[CH:1]1([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC1CCc2ccccc21
Reactant: Cl
Agent: N#N
Solvent: C1CCCCC1
Product: ClC1CCc2ccccc21

Procedure:
20 g Indanone (obtained according to Example VIII) is added to a solution of 1.5 molequivalent NaAlH2 (OC2H4OCH3)2 in a mixture of benzene and ether in the course of which the temperature raises to 35° C. Then the reaction mixture is stirred during one hour, poured out into ice and extracted with ether. The solution in ether is washed with NaCl solution, dried and evaporated. The residue is distilled under diminished pressure yielding 15.1 g indanol. B.p. 115° C./1 mm Hg. The indanol is dissolved in 100 ml cyclohexane and during 30 min. gaseous HCl is introduced followed by N2 to remove the excess of HCl. The reaction mixture is evaporated and the residue is distilled under diminished pressure yielding 12.9 g indanyl chloride. B.p. 95° C./1 mm Hg.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3CC(C)(C)C([O-])=O)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:34]C(C)=O.CCCCCC>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([OH:34])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(Cc1cccc2nc(C#Cc3ccccc3)ccc12)C(=O)[O-]
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1cccc2nc(C#Cc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(Phenylethynyl)quinoline-5-ylpivalate (15.4 mg, 0.0468 mmol) was dissolved in THF (0.78 mL), followed by cooling down to 0° C. After LiAlH4 (0.06 mL, 0.117 mmol) was added thereto, the resulting mixture was warmed to room temperature and stirred for 1 hr. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:1). When the reaction was completed, a saturated aqueous solution was added thereto, and the resulting mixture was extracted with diethylether, to thereby obtain an organic layer. The organic layer was dried over anhydrous MgSO4 and filtrated. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:1, R.f: 0.7), to thereby obtain 2-(phenylethynyl)quinoline-5-ol (5.6 mg, 49%) as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>ClCCl>[S:13]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[N:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:28]=[N:27][N:26]=1)([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCOc1nnnn1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2nnnn2-c2ccccc2)cc1
Reaction time: 6 h
Yield: 54 %

Procedure:
0.5 g of pyridine and 0.31 g of p-toluenesulfonyl chloride were added to a solution of 0.4 g of the compound obtained in Example 1a in dichloromethane (10 ml) and the mixture was stirred for 6 hours. The organic layer was washed with 10% aqueous citric acid and then with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.35 g of the title compound (yield: 54%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([CH2:14][OH:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][CH:11]2[O:10][C:9]3[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.9 g, 3.7 mmol), p-toluenesulfonyl chloride (1.0 g, 5.5 mmol), TEA (0.76 ml, 5.5 mmol) and 4-DMAP (0.4 g, 3.7 mmol) in DCM (20 ml) was stirred at room temperature for 1 h and 30 min. The solution was diluted with DCM and washed with HCl (1 N), water and brine. The organic phase was dried and concentrated to give the title compound (1.1 g). MS m/z (rel. intensity, 70 eV) 398 (M+, 51), 226 (bp), 225 (23), 213 (30), 91 (62).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]1([NH:26][CH2:27][C:28]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][C:28]([CH2:27][NH:26][CH:23]5[CH2:24][CH2:25]5)([OH:33])[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: OC1(CNC2CC2)CCNC1
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)(CNC4CC4)C3)c(F)cc2c1=O

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 6 with 3-cyclopropylaminomethyl-3-hydroxypyrrolidine dihydrochloride to give 1-cyclopropyl-7-(3-cyclopropylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 161°-162° (with decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][Cl:22])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(OCCCCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-(4-phenylbutoxy)benzyl alcohol (556 mg, 2.17 mmol) in chloroform (10 ml) was added with thionyl chloride (0.288 ml) and left under stirring at room temperature for 24 h, then evaporated to dryness under reduced pressure to obtain 595 mg of the title compound (quantitative yield).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:42]1[CH2:41][CH2:40][N:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH2:44][CH2:43]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(C3CCN(C)CC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(1-methylpiperidin-4-yl)piperazine (85 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 615 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=O)[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[S:26])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Oc1cccc2c1CCCC(=O)N2
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cccc2c1CCCC(=S)N2
Yield: 135.5 %

Procedure:
A suspension of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-one (50 mg, 0.23 mmol) and Lawesson reagent (65 mg, 0.16 mmol) in 3 mL of toluene was refluxed for about 1 h. The residue obtained after evaporation of the solvent was chromatographed on silica gel PTLC (5% MeOH--CH2Cl2) to give 51 mg (94%) of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-thione; MS 235.
Reaction SMILES: [CH2:1]([C@@H:5]([C:11]([OH:13])=[O:12])[C@H:6]([OH:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]1C=CC(S(O)(=O)=O)=C[CH:20]=1>COC(OC)(C)C.C(Cl)Cl>[CH3:14][C:15]1([CH3:20])[O:8][C:7](=[O:9])[CH:6]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11]([OH:13])=[O:12])[O:10]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,3R)-3-(n-butyl)-2-hydroxysuccinic acid B-4 (300 mg, 1.58 mmol) in 2,2-dimethoxypropane (10 mL) is added p-TSA (20 mg) and the reaction is stirred at rt for 16 hours. The solution is diluted with DCM and washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O1CCCC1.C([Li])CCC.[C:19](=[O:21])=[O:20].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:8])=[CH:4][N:3]=1)[C:19]([OH:21])=[O:20]
Reactant: Fc1ccc(Br)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ncc1F
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-fluoropyridine (5.0 g) in tetrahydrofuran (100 mL) was 2.6 mol/L n-butyllithium tetrahydrofuran solution (12 mL) in a dropwise manner at −70° C., and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added excessive amounts of dry-ice at −70° C., and this mixture was stirred at room temperature for 12 hours. This mixture was poured into water, and this mixture was extracted with diethyl ether. To this obtained aqueous layer was added 1 mol/L hydrochloric acid (2 mL), and this mixture was extracted with ethyl acetate. This organic layer was concentrated to give the title compound (5.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[CH2:22]([NH:26][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Reactant: CC(C)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.7 %

Procedure:
A THF solution of crude ˜0.12M intermediate 15, 3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (160 mL, 19.3 mmol) was combined with isobutylamine (3.8 mL, 38.2 mmol) and T3P (50% wt in EtOAc, 13.8 mL, 23.2 mmol) and stirred at room temperature for 20 h. The mixture was made basic with saturated aqueous NaHCO3 and EtOAc (50 mL) was added. The phases were separated and the aqueous phase was extracted again with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated to yield an orange oil. Flash chromatography on a 2″×4″ silica gel column flushing first with EtOAc (1 L) and 10% MeOH/EtOAc (500 mL) to remove higher Rf impurities followed by elution with an additional 500 mL of 10% MeOH/EtOAc and 500 mL 20% MeOH/EtOAc afforded 4.22 g (63%) of the title compound as an waxy, orange solid: Rf=0.3 (30% MeOH/EtOAc); 1H NMR (CDCl3) δ 7.34 (t, J=7.9 Hz, 1H), 7.20-7.13 (m, 2H), 5.84 (br s, 1H), 3.66 (d, JH-F=1.3 Hz, 2H), 3.11 (t, J=6.4 Hz, 2H), 2.84-2.76 (m, 3H), 2.55-2.45 (m, 6H), 1.81-1.72 (m, 4H), 0.91-0.87 (d @ 0.90 (J=6.6 Hz, 6H) overlapping m (1H)); LRMS m/z Calcd for C20H29FN2O2, 348.5, found, 349.4 (M+H) APCI.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:36][CH:37]1[CH2:42][CH:41]2[CH2:43][CH:38]1[C:39](=[O:44])[O:40]2.Cl>C(O)(CC)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:36][CH:37]3[CH2:42][CH:41]4[CH2:43][CH:38]3[C:39](=[O:44])[O:40]4)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: NC1CC2CC1C(=O)O2
Agent: Cl
Solvent: CCC(C)O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CC4CC3C(=O)O4)n2)cc1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A microwave vial was charged with 1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (150 mg, 0.280 mmol), 5-amino-2-oxa-bicyclo[2.2.1]heptan-3-one (89 mg, 0.70 mmol), a drop of concentrated HCl, and s-butanol (2.0 mL). The mixture was stirred at 130° C. under microwave irradiation for 3 hours. After completion of the reaction, the mixture was concentrated to give 1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(3-oxo-2-oxa-bicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (164 mg, 100% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 285.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A mixture of 1.37 g. of 4-aminobenzoic acid, 3.50 g. of methyl 16-bromohexadecanoate, 2.12 g. of sodium carbonate and 140 ml. of hexamethylphosphoramide is stirred at 120° C. for 18 hours, allowed to cool, and poured into dilute hydrochloric acid. The precipitate is collected by filtration, dried, and crystallized from acetonitrile to yield 4-(15-carbomethoxypentadecylamino)benzoic acid as a white solid.