Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O-:14])=[O:13])[CH:2]=[CH2:3].[Na+].C(O)C.S(O[CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1CC(=O)[O-]
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccccc1CC(=O)OC(C)C(=O)OCC

Procedure:
To a warm mixture of 7 g. sodium 2-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 2-(allylamino)phenylacetate as colorless crystals.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23])=O)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[NH2:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23]
Reactant: [H][H]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1
Yield: 77 %

Procedure:
(3S, 4R)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (1.85 g. 5.9 mmole) is hydrogenated with 2 g of 10% palladium on activated carbon in THF (30 ml) and ethyl acetate (30 ml) at 50 psi hydrogen pressure at room temperature for 2 hours. After removal of catalyst by filtration, 810 mg of deprotected (3S, 4R)-3-amino-4-phenoxy-azetidin-2-one is obtained.
Reaction SMILES: N1C=CN=C1[C@@H]1CCCN1C(OC(C)(C)C)=O.[I:18][C:19]1[N:20]=[C:21]([C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][C:23]=1I.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.N1CCCCC1>CN(C=O)C.[Cu]I>[I:18][C:19]1[N:20]=[C:21]([C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c(I)[nH]1
Agent: [Cu]I
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc[nH]1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c[nH]1
Temperature: 40 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 5 (630 mg, 1.53 mmol), 6 (520 mg, 1.53 mmol), Pd (PPh3)2Cl2 (56 mg, 0.080 mmol) and CuI (8 mg, 0.04 mmol), P(t-Bu)3 (1.1 mL, 0.31 mmol), piperidine (1.05 mL, 4.60 mmol) in DMF (20 mL) was stirred at 40° C. for 12 h. The reaction mixture was partitioned between H2O and DCM. The organic layer was washed with H2O (4×50 mL) and brine (15 mL), dried over anhydrous Na2SO4, filtered and then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=50/1 (v/v)) to afford 7 (550 mg, 50% yield) as a pale yellow solid. LC-MS (ESI) m/z 623.3 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])=[N:6][CH:5]=1.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:21](O)=O)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][C:7]([CH2:11][CH:12]([CH3:13])[CH3:14])=[C:8]([CH3:10])[CH:9]=3)[N:15]=2)[CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH3:17]
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cnc1CC(C)C
Product: CCc1cc(-c2nc(-c3cnc(CC(C)C)c(C)c3)no2)cc(C)c1O

Procedure:
2-Ethyl-4-[3-(6-isobutyl-5-methyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is prepared from N-hydroxy-6-isobutyl-5-methyl-nicotinamidine and 3-ethyl-4-hydroxy-5-methyl-benzoic acid in analogy to Example 13, LC-MS: tR=1.02 min, [M+1]+=352.09.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([F:20])[C:9]([F:19])=[C:10]([CH:18]=2)[C:11]([O:13]C2CCC2)=[O:12])[CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([F:20])[C:9]([F:19])=[C:10]([CH:18]=2)[C:11]([OH:13])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OC1CCC1)c1cc(OC2CCC2)cc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(OC2CCC2)cc(F)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate (49 g, 174 mmol), ethanol (300 mL), sodium hydroxide (20 g, 500 mmol) and water (300 mL) stirred at 60° C. overnight. The mixture was cooled to room temperature and extracted with petroleum ether (2×100 mL). The pH of the aqueous layer was adjusted to 5 with 6 M hydrochloric acid, and then it was extracted ethyl acetate (3×300 mL). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 5-cyclobutoxy-2,3-difluorobenzoic acid (38 g, 96%) as a white solid. MS (ESI, neg. anion) m/z 227 [M−H]−.
Reaction SMILES: C(OCC)=O.[CH2:6]([N:9]1[C@H:18]2[C@@H:13]([CH2:14][CH2:15][C:16](=[O:19])[CH2:17]2)[CH2:12][CH2:11][CH2:10]1)[CH2:7][CH3:8].[K].[ClH:21].C([O-])(=O)C.[Na+].NC1C=CC=CC=1.N#N.[Cl-].[C:37]1([N+:43]#[N:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1.O>[Cl-:21].[C:37]1([N+:43]#[N:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH2:6]([N:9]1[C@H:18]2[C@@H:13]([CH2:14][C:15](=[N:44][NH:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:16](=[O:19])[CH2:17]2)[CH2:12][CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: CCCN1CCC[C@@H]2CCC(=O)C[C@H]21
Reactant: Cl
Agent: CC(=O)[O-]
Agent: N#N
Agent: N#[N+]c1ccccc1
Solvent: Nc1ccccc1
Solvent: CCOC=O
Solvent: C1CCOC1
Product: CCCN1CCC[C@@H]2CC(=NNc3ccccc3)C(=O)C[C@H]21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Alternatively, the above reaction was carried out using a reverse addition procedure: a solution was prepared from 5.5 ml of ethyl formate, 3.3 g of trans-(±)-1-n-propyl-7-oxodecahydroquinoline and 20 ml THF. This solution was added to a solution of 3.8 g of potassium t-tutoxide in 80 ml of THF. The reaction mixture was stirred for 2 hours at about 0° C. at which time TLC indicated that all the starting ketone had reacted. The pH was adjusted to about 6 by the addition of 10% hydrochloric acid. A solution of 7.2 g of sodium acetate in 20 ml of water was added. Next, a phenyldiazonium chloride solution was prepared as above from 1.6 g aniline. The solution of the trans-(±)-1-n-propyl-6-formyl-7-oxo-decahydroquinoline was cannulated rapidly under positive N2 pressure beneath the surface of the phenyldiazonium chloride solution held at 0° C. The reaction mixture was stirred at that temperature for 2 hours and then worked up as above. Flash chromatography yielded 43.5% of the desired trans-(±)-1-n-propyl-6-phenylhydrazono-7-oxodecahydroquinoline (compared with 31.4% by normal addition).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]2[N:29]=[CH:28][C:27]3[N:26](COCC[Si](C)(C)C)[C:25]4[N:38]=[CH:39][C:40]([C:42]5[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=5)=[CH:41][C:24]=4[C:23]=3[CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH3:47][N:45]1[CH:46]=[C:42]([C:40]2[CH:39]=[N:38][C:25]3[NH:26][C:27]4[CH:28]=[N:29][C:21]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][C:15]=5[O:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:22][C:23]=4[C:24]=3[CH:41]=2)[CH:43]=[N:44]1
Reactant: Cn1cc(-c2cnc3c(c2)c2cc(-c4cnccc4OC4CCN(C(=O)OC(C)(C)C)CC4)ncc2n3COCC[Si](C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cn1cc(-c2cnc3[nH]c4cnc(-c5cnccc5OC5CCNCC5)cc4c3c2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A mixture of 4-{3-[3(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxy methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl]-pyridin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.15 mmol) in TBAF (1N in THF, 10 mL) was heated at 50° C. for 19 h. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo, to afford a residue which was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM). This resultant residue was dissolved in DCM (5 mL) and TFA (1 mL) and left to stir for 30 minutes. The mixture was diluted with DCM and water. The aqueous layer was separated, evaporated and the resultant residue was loaded onto an SCX-2 cartridge and washed with methanol and 2M ammonia in methanol. The combined basic fraction was purified by HPLC (C18 column, eluting with 5-60% MeCN in water (with 20 mM triethylamine) over 20 minutes) to afford the title compound as a white solid (25 mg, 39%). 1H NMR (MeOD, 400 MHz): 8.97 (s, 1H), 8.83-8.78 (m, 2H), 8.72 (s, 1H), 8.58 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.28 (d, J=6.0 Hz, 1H), 4.91-4.80 (m, 1H), 3.98 (s, 3H), 3.01-2.91 (m, 2H), 2.80-2.70 (m, 2H), 2.11-2.00 (m, 2H), 1.83-1.73 (m, 2H) plus 2 exchangeables not observed. LCMS (Method A): RT=4.0 min, M+H+=426.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:13]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=1[O:12][CH2:1][C:3]1[CH:11]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Yield: 115.1 %

Procedure:
A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol), benzyl bromide (15.39 g, 90 mmol), potassium carbonate (16.59 g, 120 mmol), and methyl ethyl ketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1), suspended and washed with isopropyl ether under heating at reflux to give the title compound (5.98 g, 57.5%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(CC)Nc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoformate (0.081 g, 0.766 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in benzene was heated at reflux using Dean-Stark apparatus for 24 hours. Benzene was removed and toluene was added and an excess of trimethyl orthoformate (0.084 ml) was added to the reaction mixture. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated as a white crystal, mp 78–80° C.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Product: Cc1nc(-c2cccc(CN3C(=O)CCC3c3ccccc3-c3ccccc3)c2)cs1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 425.01 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[C:44]([CH3:46])([CH3:45])[CH:43]1[C:47](O)=[O:48]>CCOC(C)=O.C1COCC1.CCN(CC)CC>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:47]([CH:43]3[C:44]([CH3:46])([CH3:45])[C:42]3([CH3:50])[CH3:41])=[O:48])[S:8][C:4]=2[CH:3]=1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C(C(=O)Nc2nc3ccc(F)cc3s2)C1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1 equiv), 1-hydroxybenzotriazole, triethylamine (1.1 equiv), and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1 THF/Et3N (1 M) and were stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Puried by silica gel chromatography afforded the title compound. MS (ESI+) m/z 293 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17](S(C)(=O)=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41](C2C=CC(B(O)O)=CC=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([N:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]4)=[CH:18][CH:19]=3)[S:13][C:6]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)CC1
Yield: 70 %

Procedure:
Starting from the nitro-bromo compound 42, following the procedure described above for the synthesis of compound 48 (scheme 10, example 55) but substituting 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane for 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid, title compound 156 was obtained in 70% yield. LRMS (M+1) 550.6 (100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH2:15])=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=O)[CH2:8][CH2:7]2.Cl.[NH2:23][OH:24].N1C=CC=CC=1>C(O)C.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH2:15])=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[N:23][OH:24])[CH2:8][CH2:7]2
Reactant: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=NO)CC2

Procedure:
An ethanol solution containing 120 g of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one, 45 of hydroxylamine hydrochloride and 200 ml of pyridine in 1,200 ml of ethanol was refluxed for 4 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under a reduced pressure, then the residue thus obtained was dissolved in 2 liters of ethyl acetate and washed three times with 1 liter of water each time, and the residue was dried again under a reduced pressure. Recrystallized from ethyl acetate/n-hexane mixture to obtain 90 g of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one oxime. Light yellow flake-like crystals. Melting point: 146° C. (Decomposed).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[F:1][B-:2]([F:5])([F:4])[F:3].[NH+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccncc1
Agent: F[B-](F)(F)F
Agent: [H+]
Product: c1cc[nH+]cc1
Reaction time: 0.5 h

Procedure:
Tetrafluoroboric acid (250 ml, 2.00 mol) was added to cool (0° C.) pyridine (157.7 ml, 1.95 mol) within 25 mins. resulting in a colorless precipitate. After the acid was completely added, the mixture was further stirred for 30 mins. and held at the same temperature. Thereafter, the reaction mixture was filtered. The residue was washed twice with cold ethanol and dried for 12 hrs at high vacuum to yield 201.9 g (60%) of pyridiniumtetrafluoroborate in the form of colorless crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:20])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.32M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-bromo-phenyl)-acetic acid methyl ester (1.48 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Iodomethylcyclopentane (1.49 g, 7.13 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.60 g, 79.3%) as a clear oil: EI-HRMS m/e calcd for C15H19O2Br (M+) 310.0568 found 310.0564.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:33]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:33][C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[CH:10][CH:9]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2nccs2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ccc(-c3nccs3)[nH]2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
To a solution (5 mL) of 6-cyclopentyl-5-[4-(methylsulfonyl)phenyl]-1-(1,3-thiazol-2-yl)hexane-1,4-dione (300 mg) in N,N-dimethylformamide was added ammonium acetate (310 mg), and the mixture was stirred at 100° C. for 1.5 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (150 mg, yield 53%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 401 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:23][S:24]([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:26])=[O:25].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:25])=[O:26])[CH2:34][CH2:33]1)[CH3:2]
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 69.6 %

Procedure:
1-Ethyl-2-fluoro-4-(ethyloxy)-5-nitrobenzene (Example 208, step A) (0.50 g, 2.3 mmol) was dissolved in DMSO (15 mL). K2CO3 (0.97 g, 7.0 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (1.0 g, 4.7 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir over the weekend. The mixture was then heated to 120° C. for 4 h. The mixture was cooled to rt then poured into H2O and extracted with DCM. The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified on a 40 g ISCO column (EtOAc to 10% MeOH in EtOAc). The desired fractions were combined and the solvent removed in vacuo to give the title compound of Step A (0.63 g, 1.6 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.56 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.23-3.12 (m, 2H), 3.03 (s, 3H), 3.00-2.91 (m, 6H), 2.72-2.62 (m, 4H), 2.57 (q, J=7.5 Hz, 2H), 2.22 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H). MS (M+H, ES+) 386.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:31])[CH3:30].CCOC(/N=N/C(OCC)=O)=O.C(=O)([O-])O.[Na+]>C1COCC1>[C:29]([O:3][C@@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)(=[O:31])[CH3:30]
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reactant: CC(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C=C[C@H]2CO[C@@H]1O2
Temperature: 0 °C
Yield: 51.1 %

Procedure:
4.15 g (32.4 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 17.20 g (65.6 mmol) of triphenyl phosphine, and 3.94 g (65.6 mmol) of acetic acid were added to 30 ml of dry THF, and a solution obtained by dissolving 11.42 g (65.6 mmol) of diethylazodicarboxylate in 50 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 24 hours. The reaction solution was neutralized with a 1% aqueous sodium hydrogencarbonate solution in the ice-water bath, and the THF was distilled at a reduced pressure. The residue was extracted using diethyl ether. The extract was dried with magnesium sulfate, and the diethyl ether was distilled at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1 to 3:1). The purified residue was distilled at a reduced pressure (2 mmHg) to obtain 2.82 g (yield: 51.2%) of 2-O-acetyl-1,6-anhydro-3,4-dideoxy-β-D-erythro-hex-3-enopyranose.