Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]=2[O:4][C:3]1=[O:19].[OH-:20].[K+].CO>>[OH:4][C:5]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:2]([CH3:1])[C:3]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: CC1C(=O)Oc2c(Sc3ccccc3F)cccc21
Agent: [K+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(Sc2ccccc2F)c1O

Procedure:
3-Methyl-7-(2-fluorophenylthio)-2,3-dihydrobenzofuran-2-one was hydrolyzed by treating with potassium hydroxide-methanol to give 2-[2-hydroxy-3-(2-fluorophenylthio)phenyl]propionic acid, mp. 116°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][CH:14]([CH3:21])[CH:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].BrN1C(=O)CCC1=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][C:14]([CH3:21])=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)C1N=C(c2ccc([N+](=O)[O-])c(OC)c2)OC1C
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: COC(=O)c1nc(-c2ccc([N+](=O)[O-])c(OC)c2)oc1C
Yield: 51.6 %

Procedure:
The same operation as in Example (96a) was performed using methyl 2-(3-methoxy-4-nitrophenyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (105b) (3.6 g, 12.2 mmol), α,α-bisisobutyronitrile (99 mg, 0.6 mmol), N-bromosuccinimide (2.40 g, 13.5 mmol) and benzene (50 mL). Purification by silica gel column chromatography (elution solvent: chloroform/methanol=99/1, 98/2, 96/4, 94/6) gave 1.84 g of the title compound as a light yellow solid (51%).
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:59][CH:60]([F:77])[CH2:61][NH:62][CH:63]1[CH2:69][CH2:68][C:67]2=[C:70]([NH2:76])[C:71]([O:74][CH3:75])=[CH:72][CH:73]=[C:66]2[CH2:65][CH2:64]1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:76][C:70]2[C:67]3[CH2:68][CH2:69][CH:63]([NH:62][CH2:61][CH:60]([F:77])[F:59])[CH2:64][CH2:65][C:66]=3[CH:73]=[CH:72][C:71]=2[O:74][CH3:75])=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2CCC(NCC(F)F)CC3)ncc1Cl

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide. LC/MS (ESI): 531.23. 1H NMR (400 MHz, DMSO, d6) δ 9.07 (m, 2H), 8.87 (m, 1H), 8.74 (m, 1H), 8.16 (m, 1H), 8.01 (m, 1H), 7.71 (m, 1H), 7.01 (m, 2H), 6.89 (m, 1H), 6.38 (td, 1H), 3.78 (s, 3H), 3.55 (m, 2H), 3.38 (m, 1H), 3.07 (m, 1H), 2.79 (s, 3H), 2.68-2.86 (m, 2H), 2.32 (m, 3H), 1.33 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:10].[H-].[Na+]>N1C=CC=CC=1.[Cu](Cl)Cl>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:10]
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)CSc1ccc(O)cc1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CSc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-bromo chlorobenzene (1.92 g, 10 mmol), (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper(II) chloride (500 mg) was refluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixture was carefully quenched with ice cold water and acidified with concentrated HCl. The product was extracted with choroform, washed well with water; dried and concentrated. The product was purified by silica gel column chromatography by eluting with 30% ethyl acetate: hexane. Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H)+. Alternatively the title compound may be prepared from 4-(4-chloro-phenoxy)-benzenethiol and bromo ethyl acetate as described in example 83.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C=O)c23)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
To a solution of 9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (249 mg, 0.622 mmol) in tetrahydrofuran (3 mL) was added trimethyl(trifluoromethyl)silane (0.276 mL, 1.87 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.124 mL, 0.124 mmol) at 0° C. After the mixture was stirred at 0° C. for 15 min, to the reaction mixture was added trimethyl(trifluoromethyl)silane (0.276 mL, 1.87 mmol) (and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.124 mL, 0.124 mmol) at 0° C. After the mixture was stirred at 0° C. for 15 min, to the mixture was added 1N hydrochloric acid (3 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 10 min. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (241 mg, 0.512 mmol, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([CH:6]=[CH:14][N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C=C[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, 3-methoxy-benzaldehyde (16.0 g, 118.518 mmol) in ethanol (160 mL) was reacted with nitro methane (7.0 mL, 118.518 mmol) and 10N NaOH (4.7 g, 118.518 mmol). The resulting mixture was stirred at 0° C. for 4 hours to afford 10.5 g of the product (49% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([O:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Product: Cc1cc(-c2cc(C(=O)O)cnc2OC2CCC2)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-cyclobutoxy-nicotinic acid (example BY) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; MS (ESI): 316.2 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCCN2
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCCc2cc(Br)ccc21
Yield: 60.2 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 6-bromo-1,2,3,4-tetrahydroquinoline (0.40 g, 1.89 mmol) and methanesulfonyl chloride (0.22 mL, 2.8 mmol) to provide 6-bromo-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline (0.33 g). MS (ES) m/z 289.7; HPLC purity 97.2% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]2=[O:22].BrCCCCC.Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>>[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[C:18](=[O:21])[C:17]2=[O:22]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with 7-fluoroisatin, and 1-bromopentane with 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (34%): MS (ES+) m/z 336.2 (M+23).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[Br:21][C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=1[NH2:24]>O>[Br:21][C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=1[NH:24][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1Br)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (427 mg, 2.39 mmol, commercially available product) and triethylamine (410 μl, 2.94 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-bromo-5-(trifluoromethyl)aniline (480 mg, 2.00 mmol; commercially available product). The resulting mixture was warmed to room temperature and stirred for 24 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate). Thus, N-[2-bromo-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0612) (308 mg, 44.8%) was yielded as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH2:21]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[O:19][CH3:20])=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid and 4-benzylphenol following the Standard Procedure J. MS (ES) for C27H30O6 [M+NH4]+: 468, [M+Na]+: 473.
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:43][CH2:44][CH3:45])[C:36]=1[C:37]1[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=1)[C:31](O)=[O:32])[CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:31]([C:30]3[CH:34]=[C:35]([O:43][CH2:44][CH3:45])[C:36]([C:37]4[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=4)=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)=[O:32])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NCC(N)=O)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N-Carbamoylmethyl-4-oxospiro[chroman-2,4′-piperidine]-6-carboxamide hydrochloride (354 mg), 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (145 mg), WSC hydrochloride (115 mg), HOBT (91.2 mg) and triethylamine (0.209 mL) were suspended in DMF (3 mL), and stirred at 50° C. for 16 hours. Water was added to it, the formed solid was taken out through filtration, and the resulting solid was purified through silica gel column chromatography (chloroform/methanol), and crystallized from chloroform/diethyl ether to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.75 (1.0H, t, J=5.6 Hz), 8.35-8.28 (1.0H, m), 8.09 (1.0H, dd, J=8.8, 2.2 Hz), 8.04 (1.0H, s), 7.92 (1.0H, s), 7.35 (1.0H, s), 7.17 (1.0H, d, J=8.8 Hz), 7.00 (1.0H, s), 6.68 (2.0H, s), 4.31-4.02 (1.0H, m), 4.08 (4.0H, q, J=7.0 Hz), 3.86 (3.0H, s), 3.77 (2.0H, d, J=5.9 Hz), 3.64-3.02 (3.0H, m), 2.93 (2.0H, s), 2.10-1.72 (4.0H, m), 1.37 (6.0H, t, J=7.0 Hz). MS [M+H]+=590.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC(c1cccs1)c1cccnc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)c1cccnc1Cl
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a toluene (100 ml) solution of α-(2-chloropyridin-3-yl)-2-thiophenmethanol (6.14 g, 27.2 mmol) was added 85% manganese dioxide (25 g, 245 mmol), followed by 2 hours of heating under reflux. The reaction solution was passed through celite and the resulting filtrate was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-chloroform) to give 2-chloro-3-(2-thiophenecarbonyl)pyridine (5.32 g, 23.8 mmol, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH:6]([CH2:7]2)[C:5]([CH3:11])([S:9][CH3:10])[C:4](=[O:12])[C:3]=1[C:13]([C:15]1[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1)=[O:14].I([O-])(=O)(=O)=[O:27].[Na+]>CO>[OH:1][C:2]1[CH:8]2[CH:6]([CH2:7]2)[C:5]([S:9]([CH3:10])=[O:27])([CH3:11])[C:4](=[O:12])[C:3]=1[C:13]([C:15]1[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1)=[O:14]
Reactant: CSC1(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C(O)C2CC21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CC2C(C)(S(C)=O)C1=O

Procedure:
0.87 g (2.3 mmol) of 5-hydroxy-2-methyl-2-methylsulfanyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[4.1.0]hept-4-en-3-one (compound A2-D 113), dissolved in 8 ml of methanol, is warmed for 3 hours at a temperature of 50° C. in the presence of 0.56 g of sodium periodate. The mixture is then partitioned between ethyl acetate and sodium chloride solution, concentrated, and the crude product is purified by chromatography (mobile phase: ethyl acetate/methanol 19:1). Pure 5-hydroxy-2-methanesulfinyl-2-methyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[4.1.0]hept-4-en-3-one is obtained as tautomer and isomer mixture of melting point 159.5-160° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]1([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:34][C:30]([C:32]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:33]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:31]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(C)(O)c1ccccc1
Product: CC(O)(c1ccccc1)c1cn(C2CCc3c(CC(=O)O)c4ccccc4n3C2)nn1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2-phenylbut-3-yn-2-ol. MS (+ESI) m/z: 417.1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5].[OH:23]O.O.[OH-].[Li+]>C1COCC1.O.O>[OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH3:22])[C:4]([OH:5])=[O:23]
Reactant: OO
Reactant: CCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a 2000 mL roundbottom flask was added (4S)-3-[(2R)-2-(hydroxymethyl)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (4) (82 g, 0.268 mol) in THF/water (4:1, 750 mL). The solution was cooled to 0° C. and H2O2 (130 mL, 1.07 mol) was added dropwise, followed by lithium hydroxide monohydrate (22.58 g, 0.537 mol) in water (130 mL). The reaction mixture was warmed up to rt and stirred overnight. THF was removed under vacuum, and the aqueous solution was washed with ethyl acetate. The aqueous solution was then acidified to pH ˜3.0 and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated to provide the title compound (42 g, 107%). LCMS: (2M+H)+: 313.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1n[nH]c2ncccc12

Procedure:
To a solution of tert-butyl 3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (B-4) (699 mg, 3 mmol) in CCl4 (15 mL) were added NBS (641 mg, 3.6 mmol) and AIBN (70 mg, 0.3 mmol). The reaction mixture was stirred under reflux overnight and then filtered. The filtrate was washed with saturated aqueous Na2CO3 (15 mL). The organic layer was dried over Na2SO4 and concentrated to afford the crude product. The crude product was used for next step without further purification. MS (m/z): 212 (M+1)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].C(O)(C(F)(F)F)=O.[F:12][C:13]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:14]=1[O:15][C:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.[OH-].[Na+]>O.C(O)(=O)C>[F:12][C:13]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:14]=1[O:15][C:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][N:18]([N:1]=[O:3])[CH2:17]1
Reactant: O=N[O-]
Reactant: OCC1(Oc2cc(F)ccc2F)CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (2 mmol, 138 mg) in water (3 mL) was added dropwise to a solution of TFA salt of (3-(2,5-difluorophenoxy)piperidin-3-yl)methanol (1 mmol, 243 mg) in acetic acid (5 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hour, and then heated to 60° C. and stirred for 4 hours. The reaction mixture was cooled to room temperature. Sodium hydroxide aqueous solution was added to adjust the pH of the solution slightly basic. The organics were extracted with EtOAc. The product, (3-(2,5-difluorophenoxy)-1-nitrosopiperidin-3-yl)methanol, was obtained after removal of the solvent.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1C=CC=CC=1.C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C.[NH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH:40][CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[CH3:2]
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 16 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-ethyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 16% yield: mp 163-164° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.48 (m, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.28-7.17 (m, 1H), 6.23 (t, J=5.7 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.12-4.03 (m, 2H), 3.58-3.53 (m, 2H), 3.35 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 1.18 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.1, 153.6, 149.2, 148.8, 135.6, 133.9, 123.6, 116.6, 42.0, 41.5, 41.3, 38.5, 17.2, 12.5; MS (ES+) m/z 346.3 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][Cl:6])[O:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24][C:22](=[O:23])[C@H:18]([CH:19]([CH3:21])[CH3:20])[NH:17][C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)CO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)COC(=O)OCCl
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Chloromethyl chloroformate (1.50 mL, 16.6 mmol) was added to a solution of the alcohol (2.74 g, 8.12 mmol) from step (a) and pyridine (4.9 mL, 61 mmol) in 40 mL dry CH2Cl2, in an ice bath. After stirring for 1 h, the mixture was diluted with CH2Cl2 and washed successively with water, saturated NaHCO3, and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated, coevaporating several times with toluene on a rotavapor. Flash column chromatography (silica, 2/1 petroleum ether-ethyl acetate) gave 3.31 g (95%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[SH:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:4]=[C:3]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:6][CH2:2]1
Reactant: Nc1ccccc1S
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CSc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of bromo acetylbromide in toluene (20 ml) was added dropwise to an ice-cooled stirred solution of 0-mercaptoaniline (10 mmol, 2.5 g) in a mixture of pyridine and toluene (50 ml, 30 ml). The mixture was allowed to heat to room temperature and stirring was continued for 2 hours followed by reflux for 30 min., whereafter water (100 ml) was added. The organic phase was separated, dried (MgSO4) and evaporated to give 3,4-dihydro-3-oxo-2H-1,4-benzothiazine. M.p. 170°-171° C.