Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:7][CH:4]([CH2:5][OH:6])[CH:3]([C:8]([F:9])([F:10])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.8 %

Procedure:
To a solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propyl amine (79 mg, 0.374 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.1 mL, 0.749 mmol) and 4-fluorobenzenesulfonyl chloride (80.5 mg, 0.4 mmol) in CH2Cl2 (1 mL). The solution was stirred for 20 hours at 25° C. and then concentrated. EtOAc (5 mL) was added and the solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4), to give 4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene sulfonamide (2.5 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)[CH3:9].Cl[C:25]1[C:34]([F:35])=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1.O>C(#N)C>[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:25]2[C:34]([F:35])=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=2)[CH2:15]1)[CH3:9]
Reactant: COC(=O)c1cnc(Cl)c(F)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)OC)cc2F)C1
Temperature: 50 °C
Yield: 66.8 %

Procedure:
Triethylamine (0.45 mL, 3.3 mmol) was added to a stirred solution of (R)-3-(2-ethoxy-phenoxy)-piperidine (0.41 g, 1.6 mmol) and methyl 6-chloro-5-fluoronicotinate (0.30 g, 1.6 mmol) in acetonitrile (15 mL) at 0° C. The reaction mixture was heated at 50° C. for 18 h. The mixture was cooled to ambient temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (30% ethyl acetate-hexanes) to afford methyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate (0.40 g). MS (ES+) 375.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38]([C:40]2[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=2)[NH2:43])[CH:37]=[N:36]1.Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F.CCOC(C)=O>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:41]=3)[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c2)cn1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.100 g, 0.217 mmol) and 3-(1-methyl-1H-pyrazol-4-yl)aniline (0.0563 g, 0.325 mmol) was dissolved in 4 mL of trifluoroethanol with stirring. HCl (0.11 mL, 4N in dioxane, 0.44 mmol) was added, and the vessel was sealed. The reaction was heated to 80° C. for 4.5 days and cooled to rt. The reaction was poured into half-saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded a solid that was triturated with diethyl ether to yield 0.0823 g (63%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.73 (s, 1H), 9.52 (d, J=5.1 Hz, 1H), 8.37-8.30 (m, 2H), 8.03 (d, J=7.3 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.42-7.32 (m, 1H), 7.26-7.11 (m, 4H), 7.00-6.92 (m, 1H), 6.61 (d, J=5.3 Hz, 1H), 3.80 (s, 3H). MS (M+H, ES+) 599.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1)(=[O:24])=[O:23]
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC(CCO)O3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of Example 67C (0.23 g, 0.87 mmol) and methanesulfonyl chloride (0.075 mL, 0.96 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.13 mL, 9.4 mmol). The mixture was stirred for 30 minutes, diluted with CH2Cl2 (75 mL), washed with water (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2Cl2 to provide the titled compound (0.278 g, 90%). 1H NMR (CDCl3): H NMR: 1.95 (m, 2H), 2.93 (m, 2H), 3.00 (s, 3H), 3.46 (m, 2H), 5.00 (m, 1H), 6.81 (d, J=7 Hz, 1H), 7.40 (m, 2H), 7.65 (m, 4H); MS (DCI) 343 (M+), 361 (M+NH4+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[O:14][CH:13]=[N:12][C:11]=1[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1.O>[CH3:15][C:11]1[N:12]=[CH:13][O:14][C:10]=1[C:3](=[N:2][O:1][CH2:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ncoc1C(=NO)c1ccccc1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncoc1C(=NOCc1csc(N)n1)c1ccccc1

Procedure:
To a solution of N-hydroxy-1-(4-methyl-1,3-oxazol-5-yl)-1-phenylmethanimine (0.18 g, 0.89 mmol prepared as described for example 320), dissolved in dioxane (17 mL) were added 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (181 mg, 0.98 mmol), cesium carbonate (1.16 g, 3.56 mmol) and potassium iodide (15 mg, 0.9 mmol). After stirring for 48 hours at room temperature water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford after purification on silica 4-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (95 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>>[OH:18][C:15]1([C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: Cc1ccc(Br)c(CO)c1
Reactant: CN1CCC(=O)CC1
Product: Cc1ccc(C2(O)CCN(C)CC2)c(CO)c1

Procedure:
Reaction of 2-bromo-5-methylbenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-hydroxy-4-(α-hydroxy-5-methyl-2-tolyl)-1-methylpiperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14]C(N3CCCCC3)[CH2:12][CH2:11]2)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH2:22]([N:26]1CCN(C2C=CC(N)=NC=2)CC1)[CH:23]([CH3:25])[CH3:24].CN1CCN(C2C=CC(N)=NC=2)CC1>>[CH2:22]([N:26]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)[CH:23]([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Reactant: CC(C)CN1CCN(c2ccc(N)nc2)CC1
Agent: CN1CCN(c2ccc(N)nc2)CC1
Product: CC(C)CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1

Procedure:
1-isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted 5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.88 (d, J=6.73 Hz, 6H) 1.71-1.84 (m, 1H) 2.10 (d, J=7.32 Hz, 2H) 2.46-2.58 (m, 4H) 2.97-3.07 (m, 4H) 4.12 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.75 (d, J=2.93 Hz, 1H). LCMS (ESI) 235 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][C:26]=1[F:37])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([O:22]CC)=[O:21].[OH-].[Na+].[ClH:40]>O.ClCCl.CC(C)=O.O1CCOCC1>[ClH:40].[ClH:40].[OH:1][CH:2]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][C:26]=1[F:37])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)CC1CN(CCSc2cccs2)CCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(C(O)CCC3CCN(CCSc4cccs4)CC3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 70 mg of ethyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-acetate, 1 cm3 of dioxane and 0.3 cm3 of a 1 N aqueous sodium hydroxide solution was heated, with stirring, at a temperature in the region of 60° C. for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 25 cm3 of water and 10 cm3 of dichloromethane. The aqueous phase was separated after settling out and then acidified by pouring 0.3 cm3 of 1 N hydrochloric acid. The precipitate formed was dissolved by adding 25 cm3 of dichloromethane. The organic phase was washed with 10 cm3 of a saturated aqueous sodium chloride solution and dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was then dissolved in the hot state in 2 cm3 of acetone. 0.07 cm3 of 4 N hydrochloric acid in dioxane were poured over this solution. The resulting mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 72 mg of (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxy quinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-acetic acid dihydrochloride were obtained in the form of a powder, which was white in color.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccncc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccncc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyridin-4-ylethanol (Arch. Pharm. Ber. Deut. Pharm. Ges. 1972, 305, 248-53) (58 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred for 48 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (83 mg) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=[O:4].CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:28][C@@H:25]1[C:26](=[O:27])[N:23]2[C@@H:24]1[S:29][CH2:30][C:21]([CH2:20][S:13][C:12]1[N:7]3[N:6]=[C:5]([C:3](=[O:4])[NH:2][OH:1])[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=1)=[C:22]2[C:31]([OH:33])=[O:32]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)n2nc(C(=O)NO)nc2n1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
N-Hydroxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide and 3.4 g (12.5 mmol) of 7-aminocephalosporanic acid (3.1 g) (13.9 mmol) are suspended in 75 ml of sulpholane/dichloromethane (1:1 v/v). 7.5 ml of boron trifluoride etherate are added dropwise thereto at 0° C. and the mixture is stirred at 0° C. for 2.5 hours and at room temperature for 15 hours. 200 ml of dichloromethane are now added. After stirring for 30 minutes the mixture is suction filtered. The filter material is dissolved in 100 ml of water. The product is precipitated with saturated sodium hydrogen carbonate solution (pH~5), filtered off and washed with water, ethanol and ether. There are obtained 3.5 g of (6R,7R)-7-amino-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][O:8][CH2:7][CH:6]([C:10]([O:12][CH3:13])=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]2[N:41]=[CH:3][C:4]3[CH2:9][O:8][CH2:7][CH:6]([C:10]([O:12][CH3:13])=[O:11])[C:5]=3[N:40]=2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COC(=O)C1COCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: COC(=O)C1COCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude methyl 5-[1-dimethylamino-methylidene]-4-oxo-tetrahydro-pyran-3-carboxylate (97 mg, 0.45 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (114 mg, 0.31 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow oil (8 mg, 7%). MS ISP (m/e): 396.4 [(M+H)+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([C:25]([S:28]([CH3:31])(=[O:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CN(C=O)C.O>[CH3:32][S:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([C:25]([S:28]([CH3:31])(=[O:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:10]=2)=[CH:5][CH:4]=1)(=[O:35])=[O:34]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CS(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(4′-Bromomethyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline (1.0 eq.) in DMF (0.1M) was added sodium methanesulfinate (1.3 eq.). The mixture was stirred at rt for 2 h, poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EA; 1:4) and stirring in EtOAc:Hex:Et2O (1:7:2) afforded the title compound as a white solid after filtration. 1H NMR (400 MHz, acetone-d6): δ 8.96 (dd, 1H), 8.49 (dd, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 8.08 (t, 1H), 7.81–7.75 (m, 4H), 7.63–7.59 (m, 4H), 4.48 (s, 2H), 2.90 (s, 3H), 2.75 (s, 3H), 2.03 (s, 6H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[N:18][N:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)O1.Br[C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH3:46])[S:34](=[O:45])(=[O:44])[C:35]([CH3:43])([CH3:42])[C:36](=[N:39][O:40][CH3:41])[C:37]=2[N:38]=1>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:41][O:40][N:39]=[C:36]1[C:35]([CH3:43])([CH3:42])[S:34](=[O:45])(=[O:44])[N:33]([CH3:46])[C:32]2[CH:31]=[CH:30][C:29]([C:16]3[CH:17]=[N:18][N:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:20]=3)=[N:38][C:37]1=2
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: CON=C1c2nc(Br)ccc2N(C)S(=O)(=O)C1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CON=C1c2nc(-c3cnn(-c4cccnc4)c3)ccc2N(C)S(=O)(=O)C1(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To Na2CO3 (180 mg, 1.68 mmol) was added water (1.5 ml) and acetonitrile (2 ml) and the solution was degassed for 5 min with argon. 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridine (109 mg, 0.40 mmol), a solution of 6-bromo-N-methoxy-1,3,3-trimethyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-imine (117 mg, 0.34 mmol) in acetonitrile (2 ml) and Pd(dppf)Cl2 (13 mg, 0.017 mmol) were added sequentially followed by rinsing the flask with acetonitrile (1 ml). The mixture was stirred at 100° C. for 1 h then allowed to cool to ambient temperature. Water and ethyl acetate were added then the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by chromatography afforded two oxime isomers of N-methoxy-1,3,3-trimethyl-2,2-dioxo-6-[1-(3-pyridyl)pyrazol-4 yl]pyrido[3,2-c]thiazin-4-imine.
Reaction SMILES: CO[C:3]1[CH:8]=CC(S(CC(C)=CCO)(=O)=O)=[CH:5][CH:4]=1.O1CCCC1.C([Li])CCC.Cl[CH2:29][CH:30]=[C:31](C)[CH:32]=[CH:33][C:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH2:36][C:35]=1[CH3:42]>CCCCCC.O>[CH3:42][C:35]1[CH2:36][CH2:37][CH2:38][C:39]([CH3:40])([CH3:41])[C:34]=1[CH:33]=[CH:32][CH:31]=[CH:30][CH2:29][CH2:8][CH:3]=[CH:4][CH3:5]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CCCl
Reactant: COc1ccc(S(=O)(=O)CC(C)=CCO)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC=CCCC=CC=CC1=C(C)CCCC1(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of 1.28 g. of 1-(p-methoxyphenylsulfonyl)-2-methyl-4-hydroxy-but-2-ene in 15 ml. of tetrahydrofuran (THF) was added at -70°C. 4.25 ml. of 2.37 M solution of n-butyllithium in hexane. The mixture was stirred at -70°C. for 30 minutes and a solution of 1.78 g. of 1-chloro-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-penta-2,4-diene in 5 ml. of THF was added at -70°C. The solution was stirred at -70°C. for 50 minutes and allowed to warm to 70°C. The mixture was poured into water and extracted with diethyl ether. The extracts were washed with water, dried and concentrated to give 2.6 g. of 1-hydroxy-3,7-dimethyl-4-(p-methoxyphenyl-sulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene which was chromatographed on silica get to give 0.48 g. of 1-hydroxy-3,7-dimethyl-4-p-methoxyphenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene (20% yield) having a UV in isopropanol at λmax = 241-2 mμ (ε24,625).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.Br[CH2:34][CH3:35]>>[NH:21]1[C:20]2[CH:31]=[CH:32][C:17]([N:10]3[CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])[C:13]([CH3:14])=[C:12]([O:15][CH2:34][CH3:35])[C:11]3=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Reactant: CCBr
Product: CCOC1=C(C)C(c2cccc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.22 g, 0.5 mmol), bromoethane (0.056 ml, 0.75 mmol) and P1-tBu (0.191 ml, 0.75 mmol) according to the method described above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 59.8 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-trifluoromethyl-benzyl bromide (145 mg, 0.6 mmol) to afford title product (135 mg, 60% yield); LCMS; 100% APCI+, Calcd: +451.49; Found m/z: 452.3 (M+1); 1HNMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 5.07 (s, 2H), 6.87 (s, 4H), 7.53 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[O:17]([NH2:19])[CH3:18]>C(O)C.N1C=CC=CC=1>[CH3:18][O:17][N:19]=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(c1ccccc1)c1ccc(Br)cc1
Yield: 93.1 %

Procedure:
A mixture of 4-bromobenzophenone (3.02 g, 0.0116 mol) and methoxylamine hydrochloride (4.83 g, 0.0578 mol) was heated in a mixture of ethanol (90 mL) and pyridine (18 mL) at reflux for 2 hours under an atmosphere of nitrogen. The solvents were removed under reduced pressure and the residue was partitioned between water (150 mL) and dichloromethane (100 mL). The water phase was further extracted twice with dichloromethane (80 mL each) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (2:98) as mobile phase to yield (4-bromophenyl)(phenyl)methanone O-methyloxime as a colorless oil (3.13 g, 0.0108 mol): 1H NMR (DMSO-d6, 400 MHz) 7.67 (d, 1H), 7.59 (d, 1H), 7.48 (m, 4H), 7.32 (m, 1H), 7.26 (m, 2H), 3.93 (s, 3H) TLC (ethyl acetate/heptane 1:9) Rf 0.44.