Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:42][O:43][CH3:44])[C:11]([NH:13][CH:14]2[C:40](=[O:41])[N:16]3[C:17]([C:37]([OH:39])=[O:38])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH2:28][NH:29]C(OC(C)(C)C)=O)=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.CO.Cl>C(O)=O>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:42][O:43][CH3:44])[C:11]([NH:13][CH:14]2[C:40](=[O:41])[N:16]3[C:17]([C:37]([OH:39])=[O:38])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH2:28][NH2:29])=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A solution of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.12 g.) in 98% formic acid (11 ml.) was stirred at room temperature for 2 hours. Methanol (20 ml.) and conc. hydrochloric acid (0.3 ml.) were added to the resultant solution and then stirred at room temperature for 30 minutes. After the reaction mixture was concentrated in vacuo, water (25 ml.) was added to the residue, and then the solution was adjusted to pH 3 to 4 with a saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) with an eluent of aqueous methanol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.48 g.), mp. 248° to 251° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:43])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[C:31]([CH3:43])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ncc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 120 °C
Yield: 54 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 120° C. for 20 minutes under microwave irradiation. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (49 mg, 72%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 2.10 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.CS(O[C@H:17]([C@@H:19]1[CH2:23][C:22](=[O:24])[N:21]([C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH3:26])[CH2:20]1)[CH3:18])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:17]([C@H:19]2[CH2:20][N:21]([C@@H:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[CH3:26])[C:22](=[O:24])[CH2:23]2)[CH3:18])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Oc1cc(Cl)cn2nccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4nccc34)CC2=O)cc1
Temperature: 90 °C

Procedure:
6-chloropyrazolo[1,5-a]pyridin-4-ol (120 mg, 0.712 mmol), (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (365 mg, 1.07 mmol) and cesium carbonate (278 mg, 0.854 mmol) were suspended in DMF (2.0 mL). The mixture was heated at 90° C. for 3 h. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (30-100% EtOAc in hexanes) on silica gel to afford (R)-4-((R)-1-((6-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:18])([N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]=[CH:8]1)[CH3:6])C.[H-].C([Al+]CC(C)C)C(C)C.CO.C(OCC)(=O)C>C(Cl)Cl>[CH3:18][C:5]([N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]=[CH:8]1)([CH3:6])[CH:4]=[O:3]
Reactant: CCOC(=O)C(C)(C)n1cnc(-c2cccnc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C=O)n1cnc(-c2cccnc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionic acid ethyl ester (1 eq) in DCM at −78° C. was added diisobutylaluminum hydride (4 eq). After leaving the reaction mixture stir at −78° C. for 3 hours, methanol (4 eq) was added to the reaction mixture at −78° C. and the solution was warmed to room temperature over 60 minutes. Ethyl acetate was added to the solution and after 30 minutes the solution was filtered and concentrated to give 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (70%). MH++H2O (234)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][CH:24](O)[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=4[C:34]#[N:35])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CCN(S(F)(F)[F:47])CC.CO.C(Cl)Cl>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][CH:24]([F:47])[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=4[C:34]#[N:35])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(F)CN2CCN(c3ccccc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 2-(4-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (150 mg, 0.27 mmol) in CH2Cl2 (1 mL) was treated with DAST (Et2NSF3, 7 μL, 0.60 mmol) at −78° C. The reaction mixture was slowly warmed to 25° C. for 1 h and then to 60° C. for an additional 2 h. Preparative TLC (silica, 5% MeOH/CH2Cl2) provided 75 mg (50%) of the title compound as a light yellow powder. TLC (5% MeOH/CH2Cl2): Rf=0.28. MS (electrospray): m/z 555.2 ([M+H]+, C29H30F4N6O requires 554.2). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.71 and 7.59 (AB pattern, Jab=8.2 Hz, 2H), 7.66 and 7.62 (AB pattern, Jab=8.4 Hz, 2H), 7.50-7.38 (m, 2H), 6.96-6.92 (m, 2H), 5.01 (dp, J=49.0, 3.0 Hz, 1H), 4.77 and 4.73 (AB pattern, Jab=15.7 Hz, 1.1 H), 4.59 (s, 0.9H), 4.41-4.18 (m, 2H), 3.95-3.80 (m,1H), 3.69 (dd, J=5.5, 5.5 Hz, 1H), 3.18 (m, 4H), 2.83-2.65 (m, 8H), 2.14 (s, 1.6H), 2.10 (s, 1.4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:13]1([CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:11]([S:8]([C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:24]([N:20]3[CH2:21][CH2:22][CH2:23][C@H:19]3[CH2:18][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:25])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Cl)cn1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
Procedure KK: Place 5-Chloro-2-ethanesulfonyl-pyridine (1.0 mmol), (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.1 mmol), ethanol (0.10M), potassium carbonate (3.0 mmol) and dihydrogen di-μ-chlorotetrakis(di-tert-butylphosphino-kP)dipalladate (2-) (0.01 mmol, also known as POPd1) in a microwave reactor vessel with a stir bar. Run the reaction in a CEM microwave reactor for 1 hour at 90° C. and 65 W power with cooling. After this time, concentrate the reaction in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia and dichloromethane. MS (m/e): 428.2 (M+1)
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=[O:17])[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.N1C=CC=CC=1>[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:16]([OH:2])=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
A solution of tetrabutylammonium bromide (111.68 g, 0.336 moles) in water (400 ml) was added under stirring to a solution of potassium permanganate (53.1 g, 0.336 moles) in water (1 l). The obtained solid was separated by filtration, washed with water and dissolved in 500 ml of pyridine. This solution was dropped into one of crude 3-cyclopentyloxy-4-methoxy benzaldehyde (obtained as described in J. Med. Chem., 1995, 38, page 4851) (74 g, 0.336 moles) in pyridine (200 ml), under stirring in water/ice. At the end 3 l of ice were added and it was acidified by dropping 850 ml of 12N HCl. The stirring was kept for further 1.5 hours, then the solid was separated by filtration and extracted under stirring for 30 minutes with ethyl acetate (2 l). The residual solid was removed and the mother liquors were further extracted with ethyl acetate (2×700 ml). The organic phases were washed with water, dried on sodium sulphate and concentrated to small volume to give 53.2 g of the title compound (yield: 67%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[Cl-].[Li+].[C:18]1(=[O:22])[CH2:21][CH2:20][CH2:19]1>O1CCCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:18]2([OH:22])[CH2:21][CH2:20][CH2:19]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC1
Reactant: N#Cc1cc(I)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C2(O)CCC2)ccc1Br
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To 2-bromo-5-iodobenzonitrile (1457 mg, 4.730 mmol) in tetrahydrofuran (10 mL) at −40° C. was added isopropyl magnesium chloride.lithium chloride (1.3M in THF, 4.4 mL, 5.7 mmol) dropwise. The mixture was stirred at −40° C. for 10 minutes, and was then treated with cyclobutanone (0.4 mL, 5.2 mmol) dropwise at −40° C. The reaction mixture was warmed to room temperature and stirred at that temperature for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1CBr
Yield: 45.2 %

Procedure:
A mixture of 5-bromo-1-cyclopentylmethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.46 g, 13.6 mmol), N-bromosuccinimide (2.66 g, 15.0 mmol), and benzoyl peroxide (0.33 g, 1.36 mmol) in CCl4 (130 mL) was refluxed for 16 h. The resulting suspension was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (0-25% EtOAc/hexanes) to give 2.5 g of the title compound. MS: (+) m/z 408.10 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].ClCCl.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(=O)C(N)C(=O)OC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(Br)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl aminomalonate hydrochloride (1.83 g, 10 mmol) in dichloromethane (30 mL) triethylamine (3 mL, 22 mmol) will be added at 0° C. 4-bromobenzoyl chloride (2.19 g, 10 mmol) will be slowly added the resulting solution will be allowed to stand at room temperature overnight. Water will be added and the organic layer will be separated and dried over anhydrous MgSO4. The evaporation of solvent will result in Int P.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl pyrrolidin-3-ylcarbamate. LC-MS (Condition 6) tR=1.46 min, m/z=488.9 [M+H—H2C═C(CH3)2], m/z=544.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([I:14])[N:10]=[C:9]2[CH3:15])[CH:5]=[CH:4][N:3]=1.[OH-:16].[K+]>C(O)(C)(C)C>[I:14][C:11]1[N:10]=[C:9]([CH3:15])[N:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[C:12]=1[CH3:13]
Reactant: Cc1nc(I)c(C)n1-c1ccnc(Cl)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=315.9 (M+H+), was prepared in accordance with the general method of example 1a from 2-chloro-4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-pyridine and KOH in tert-butanol.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.Br[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:33]#[N:34].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]([C:32]1[CH:31]=[CH:30][C:37]([O:38][CH3:39])=[C:36]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:21]=[C:12]([S:9]([NH:8][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]2=3)[CH:35]=1)#[N:34]
Reactant: COc1ccc(C#N)cc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(C#N)cc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Reaction time: 4 h
Yield: 70.3 %

Procedure:
A vial was charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIate M) (80 mg, 0.192 mmol), 3-bromo-4-methoxybenzonitrile (81 mg, 0.383 mmol), Xantphos (22.17 mg, 0.038 mmol), Pd2(dba)3 (17.55 mg, 0.019 mmol), and cesium carbonate (187 mg, 0.575 mmol). The vessel was flushed with Ar (g), then 1,4-dioxane (1916 μl) was added. The vessel was sealed and placed in a 100° C. heating bath for 20 h. The mixture was filtered through celite with the aid of EtOAc. The filtrate was concentrated, and the residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 4 h, mixture was diluted with MeOH, then concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM). The material this obtained was further purified by chromatography on silica gel (12-g Redi-Sep Gold column, 50-100% EtOAc/Heptane). The resulting solid was taken up in EtOAc, sonicated, and filtered. The collected solid was washed with EtOAc (2×), dried under a stream of N2 (g), then dried under vacuum to give 4-(5-cyano-2-methoxyphenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (58 mg, 0.135 mmol, 70.6% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ=12.55 (br. s., 1 H), 7.92-7.77 (m, 2 H), 7.34 (d, J=8.5 Hz, 1 H), 7.22 (d, J=4.5 Hz, 1 H), 7.16-7.06 (m, 2 H), 6.78 (d, J=4.5 Hz, 1 H), 6.21 (d, J=8.4 Hz, 1 H), 4.30 (br. s., 2 H), 3.85 (s, 3 H), 3.63 (br. s., 2 H); m/z (ESI) 429.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][CH2:61][C:62]([NH:64][C:65]1[CH:79]=[CH:78][C:68]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:67][CH:66]=1)=[O:63]>C(Cl)Cl>[C:73]([O:72][C:71]([NH:70][CH2:69][C:68]1[CH:67]=[CH:66][C:65]([NH:64][C:62](=[O:63])[CH2:61][NH:60][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:79][CH:78]=1)=[O:77])([CH3:74])([CH3:75])[CH3:76]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid (2.66 g, 7.53 mmol, 1.0 eq.) in dry DCM (50 mL) at 0° C. was added N,N-diisopropylethylamine (1.93 g, 15.1 mmol, 2.0 eq) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.86 g, 7.53 mmol, 1.0 eq.). The mixture was stirred at 0° C. for 30 min and #B119 (2.1 g, 7.53 mmol, 1.0 eq.) was added in one portion. The mixture was stirred at room temperature overnight. The mixture was filtered and solid was washed with DCM and dried in vacuo to afford #B120 (4 g, 86.4%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ 9.91 (s, 1H), 8.11 (br, 1H), 7.90 (d, 2H), 7.69 (d, 2H), 7.51 (d, 2H), 7.41 (m, 2H), 7.33 (m, 3H), 7.17 (d, 2H), 4.28 (m, 3H), 4.06 (d, 2H), 3.86 (br, 2H), 2.97 (m, 2H), 2.15 (m, 2H), 1.51 (m, 2H), 1.38 (m, 12H); LCMS (Protocol I): m/z 637.1 (M+Na]+, retention time=1.18 minutes.
Reaction SMILES: [Cl-].[C:2]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([CH2:16][NH:17][CH3:18])[CH:13]=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C>ClCCl>[C:2]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([CH2:16][N:17]([CH3:18])[S:7]([CH3:10])(=[O:9])=[O:8])[CH:13]=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])(=[O:8])=[O:9])([CH3:5])([CH3:4])[CH3:3]
Reactant: CNCc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 179.4 %

Procedure:
0.39 ml (5 mmol) of methenesulfonyl chloride dissolved in 5 ml of dichloromethane are added dropwise to a solution of 1.67 g (5 mmol) of N-tert-butyl-5-methylaminomethyl-2-methanesulfonylbenzenesulfonamide and 0.73 ml (5.3 mmol) of triethylamine in 20 ml of dichloromethane which had been cooled to 0° C. After 30 min at room temperature, the reaction solution is washed with water, dried and completely evaporated in vacuo. 1.85 g (89.7%) of N-tert-butyl-5-(N-methyl-N-methanesulfonylaminomethyl)-2-methanesulfonylbenzenesulfonamide are obtained as a viscous oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]2[CH2:13][C:14](=[O:16])[CH2:15][CH:10]2[CH2:9]1)=O)(C)(C)C.[BH4-].[Na+].[ClH:19]>CO>[ClH:19].[OH:16][CH:14]1[CH2:15][CH:10]2[CH2:9][NH:8][CH2:12][CH:11]2[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CC2CNCC2C1
Reaction time: 1 h

Procedure:
10.00 g (44.4 mmol) of 5-oxo-hexahydro-cyclopenta[c]pyrrol-2-carboxylic acid tert-butyl ester (Hanchem Co. Ltd.) was dissolved in 100 ml of methanol, the temperature was lowered to 0° C., 3.36 g (88.8 mmol) of sodium borohydride was added, and then, the mixture was stirred for 1 hour. And, 15 ml of an aqueous solution of concentrated hydrochloric acid (35% (v/v)) was slowly added, and the mixture was additionally stirred for 1 hour, and then, the solvent was removed under reduced pressure to obtain the title compound.