Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:28]Br)[CH:6]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:4]2[S:3]1.C(OCC)(=O)C.P(=O)(O)(O)O>CN(C)C=O>[CH3:1][C:2]12[CH2:28][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:4]1[S:3]2
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Temperature: -10 °C
Yield: 39.1 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2-bromomethyl-6-(2-phenylacetamido)penam-3-carboxylate(1.08 g.) in dimethylformamide (10 ml.) was added 1,8-diazabicyclo[5,4,0]undecene-7(360 mg.) under cooling at -50° to -60°C and stirred at the same temperature for an hour The inner temperature of the reaction mixture was raised to -10°C. The mixture was poured into a solution of ethyl acetate and dilute phosphoric acid and then extracted. The extract was washed with dilute phosphoric acid, water, a saturated aqueous solution of sodium bicarbonate and water in turn, treated with activated charcoal and dried over magnesium sulfate. After removing the solvent, the residue was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate(360 mg.), mp. 140° to 143°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][Cl:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:33]([C:37]1[O:41][C:40]([CH2:42][S:43][C:44]2[S:48][C:47]([NH2:49])=[N:46][CH:45]=2)=[N:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:17][CH2:16][CH2:15][N:4]([CH2:3][CH2:2][Cl:1])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:49][C:47]2[S:48][C:44]([S:43][CH2:42][C:40]3[O:41][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][N:39]=3)=[CH:45][N:46]=2)=[O:14])=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1ccc(N(CCCl)CCCl)cc1
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cnc(CSc2cnc(NC(=O)Cc3ccc(N(CCCl)CCCl)cc3)s2)o1
Reaction time: 24 h
Yield: 76 %

Procedure:
To a stirred methylene chloride solution (20 ml) was added DMAP (438 mg, 3.59 mmol) and 2-(4-(bis(2-chloroethyl)amino)phenyl)acetic acid (B-5) (906 mg, 3.27 mmol). Subsequently, DCC (690 mg, 3.35 mmol) was added to reaction mixture, followed by addition of 5-((5-tert-butyloxazol-2-yl)methylthio)thiazol-2-amine (Intermediate CY-200) (800 mg, 2.97 mmol). The mixture was stirred at r.t for 24 h. After removing dicyclohexylurea (DCU) by filtration, the filtrate was concentrated in vacuum and dried over Na2SO4. The residue was purified by silica gel chromatography eluting with CH2Cl2: EtOAc=20:1 to afford total product (1.2 g, 76%) as a gray solid. LC-MS: (M+H)+=528. 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 7.28-7.30 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.7 Hz, 2H), 6.58 (s, 1H), 3.95 (s, 2H), 363-3.79 (m, 10H), 1.26 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[F:36][C:37]([F:55])([F:54])[C@H:38](OS(C(F)(F)F)(=O)=O)[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>C(Cl)Cl>[F:55][C:37]([F:36])([F:54])[C@@H:38]([NH:1][C@@H:2]([CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([OH:5])=[O:4])[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
2(R)-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6 mmol) was dissolved in CH2Cl2 and DIPEA (112 mL, 643.8 mmol) was added and the reaction mixture was stirred for 10 min at room temperature. Trifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (70 g, 214.6 mmol) in CH2Cl2 was added and the reaction mixture was stirred overnight at room temperature. Solvent was removed under the reduced pressure and the residue was dissolved in Et2O and washed with 1N HCl, brine and dried over MgSO4. Solvent was removed give 2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (90 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]1=2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]3=4)[CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1CNCCC1(O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methyl-piperidin-4-ol (1.0 g, 4.6 mmol) in DMF (10 mL) with triethylamine (1.75 mL, 12.54 mmol), was added 5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (1.38 g, 4.18 mmol) dropwise for over a period of about 1.5 hours at about 50° C. The reaction was stirred overnight at about 50° C. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel:chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield a brown solid of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[S:23]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])(=[O:25])[NH2:24]>>[S:23]([C:27]1[CH:28]=[C:29]([NH:33][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:30]=[CH:31][CH:32]=1)(=[O:25])(=[O:26])[NH2:24]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Light yellow solid. MS (ISP) 476.0 [(M−H)−]; mp 278° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][C@@H:14]([NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:16][C:17](=O)[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][C@@H:14]([NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a stirred solution of (64) (171 mg, 0.35 mmol) in pyridine (9 mL) was added phosphoryl chloride (65 μl) at 0° under argon. After 10 minutes the mixture was brought to room temperature and stirring was continued for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (10 mL), dried, filtered and evaporated under reduced pressure to yield the crude product (101 mg) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)cc(N2CCOCC2)cc1F
Temperature: 10 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
2,4,6-Trifluoronitrobenzene (4.95 g) and potassium carbonate (4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to 10° C. under argon. Morpholine (2.56 mL) was added and the reaction mixture was allowed to warm to 25° C. and stirred under argon for 16 hours. The reaction mixture was concentrated in vacuo Brine (50 mL) was added and the product was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo). The crude material was purified by flash chromatography to furnish 2.49 g (37% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 3.43 (t, 4H), 3.69 (t, 4H), 6.87 (d, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:45])[C:6]=2[N:15]=[C:3]1[CH2:1][CH3:2]
Reactant: [NH4+]
Reactant: CCc1nc2cnc3ccccc3c2n1CCOCCON1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCON
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethoxy}-1H-isoindole-1,3(2H)-dione (11.0 g, 25.5 mmol) in chloroform (150 mL) was added mCPBA (11.4 g, 51.1 mmol). The solution was stirred at room temperature for 2 hours. Concentrated ammonium hydroxide (100 mL) was added, followed by p-toluenesulfonyl chloride (5.40 g, 28.1 mmol). The mixture was stirred overnight at room temperature. The mixture was transferred to a separatory funnel and was washed twice with 5% aqueous ammonium chloride and once with aqueous sodium carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 0-5% methanol in dichloromethane) to provide 6 g of 1-{2-[2-(aminooxy)ethoxy]ethyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([N:43](C)[C:44](=O)OC(C)(C)C)[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([NH:43][CH3:44])[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
TFA (0.5 mL, 6.49 mmol, Eq: 127) was added to a solution of tert-butyl (R)-(2S)-1-((2S)-1-(2-(2-benzoylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (32 mg, 51.0 μmol, Eq: 1.00) in DCM (0.5 mL) and the resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (1×10 mL) and the organic layer was concentrated in vacuo. The crude residue was treated with MeOH/DCM/ether to give (R)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-benzoyl-phenyl)-amide as an off-white solid (24 mg), m/z=528 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])=[C:17]([CH:27]([F:29])[F:28])[CH:16]=3)=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>[Ni](Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:17]([CH:27]([F:28])[F:29])[CH:16]=3)=[C:11]([C:30]([F:32])([F:31])[F:33])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1C(F)F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1C(F)F
Yield: 54.4 %

Procedure:
(E)-Methyl 3-(4-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-2-(difluoromethyl)phenyl)acrylate (55 mg, 0.109 mmol) in a mixed solvent system (MeOH (2 mL); water (0.5 mL)) was treated with sodium borohydride (8.2 mg, 0.218 mmol) and nickel chloride (1.5 mg, 0.011 mmol) for 10 min. The solvent was removed and the residue was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was dried, filtered, and the filtrate was concentrated under reduced pressure. The resultant residue was concentrated and purified by prep-HPLC, eluting with 20-80% acetonitrile in water (0.5% TFA) to give compound 267d as a white solid (30 mg, 54% yield).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[C:12]([CH3:19])([CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH:14]([CH3:16])[CH:13]([OH:17])[C:12]([CH3:18])([CH3:19])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1CN(Cc2ccccc2)CC(C)(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CN(Cc2ccccc2)CC(C)(C)C1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.2 g, 5.26 mmole) was added to the stirred solution of 1-benzyl-3,3,5-trimethylpiperidin-4-one (2.0 g, 8.73 mmole) in methanol (25 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-4-hydroxy-3,3,5-trimethylpiperidine as oil. Yield 1.9 g (91%), C15H23NO, m/z 234 (M+l).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[CH3:13][O-:14].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:14][CH3:13]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,2,4-Trifluoro-5-nitrobenzene (10 g, 56.5 mmol) was dissolved in methanol, cooled in ice and treated with 25% sodium methoxide in methanol. After being stirred at room temperature for 6 hours the mixture was diluted with water and extracted with ethyl acetate to give 1,4-difluoro-2-methoxy-5-nitrobenzene (10.1 g). This was dissolved in ethanol (400 ml) and hydrogenated over 10% palladium on carbon to give the title compound (7.8 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:14][CH2:15]O)[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([CH2:14][CH2:15][S:24]([CH3:27])(=[O:26])=[O:25])[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of (5)-methyl 2-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate (91c, 3.9 g, 15.7 mmol) in anhydrous dichloromethane was added triethylamine, DMAP, and mesyl chloride. The reaction was allowed to stir for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with dicholormethane and the combine organic phases were washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to yield (5)-methyl 2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) as a yellow oil. [M+H] calc'd for C12H26O6SSi, 327; found, 327.
Reaction SMILES: C(OCC(C)OCC1C=CC([C:16]2[C:21]([S:22]([NH:25][C:26]3[C:31]([O:32][CH3:33])=[N:30][C:29]([CH3:34])=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=CC=1)(C)(C)C.[Cl-].[NH4+]>FC(F)(F)C(O)=O>[CH3:33][O:32][C:31]1[C:26]([NH:25][S:22]([C:21]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:23])=[O:24])=[N:27][CH:28]=[C:29]([CH3:34])[N:30]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(COC(C)COC(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
A solution of 2-{4-[(2-tert-butoxy-1-methylethoxy)methyl]phenyl}-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (248 mg) in trifluoroacetic acid (1 ml) was left to stand for 30 minutes. Saturated ammonium chloride solution (20 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml). The extracts were dried (MgSO4) and concentrated and the residue was dissolved in dichloromethane (10 ml). The solution was washed with water (2×10 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/ethyl acetate (1:24 v/v), to give 2-[4-([2-hydroxy-1-methyl)ethoxy]methyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (82 mg), 1H NMR (d6-DMSO): 1.15 (s, 3H), 2.25 (s, 3H), 3.3-3.7 (s, 3H), 3.8 (s, 3H), 4.6 (s, 2H), 7.3-7.55 (m, 5H), 7.6 (dd, 1H), 8.45 (dd, 1H), 8.8 (dd, 1H), 10.35-10.45 (br s, 1H); mass spectrum (+ve ESP): 445 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14]Cl>O>[Cl:14][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: ClCl
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCCC(C)(C)N1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
20 g of 2,2,6,6-tetramethylpiperidine are mixed with water and 6.42 g, 0.6 eq., of calcium hydroxide, and the suspension is cooled to 5° C. Over a period of 1.5 hours, 10.8 g, 1.1 eq. of chlorine gas are introduced, then nitrogen gas is used to drive out the excess chlorine and the mixture is warmed to RT. After separating the phases, washing the aqueous phase with 25 ml of dichloromethane, drying the combined organic phases with magnesium sulphate and distilling off the dichloromethane in vacuo, 24.2 g, 99%, of 1-chloro-2,2,6,6-tetramethylpiperidine are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.O[NH:25][C:26]([C:28]1[S:29][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:31][CH:32]=1)=[NH:27]>>[CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[O:13][N:27]=[C:26]([C:28]4[S:29][C:30]([S:33]([NH2:34])(=[O:36])=[O:35])=[CH:31][CH:32]=4)[N:25]=3)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)O)cnn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.25) (161 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane/MeOH) as a light yellow solid (88 mg, 35%). MS (EI) 506.1 [(M+H)+]; mp 276° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:23]=4[F:31])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH2:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[NH:34][CH3:33])=[CH:24][C:23]=4[F:31])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(=O)O)cc4F)ncc3O2)CC1
Reactant: CN
Product: CNC(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)c(F)c1

Procedure:
The title compound is prepared from 4-[5-(4-carboxy-2-fluoro-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and methylamine following a procedure analogous to that described in Example 26. LC (method 7): tR=1.25 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:3][C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.5 %

Procedure:
To an 8 mL screw-cap vial was added 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (200 mg, 0.74 mmol), CH2Cl2 (5 mL), Et3N (200 mg, 1.98 mmol), and benzoyl chloride (114 mg, 0.82 mmol). The mixture was shaken at room temperature for 2.5 h, evaporated under a stream of nitrogen, and partitioned between EtOAc and H2O. The organic phase was dried over MgSO4, filtered, and evaporated. The crude material was partially purified by normal phase chromatography (gradient, 10 to 50% EtOAc/petroleum ether), and fractions containing the major product were evaporated and recrystallized from EtOAc and petroleum ether to yield the title product as a white solid (112 mg, 41%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 8.31-8.25 (m, 2H), 8.24 (d, J=5.8 Hz, 1H), 8.16-8.11 (m, 2H), 7.82-7.75 (m, 1H), 7.68-7.56 (m, 3H), 7.52-7.44 (m, 2H); ESIMS m/z 374 ([M+H]+), 372 ([M−H]−).