Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]S[C@@H:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12]2)[CH2:9][CH2:8]1>CO.O>[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:15][S:3](=[O:5])(=[O:2])[C@@H:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12]2)[CH2:8][CH2:9]1
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CS(=O)(=O)[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 18 h
Yield: 96.4 %

Procedure:
Oxone (488 mg, 0.80 mmol) was added to a solution of tert-butyl (2S,6S)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-thiazepan-6-ylcarbamate (60 mg, 0.16 mmol) in methanol (7.5 mL) and water (7.5 mL). After 18 h, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (63 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:11]([N:9]1[C:8](=[O:15])[N:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:4]2=[N:10]1)[CH:12]([CH3:14])[CH3:13]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cn1
Temperature: 150 °C
Yield: 32.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.04 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20° C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 5 mg of the title compound as a white solid. MS: [M+H]+=388.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][C@@H:23]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:24]#[C:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:19][O:20][C:21](=[O:34])[CH2:22][C@@H:23]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:12][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=3)[CH:16]=[CH:15][CH:14]=2)=[CH:31][CH:32]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50° C. for 16 h then filtered and concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes). Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][CH:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]2=O)=[C:4]([F:26])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][CH:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]2=[S:28])=[C:4]([F:26])[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)CC1Sc2ccccc2N(Cc2ccc(Br)cc2F)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2ccc(Br)cc2F)C1=S
Yield: 110.5 %

Procedure:
To 4 ml of toluene was added 440 mg of the compound of Example 20 and 310 mg of phosphorus pentasulfide. After the mixture was heated to reflux for 6 hours, the solvent was distilled off. Methylene chloride was added to the mixture, and the insoluble substance was filtered off and the solvent was distilled off. Then the residue was purified by silica gel chromatography to give 350 mg of ethyl 2-[4-(4-bromo-2-fluorophenylmethyl)-3,4-dihydro-3-thioxo-2H-1,4-benzothiazin-2-yl]acetate. The structural formula and physical data of this compound are shown in Table 24.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[F:36][C:37]([F:50])([F:49])[O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>ClCCl.C(OCC)(=O)C>[F:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:18]([C@@H:8]([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@H:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][S:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][C:37]([F:36])([F:49])[F:50])=[CH:44][CH:43]=3)(=[O:47])=[O:46])[CH2:13][CH2:12]2)[CH3:10])=[O:19])[CH2:21]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](C1CCC(N)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](C1CCC(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material from Step B of Example 24 (32 mg, 0.085 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.022 mL, 0.13 mmol), and 4-(trifluoromethoxy)-benzenesulfonyl chloride (0.034 mL, 0.094 mmol). After 2 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by preparative thin layer chromatography (65% ethyl acetate in hexanes) afforded the title compound as a white solid. LC/MS 496.1 (M+1-Boc).
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:11].[CH2:12](Br)[CH:13]=[CH2:14].C([OH:18])C>[OH-].[Na+]>[CH2:12]([O:18][C:4]1[CH:5]=[CH:6][C:1]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:2][CH:3]=1)[CH:13]=[CH2:14].[Na+:11]
Reactant: O=S(=O)([O-])c1ccccc1
Reactant: CCO
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1ccc(S(=O)(=O)[O-])cc1

Procedure:
30 g of sodium phenylsulfonate are dissolved in 60 ml of ethanol and 50 ml of 15% sodium hydroxide, 20 g of allyl bromide are added and the mixture is refluxed for 48 hours. The ethanol is concentrated and the precipitate obtained is filtered off and then dried under vacuum in the presence of phosphorus pentoxide to give 23.3 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C>[NH2:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])c(O)cc1F
Solvent: CCO
Product: N#Cc1cc(N)c(O)cc1F
Yield: 95.3 %

Procedure:
A solution of 2-fluoro-4-hydroxy-5-nitrobenzonitrile (D66; 270 mg, 1.483 mmol) in ethanol (35 mL) was passed through an H-Cube flow hydrogenator at room temperature and atmospheric pressure on full H2 mode, with a flow rate of 1 mL min−1 and using a CatCart30 (approx. 140 mg catalyst). The residual solution was diluted with further ethanol (8 mL) to ensure maximum recovery of material. The collected product solution was evaporated to dryness to give the desired product as a tan solid (215 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][N:11](/[N:14]=[CH:15]/[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:10]1[CH:26]=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.O>[Si:1]([O:8][C@@H:9]1[C@@H:10]2[N:11]([N:14]=[C:15]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([Cl:24])[C:17]=3[CH3:25])[C@H:26]2[OH:27])[CH2:12][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(/C=N/N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2C=O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: O
Product: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate (IIIa) 4-((E)-((2S,3S)-3-(tert-butyldimethylsilyloxy)-2-formylpyrrolidin-1-ylimino)methyl)-2-chloro-3-methylbenzonitrile (7.0 g, 0.0172 moles) in DCM (100 mL) at 0° C. was added borontrifluoride diethyl etherate (6.2 mL, 0.0207 moles) and reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was diluted with DCM, water and washed with saturated NaHCO3 aqueous solution, water, brine, dried over Na2SO4 and concentrated to get the crude product. Purification of the crude by column chromatography over silica gel using 10% EtOAc in hexane as a solvent provided the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:36]3[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
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+]
Product: COc1ccc(C(F)(F)F)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O

Procedure:
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Example 66, 100 mg; 0.171 mmol) was treated with [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid (Step B, 113 mg; 0.514 mmol), tetrakis(triphenylphosphine)palladium (0) (24 mg; 0.0206 mmol), and sodium carbonate (148 mg) as described in Example 291 to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass. LCMS=612.1 (M−19)+. 1H NMR (benzene-d6, 500 MHz, mixture of atropisomers): δ 7.61 (s, 1H), 7.40-7.36 (m, 1 H), 7.31 (s, 1 H), 7.27-7.23 (m, 4 H), 6.74-6.72 (m, 1 H), 6.35 (d, J=8.7 Hz, 1 H), 4.42-4.32 (m, 2 H), 3.70 (d, J=15.8 Hz, 1 H), 3.14 (s, 3 H), 2.28 (t, J=8.7 Hz, 1 H), 1.98 (t, J=8.2 Hz, 1 H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:6][CH:3]2[CH2:4][CH2:5][S:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC1CCSC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCSC2)cc1
Temperature: 16 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a chilled solution of 1.12 g (0.0098 mole) of tetrahydrothiophene-3-ol in 15 mL of pyridine was added 1.91 g (0.01 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred in the cold, about 16° C., for 1 hour then placed in a cold refrigerator for 16 hours. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. An additional 0.3 g (0.0016 mole) of 4-methylphenylsulfonyl chloride was added, and the reaction mixture was stirred at room temperature for 64 hours. The reaction mixture was poured into water, and the whole was extracted with methylene chloride. The methylene chloride solution was dried and concentrated to give 1.28 g of product as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH:17]4[CH2:19][CH:15]3[CH2:16]4)[N:11]=[C:10]([N:20]3[CH2:25][C@@H:24]4[CH2:26][C@H:21]3[CH2:22][N:23]4C(OC(C)(C)C)=O)[CH:9]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].FC(F)(F)C(O)=O>ClCCl>[CH:15]12[CH2:16][CH:17]([CH2:19]1)[CH2:18][N:14]2[C:12]1[N:13]=[C:8]([C:5]2[CH:4]=[C:3]([C:34]([F:37])([F:36])[F:35])[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=[C:10]([N:20]2[CH2:25][C@@H:24]3[CH2:26][C@H:21]2[CH2:22][NH:23]3)[N:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CN4)nc(N3CC4CC3C4)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To an ice-cooled solution of (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 0.25 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 0.5 h. After removal of the solvent, the residue was dissolved with water (30 mL), basified and extracted with dichloromethane (3×30 mL). The organic layer was dried over sodium sulfate, concentrated to provide 5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80 mg, 75.0% yield). LCMS (ESI): [MH]+=417.9.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH2:30])=[CH:18][CH:17]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:30][C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[S:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OC)cc3)ccnc2n1
Yield: 98.4 %

Procedure:
The product from Example 3f (79 mg, 0.41 mmol) was reacted with the product from Example 50b (88 mg, 0.41 mmol) for 23 h giving following the procedure from Example 1g providing the crude title compound that was triturated with 3:1 ether/THF to give the title compound (162 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.35 Hz, 3H) 2.34 (s, 3H) 3.05 (q, J=7.35 Hz, 2H) 3.72 (s, 3H) 6.27 (d, J=6.98 Hz, 1H) 6.85 (m, J=8.82 Hz, J=2.20 Hz, 2H) 7.10 (d, J=8.09 Hz, 1H) 7.23-7.32 (m, 4H) 7.83 (d, J=8.83 Hz, 1H) 8.41 (d, J=6.98 Hz, 1H) 9.11 (d, J=8.83 Hz, 1H) 11.16 (br s, 1H) 14.39 (br s, 1H); MS (ESI+) m/z 402 (M−Cl)+; (ESI−) m/z 400 (M−HCl)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=1)=[O:4].Cl.[O:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:21]1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([N:17]2[CH2:18][CH2:19][CH2:20][O:14][CH2:15][CH2:16]2)=[O:12])[CH:9]=1)=[O:4])[CH3:21]
Reactant: COC(=O)c1cc(C(=O)O)c[nH]1
Reactant: C1CNCCOC1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N2CCCOCC2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.7 %

Procedure:
To 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (291 mg) in DCM (18 mL) was added [1,4]oxazepane hydrochloride (236 mg), PyBroP (802 mg) and DIEA (878 μL). The mixture was stirred for 3 h at RT after which it was washed with saturated aqueous NaHCO3 solution and 1 N HCl. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate) to provide 4-([1,4]oxazepane-4-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (533 mg). This material was used directly used in the next step although traces of phosphine oxide impurities resulting from the coupling reagent were still present.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C@H:16]2[NH:21][C:20](=[O:22])[CH2:19][O:18][CH2:17]2)=[CH:13][CH:12]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[I:8][C:24]1[CH:23]=[C:14]([CH:13]=[CH:12][C:11]=1[O:10][CH3:9])[CH2:15][C@H:16]1[NH:21][C:20](=[O:22])[CH2:19][O:18][CH2:17]1
Reactant: COc1ccc(C[C@@H]2COCC(=O)N2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@@H]2COCC(=O)N2)cc1I
Reaction time: 0.67 h

Procedure:
A solution of NIS (559 mg, 2.49 mmol) in DCM (3 mL) was added dropwise to a RT solution of (R)-5-(4-methoxy-benzyl)-morpholin-3-one C-6 (500 mg, 2.26 mmol) and trifluoromethanesulfonic acid (220 μL, 2.49 mmol) in DCM (3 mL) under argon and the resulting mixture was stirred for 40 min. The reaction was quenched with sat. aq. NaHCO3 and the layers were separated. The organic layer was washed with water (2×), dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a pale yellow solid. LC-MS B: tR=0.62 min; [M+H+MeCN]+=388.95.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7](F)([F:9])[F:8])[CH2:3][CH2:2]1.[B:11]([F:14])([F:13])[F:12].CCOCC>C(OCC)C>[B-:11]([F:8])([F:14])([F:13])[F:12].[CH2:3]1[N+:4](=[S:7]([F:9])[F:8])[CH2:5][CH2:6][O:1][CH2:2]1
Reactant: FS(F)(F)N1CCOCC1
Reactant: FB(F)F
Solvent: CCOCC
Product: FS(F)=[N+]1CCOCC1
Product: F[B-](F)(F)F
Temperature: 25 °C
Yield: 150.2 %

Procedure:
To an ice-cold solution of morpholinosulfur trifluoride (4.9 mL, 40 mmol) in anhydrous diethyl ether (100 mL) is added, dropwise and under nitrogen, a solution of borontrifluoride etherate (4.2 mL, 40 mmol) in anhydrous diethyl ether (25 mL) over a period of 60 min, while keeping the reaction temperature below 5° C. The resulting suspension is stirred for an additional hour at the same temperature, then allowed to warm to room temperature and filtered under a blanket of nitrogen. The solid material is rinsed twice with diethyl ether (2×50 mL), then dried under vacuum to provide morpholinodifluorosulfinium tetrafluoroborate (7.3 g, 75%) as a white solid; m.p. 122-125° C.; 1H NMR (CD3CN, 300 MHz) δ 3.90-3.85 (m, 8H); 19F NMR (CD3CN, 282 MHz) δ 10.2 (s, 2F), −151.3 (s, 4F); 13C NMR (CD3CN, 75 MHz) δ 65.7, 48.3 (br).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7](OC(=O)C)[C@@H:6]1[NH:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:11][C@H:10]1[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7]2[C@H:6]([N:24]=[C:25]([CH3:26])[O:27]2)[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:14])[CH3:13]
Reactant: CC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Yield: 120.3 %

Procedure:
Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 ml, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step. MS (ISP): 330.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18](C1SC(C#N)=CC=1)=[O:19])[CH2:10]2>>[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:19])[CH2:10]2
Reactant: N#Cc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1
Reactant: COc1cccs1
Agent: Cl
Product: COc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1

Procedure:
This compound is prepared from 2-methoxythiophene according to the procedure used to make the compound of Example 18, making noncritical variations. Yield for 2 steps 33%. mRMS (FAB) calculated for C13H18N2O2S+H 267.1167, found 267.1167.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:18])[CH2:14][C:15](=O)[CH3:16].[CH3:19][O:20][C:21](=[O:24])[C:22]#[CH:23]>CO>[CH3:19][O:20][C:21](=[O:24])[CH:22]=[CH:23][C:14](=[C:15]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:16])[C:13]([O:12][CH3:11])=[O:18]
Reactant: COC(=O)CC(C)=O
Reactant: C#CC(=O)OC
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 4-methoxybenzyl amine (3 g, 21.9 mmol) and 3-oxo-butyric acid methyl ester (2.83 mL, 26.2 mmol) in MeOH (80 mL) was refluxed for 2 h. Propynoic acid methyl ester (2.92 mL, 32.8 mmol) was added, and the resulting mixture was refluxed for 48 h. After cooling to r.t., the solvent was evaporated, and the crude residue was recrystallized from MeOH to give 5 g of the title compound as a yellow solid. 1H NMR (CDCl3, 200 MHz): δ=10.87 (br s, 1H), 7.76 (d, 1H, J=15.4 Hz), 7.18 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.8 Hz), 6.09 (d, 1H, J=15.4 Hz), 4.50 (d, 2H, J=5.8 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][N:2](C(=O)C)[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].Cl.N>C(O)C>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: CC(=O)N(C)c1sccc1C(=O)c1ccccc1F
Agent: Cl
Agent: N
Solvent: CCO
Product: CNc1sccc1C(=O)c1ccccc1F
Temperature: 90 °C

Procedure:
To a solution of 2.5 g of N-methyl-2-acetylamino-3-(o-fluorobenzoyl)thiophene in 12.5 ml of ethanol, is added 6.6 ml of 6 N aqueous hydrochloric acid. The mixture is heated at 90°C for 3 hours. After cooling, the reaction mixture is neutralized with aqueous ammonia, then extracted with ether. The ether extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give an oil, which is crystallized from ethanol to give 2-methylamino-3-(o-fluorobenzoyl)thiophene as crystals having a melting point of 184.5° - 186°C.