Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: N#Cc1ncccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncccc1-n1cncn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-3-fluoro-pyridine (2.99 g, 24.49 mmol) in DMF (30 ml) is added cesium carbonate (2.03 g, 29.39 mmol) and 1,2,4-triazole (2.03 g, 29.39 mmol) and the reaction mixture is stirred at 65° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The aqueous layer is saturated with LiCl and further extracted with EtOAc. The combined organic layer is dried on sodium sulfate, concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 2% MeOH containing 10% NH4OH in CH2Cl2 to 6%) to give 3-[1,2,4]Triazol-1-yl-pyridine-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) δ8.95 (s, 1H); 8.8 (d, J=4 Hz, 1H); 8.24 (s, 1H); 8.22 (d, J=8.5 Hz, 1H); 7.75 (dd, J=4, 8.5 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Br:30])=[C:6]([CH:29]=1)[CH2:7][N:8]1[C@@H:12]([CH3:13])[C@@H:11]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[O:10][C:9]1=[O:28].N(OC(C)(C)C)=O.[CH3:38][S:39]SC>>[F:25][C:24]([F:27])([F:26])[C:16]1[CH:15]=[C:14]([C@H:11]2[O:10][C:9](=[O:28])[N:8]([CH2:7][C:6]3[CH:29]=[C:2]([S:39][CH3:38])[CH:3]=[CH:4][C:5]=3[Br:30])[C@H:12]2[CH3:13])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(N)ccc1Br
Reactant: CSSC
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (457 mg, 0.92 mmol) in methyl disulfide (4 mL) was added tert-butyl nitrite (182 μL, d=0.867, 1.38 mmol). The resulting mixture was stirred at 80° C. for 1 h. An aliquot indicated completion of the reaction. The titled compound was obtained as a glassy material after preparative TLC plates eluted by 25% EtOAc in hexanes. LC-MS: 529.71 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)C(C)Oc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)Oc1ccc(CBr)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
17 gm (0.08 mol) of ethyl 2-(4-methyl-phenoxy) -propionate and 0.2 gm of 2,2'-azo-bis-(2-methyl-propionitrile) were dissolved in 100 ml of chloroform, and the solution was heated to its boiling point. One-half of a solution of 5.4 ml of bromine in 20 ml of chloroform was then added to the boiling solution over a period of 45 minutes. The reaction mixture was now cooled to about 40° C., an additional 0.2 gm of the catalyst was added, the mixture was again heated to its boiling point, and the other half of the chloroformic bromine solution was added. The mixture was kept boiling for two hours more and was then cooled to room temperature. The resulting reddish-brown solution was extracted three times with 100 ml each of a saturated aqueous sodium bicarbonate solution, the combined aqueous extracts were extracted twice with 50 ml each of methylene chloride, and the combined organic extracts were dried over sodium sulfate. The methylene chloride was now distilled off in a water aspirator vacuum, and the liquid evaporation residue was fractionally distilled in an oil pump vacuum, yielding 70% of theory of ethyl 2-(4-bromomethyl-phenoxy)-propionate, b.p. 128°-134° C. at 0.2 mm Hg.
Reaction SMILES: O[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1)[CH2:3][N:4]([CH2:12][CH2:13][OH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH3:24][C:17]1[CH:16]=[C:15]([CH:2]2[O:14][CH2:13][CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:3]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1cc(C(O)CN(CCO)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-hydroxy-2-(3-methyl-4-nitrophenyl)ethyl(2-hydroxyethyl)carbamate (6.55 g) and triethylamine (3.22 ml) in THF (50 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (1.65 ml). The reaction mixture was then stirred at room temperature for 30 min to afford a yellow suspension. TLC analysis showed a small amount of starting material remaining and so further aliquots of triethylamine (0.5 ml) and methanesulfonyl chloride (0.2 ml) were added. The reaction mixture was stirred at room temperature for a further 20 min and was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (17.0 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-methyl-4-nitrophenyl)morpholine-4-carboxylate (2.21 g, 36%) as a yellow oil. MS (ISP): 223.1 ([M+H—O5H8O2]+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1ccncc1
Product: O=C(CNC(=O)c1ccncc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and isonicotinic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].ClCCl.[CH3:50][C:51]([CH3:53])=O>C(O)(=O)C>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH:51]([CH3:53])[CH3:50])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 60 %

Procedure:
To a suspension of 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.23 mmol) in dichloromethane/acetone is added NaBH(OAc)3 (488 mg, 2.3 mmol) followed by 3 drops of glacial acetic acid. After reaction is completed and concentrated. Diluted with 100 mL of H2O and basified to pH12 with 50% NaOH solution dropwise (2 mL). Extracted with dichloromethane (3×100 mL) and concentrated to give 7-cyclopentyl-2-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (65 mg, 60%). MS (ESI) m/z 476.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=2[C:24]#[N:25])[CH:17]=1.FC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(C=1)C#N.ClC1C=C(Cl)C=CN=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]([C:18]2[CH:17]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:21]=[CH:20][N:19]=2)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1cc(F)ccc1-c1cc(Cl)ccn1
Agent: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Agent: Clc1ccnc(Cl)c1
Product: CC(C)(O)c1ccn2c(-c3ccnc(-c4ccc(F)cc4C#N)c3)cnc2c1F

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 2-(4-chloropyridin-2-yl)-5-fluorobenzonitrile (prepared from 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile and 2,4-dichloropyridine by an analogous procedure to that described in WO 02/076983), by the method of Example 23, to give 5-fluoro-2-{4-[8-fluoro-7-(2-hydroxyprop-2-yl)imidazo[1,2-α]pyridin-3-yl]pyridin-2-yl}benzonitrile: δH (500 MHz, CDCl3) 1.75 (6H, s), 2.08 (1H, s), 7.32 (1H, t, J 7.0), 7.45-7.49 (1H, m), 7.53-7.56 (2H, m), 7.92 (1H, s), 7.98 (1H, t, J 0.7), 7.99 (1H, dd, J 3.4, 5.4), 8.50 (1H, d, J 7.3), 8.87 (1H, d, J 5.1); m/z (ES+) 391. Also isolated from the above reaction was 5-fluoro-2-{4-[8-fluoro-7-(2-hydroxyprop-2-yl)imidazo[1,2-α]pyridin-3-yl]pyridin-2-yl}benzamide: δH (500 MHz, DMSO) 1.59 (6H, s), 7.35-7.44 (3H, m), 7.60 (1H, t, J 0.6), 7.66 (1H, dd, J 0.5, 0.7), 7.82-7.84 (1H, m), 7.85 (1H, s), 7.95 (1H, s), 8.05 (1H, s), 8.60 (1H, d, J 7.1), 8.73 (1H, d, J 5.4); m/z (ES+) 409.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[S:3].Br[CH:24]1[C:30](=O)[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[O:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CCO>[CH2:15]([O:14][C:13](=[O:22])[NH:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][NH:4][C:2]2[S:3][C:24]3[CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=4[C:30]=3[N:1]=2)[CH2:7][CH2:8]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2OCCC1Br
Reactant: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1)OCc1ccccc1
Yield: 64.3 %

Procedure:
A solution containing benzyl N-(4-{[(aminocarbothioyl)amino]methyl}-cyclohexyl)carbamate (3.45 g, 10.73 mmol), 4-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-one (2.60 g, 10.78 mmol), and diisopropylethylamine (2.50 ml) in EtOH (50 ml) was heated at reflux for 4 hours. The solvent was removed and the residue was chromatographed on silica gel eluting with 1:3 EtOAc/hexane to yield 65% (3.2 g) of the product as a white solid: m.p. 124-127° C.; 1H-NMR (CDCl3) δ 1.09 (4H, pentet, J=10.4 Hz), 1.55 (1H, broad), 1.83 (2H, m), 2.04 (2H, broad), 3.10 (2H, t, J=6.2 Hz), 3.15 (2H, t, J=5.2 Hz), 3.43 (1H, broad) 4.33 (2H, t, J=5.2 Hz), 4.62 (1H, d, J=8.0 Hz), 5.08 (2H, s), 5.31 (1H, m), 7.00 (1H, dd, J=1.2 Hz, 7.8 Hz), 7.12 (2H, m), 7.35 (5H, s), 8.25 (1H, dd, J=1.7 Hz, 7.8 Hz). ESIMS m/z=464 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].[I-].[Na+]>CN(C=O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][C:9]12[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]1[C:7]([NH:11][C:10]2=[O:12])=[O:17]
Reactant: CC(C)(O)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)CC12C=CC=CC1C(=O)NC2=O
Yield: 37 %

Procedure:
A solution of 1-chloro-2-methyl-2-propanol (2.23 g, 97%, 0.02 mol), potassium phthalimide (3.780 g, 98%, 0.02 mol) and sodium iodide (60 mg, 4 mmol) in anhydrous DMF (40 mL) was heated to reflux overnight. The solvent was evaporated under reduced pressure. The resulting product was triturated with a mixture of 3:2 ethyl acetate/hexanes and the ensuing white precipitate was removed by filtration. The yellow filtrate was concentrated under reduced pressure and purified by flash chromatography in a mixture of 2:3 ethyl acetate/hexanes. The impure product thus isolated was triturated with hot hexanes (125 mL) and filtered to remove an insoluble white impurity. After evaporation of the solvent under reduced pressure, the obtained white solid was recrystallized in hexanes. The product was yielded as colorless crystals that were collected by filtration and dried under high vacuum (1.63 g, 37% yield). m.p.: 104-105° C.; TLC Rf 0.20 (2:3 ethyl acetate/hexanes); FTIR (KBr): 3524, 3456, 3097, 3031, 2973, 2930, 1773, 1698, 1611, 1466, 1427, 1389, 1319, 1190, 1076, 990, 965, 912, 890, 838, 766, 724, 712, 638 cm−1; 1H-NMR (500 MHz, CDCl3): δ 1.26 (s, 6H, 2 CH3), 2.74 (s, 1H, OH), 3.75 (s, 2H, CH2), 7.72 (dd, 2H, Jo=5.44 Hz, Jm=3.04 Hz, 2 Hc), 7.85 (dd, 2H, Jo=5.42 Hz, Jm=3.06 Hz, 2 Hh); 13C-NMR (126 MHz, CDCl3): δ 27.6 (2 CH3), 49.3 (CH2), 71.6 (CMe2), 123.6 (2 Cb), 132.0 (2 Ca), 134.3 (2 Cc), 169.3 (2 CO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:8]2=[O:17]
Reactant: CC(=O)[O-]
Reactant: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Intermediate 23 (5 g, 16.17 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (9.2 g, 82.03 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as off-white solid (3.81 g, 71% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.34(d, J=2.3Hz, 1H), 7.76(dd, J=8.8, 2.2Hz, 1H), 7.41(m, 2H), 7.24(m, 2H), 7.18(t, J=8.9Hz, 1H), 2.30(s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:37].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:35])=[O:37])=[CH:32][CH:33]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methylsulfanyl-phenyl)-ethanol (5 g, 10 mmol) in methanol (100 mL) and water (30 mL) was added sodium metaperiodate (4.3 g, 20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methaneylsulfinyl-phenyl)-ethanol (5.1 g, quant.) as a light yellow solid: LC/MS m/e calcd for C27H27FN2O4S2 [M+H]+ 527.65, observed 527.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3C(=O)[C:11](=[O:14])[C:12]([CH:13]=1)=[C:5]23.[OH-:16].[Na+].OO>O>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][NH:6][C:5]2=[C:12]([C:11]([OH:14])=[O:16])[CH:13]=1
Reactant: O=C1C(=O)N2CCOc3cc(Cl)cc1c32
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1NCCO2
Yield: 80.5 %

Procedure:
To a stirred suspension of 8-chloro-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5,6-dione (4.47 g) in water (50 ml) was added 2N sodium hydroxide solution (30 ml), and the mixture was stirred to a solution. 30% hydrogen peroxide solution (20 ml) was added and stirred for an hour, insoluble material was filtered off and then acidified with concentrated hydrochloric acid. The yellow precipitate was collected by filtration, washed with water and dried to yield 3.44 g (80.5%) of the title compound. The compound was recrystallized from benzene (75 ml) to give pale yellow prisms, mp 209°-210° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@H:13]([O:15][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of Boc-Pro(4-cis-OH)-OBn (8.45 g, 26.3 mmol) in pyridine (65 mL) at 0° C., was added methanesulfonyl chloride (3.4 mL, 44 mmol) dropwise over 7 min. The reaction mixture was allowed to warm to room temperature over 2 h, then stirred overnight. A solution of 10% water in pyridine (20 mL) was added over 15 min and the reaction mixture was concentrated. The residue was dissolved in water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×50 mL) saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated. The resulting residue was dissolved in toluene (100 mL) and concentrated to remove traces of pyridine. The residue was dried in vacuo for 30 min to afford the title compound (10.7 g, 102%), then used in the next step without purification.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH:18]([C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]2[C:26]([CH3:33])([CH3:32])[CH2:25][CH2:24][C:23]([CH3:35])([CH3:34])[C:22]=2[CH:21]=1)=O>CS(C)=O>[CH3:31][O:30][C:29]1[C:20]([C:18]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:21][C:22]2[C:23]([CH3:35])([CH3:34])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:33])[C:27]=2[CH:28]=1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Solvent: CS(C)=O
Product: COc1cc2c(cc1C#Cc1ccc(C)cc1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A solution of 20.2 g (0.18 mole) of potassium tert.-butylate in 45 ml of dimethyl sulfoxide was added dropwise to a solution of 23.2 g (0.09 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate and 22.1 g (0.09 mole) of 2-formyl-5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethylnaphthalene in 270 ml of dry dimethyl sulfoxide at room temperature. The mixture was stirred for 30 minutes, poured onto 1 liter of ice water and extracted three times with ether. The ether phase was washed twice with water, dried over sodium sulfate and evaporated down to give 22.6 g (76%) of a slightly impure product. Recrystallization from methanol gave 15.2 g (51%) of the pure title compound of melting point 127° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3](/[C:7](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:8]\[OH:9])=[N:2]1.[C:17](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:17][O:9]/[N:8]=[C:7](\[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: O/N=C(\C1=NOCCO1)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CO/N=C(\C1=NOCCO1)c1ccccc1O
Reaction time: 16 h
Yield: 62.7 %

Procedure:
1.2 g (0.0054 mol) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) in 5 ml of dimethylformamide are stirred at 20° C. together with 0.66 g (0.0062 mol) of sodium carbonate initially for 30 minutes. 0.83 g (0.00658 mol) of dimethyl sulphate is then added and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is adjusted to a slightly acidic pH using 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 0.8 g (50.35% of theory) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 80.3% (HPLC) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[S:16][C:17](Br)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[S:16][C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)s2)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)s2)c1
Temperature: 80 °C

Procedure:
{3-[(5-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (220 mg, 0.60 mmol) was coupled to phenylboronic acid using Method E except that the reaction mixture was heated at 80° C. for 25 min under microwave conditions. The crude product was purified by column chromatography using 33% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([F:22])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:28][C:29](=[CH2:33])[C:30](Cl)=[O:31]>C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:30](=[O:31])[C:29]([CH3:33])=[CH2:28])=[C:17]([F:22])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reaction time: 2 h

Procedure:
To 4′-Amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (5.000 g, 15.51 mmoles) at room temperature in ethyl acetate (50 ml) was added saturated sodium bicarbonate, aqueous, 50 ml and then 2-methyl-acryloyl chloride (1.25 equiv.). Stirred for 2 hours then added a further 1 ml of the acid chloride. After 2 hours an aliquot showed product by NMR. Product seems to co-run with starting material. Extracted into ethyl acetate, washed with brine, dried MgSO4, and then concentrated in vacuo. Collected some crystalline product from ethyl acetate hexane, 0.48 g. Columned mother liquor to afford product. Combined with previously crystallized fraction to afford N-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-yl)-2-methyl-acrylamide (4.520 g). APCI (AP+): 391 (M+H)+.