Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: OCCCCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCCCCO)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 6-bromohexanol (1.28 g, 7.0 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:18])C(=O)C1>>[Br:18][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a suspension of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16 mmol) in CDCl3 (65 mL) was added NBS (2.9 g, 16 mmol) and the reaction mixture stirred and heated at reflux for 2.5 hours. The mixture was cooled to room temperature, the solids isolated by vacuum filtration, rinsed with cold CHCl3 and air dried to give 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 79%.) LCMS (APCI+) m/z 232 and 234 [M+H]+; Rt: 2.32 min. 1H NMR (DMSO-d6, 400 MHz) δ 12.98 (1H, br. s), 8.63 (1H, s), 7.96 (1H, s.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]1(=[O:34])[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29]1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:30]1[CH2:31][CH2:32][CH2:33][C:28](=[O:34])[CH:29]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1C
Reactant: O=C1C=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4=CC(=O)CCC4)cc3c2c1C
Yield: 7.2 %

Procedure:
In a pressure vessel, 1.08 g (3 mmol) of 6-iodo-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated to 140° C. for 3 hours with 72 mg (0.06 mmol) of palladium(II) acetate, 0.48 ml (3.6 mmol) of triethylamine, and 432 mg (4.5 mmol) of 2-cyclohexen-1-one in 10 ml of absolute dimethylformamide. After concentration, the mixture is chromatographed over silica gel with methylene chloride:ethanol=10:2. After recrystallization of the combined polar fractions from methylene chloride/cyclohexane, 75 mg (6.7% of theory) of 6-(1-oxo-2-cyclohexen-3-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is obtained, mp 245°-248° C. After recrystallization from ethyl acetate, the combined nonpolar fractions, which are chromatographed twice over silica gel with toluene:glacial acetic acid:water=10:10:1, yield 60 mg (5.8% of theory) of 6-(1-oxocyclohex-3-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 182°-189° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1(S)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([S:8][C:11]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[N:7]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. EI-MS m/e (%): 304 (M+, 76), 303 ([M—H]+, 100).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1>C(Cl)Cl>[C:1]([NH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Acetic anhydride (0.173 ml, 1.83 mmol) and pyridine (0.296 ml, 3.67 mmol) were added to a solution of 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.367 mmol) in DCM (3 ml). The reaction mixture was stirred for 4 h at r.t. and then evaporated to dryness under vacuum. The residue was purified by PTLC (10% methanol in DCM) to give product as a white solid (0.115 g, 99%). M.p. 143-5° C. MS (m/z): [M+H]+=315.
Reaction SMILES: [F:1][C:2]1[C:3]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([N+:15]([O-])=O)=[CH:13][N:12]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:11]=3)=[N:7][C:6]=2[CH:24]=1.[H][H]>CO.[Pd]>[CH3:31][N:29]([CH3:30])[CH2:28][CH2:27][CH2:26][O:25][C:3]1[C:2]([F:1])=[CH:24][C:6]2[N:7]=[C:8]([C:10]3[C:14]([NH2:15])=[CH:13][N:12]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:11]=3)[NH:9][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3N)nc2cc1F
Yield: 93.4 %

Procedure:
A suspension of 2.3 g of (3-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yloxy}propyl)dimethylamine in 40 mL of methanol and 0.2 g of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 18 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 2.0 g of 3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are obtained in the form of a brown solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.46 to 2.21 (m, 8H); 2.17 (s, 6H); 2.40 (t, J=7.0 Hz, 2H); 3.63 (m, 1H); 3.95 (m, 1H); 4.08 (m, 2H); 4.92 (broad s, 2H); 5.32 (dd, J=2.5 and 10.0 Hz, 1H); from 7.01 to 7.47 (m, 2H); 7.31 (s, 1H); 12.55 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[N:10](C(OC(C)(C)C)=O)[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.3 %

Procedure:
To a solution of compound 11c (705 mg, 1.91 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to give compound 11d (603.3 mg) as a white solid. MS m/z (M+H+) 270.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25]>>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH2:18][N:12]([C:4]2[CH:3]=[C:2]([NH:25][CH2:24][CH2:23][NH2:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:13][CH2:14]1
Reactant: NCCN
Reactant: Clc1cc(N2CCOc3ccccc3C2)nc2ccccc12
Product: NCCNc1cc(N2CCOc3ccccc3C2)nc2ccccc12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The mixture of 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) and 1.6 mL of ethane-1,2-diamine was heated with stirring in a 5 mL microwave process vial for 3 hours at 150° C. under microwave irradiation. The mixture was concentrate in vacuo to give a residue which was purified by preparative HPLC to give 31 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 335. 1H NMR (400 MHz, CD3OD) δ ppm 8.61 (s, 1 H), 7.90 (d, J=7.6 Hz, 1 H), 7.60-7.51 (m, 3 H), 7.23 (brs, 2 H), 7.09-6.98 (m, 2 H), 6.05 (s, 1 H), 4.89 (s, 2 H), 4.27 (s, 2 H), 4.25 (s, 2 H), 3.61 (s, 2 H), 3.15 (s, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH:9]([CH3:30])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:17]([CH3:18])[C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:32][CH:31]=2)[CH3:30])=[O:29])=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)C(C)Oc1ccc(N)cc1
Yield: 72.1 %

Procedure:
2-(4-nitrophenoxy)propionic acid-2-[2-(4-nitrophenoxy)propionyloxy]ethyl ester 49 (50 g, 89.3 mmol) was dissolved in dry dimethylformamide (400 ml) in a pressure vessel, palladium on carbon (5%, 12.5 g) added, and the mixture stirred under an atm. of hydrogen (4 Kg) for 4 hours. The catalyst was removed by filtration and ice water (3 L) was added to the filtrate. Crude 50 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using chloroform as eluant to give pure 50 (25 g, 58%) as a syrup.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:6]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[N:5]=1)(=[NH:3])[NH2:2].[N:30]#[C:31]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([NH:3][C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:6]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[N:5]=1)=[NH:2])#[N:30]
Reactant: N#CBr
Reactant: N=C(N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CNC(=N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Yield: 40.9 %

Procedure:
A mixture of 6-carbamimidoyl-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (0.013 g, 0.034 mmol), CNBr (3N, 0.017 mL, 0.051 mmol), DIPEA (0.0085 mL, 0.051 mmol), in DCM (0.10 mL) was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated to dryness and purified by RP-HPLC using a mixture of acetonitrile and H2O to give 6-(N-cyanocarbamimidoyl)-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide as a solid (0.0058 g, 41%). LC/MS (M+H+) m/z 418.1.
Reaction SMILES: Br[C:2]1C=CC(Cl)=C(C(C2C=CC(OCC)=CC=2)O)C=1.[H-].[Na+].CI.Cl.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:44])=[C:30]([CH:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)[O:33][CH3:34])[CH:31]=1>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:44])=[C:30]([C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)([O:33][CH3:34])[CH3:2])[CH:31]=1
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Reactant: CCOc1ccc(C(OC)c2cc(Br)ccc2Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)(OC)c2cc(Br)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
3.42 g of (5-bromo-2-chlorophenyl)(4-ethyoxyphenyl)methanol prepared according to example 1 and 10 ml of anhydrous THF were added into a 100-ml round-bottomed flask, and the resulting solution was cooled in ice-water bath and magnetically stirred. 0.40 g (60%) of solid NaH was added in portions, after which, the resulting mixture was stirred for another one hour, and then 1.70 g of dried MeI was added. The reaction mixture was stirred overnight at room temperature, poured carefully into 200 ml of ice water, and adjusted pH to 4-5 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness on a rotary evaporator to afford a colorless oily product, which was (5-bromo-2-chlorophenyl)(4-ethyoxyphenyl)(methoxy)methane. ESI-MS, m/z=355.2 ([M(79Br)+1]), 357.2 ([M(81Br)+1]).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC>C(O)(=O)C>[CH3:15][O:14][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[NH:16][C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])=[N:1][C:2]=3[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1ncccc1-c1ccc(N)c(N)c1
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COc1ncccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-(2-methoxypyridin-3-yl)phenylamine 3 obtained from above reaction (0.215 g, 1 mmol) in acetic acid (2 mL) cooled to 0° C. was added methyl trichloroacetimidate (0.193 g, 1.1 mmol) under N2 atmosphere and resulting reaction mixture was stirred at room temperature for 3 h. Acetic acid was evaporated to give crude 5-(2-methoxypyridin-3-yl)-2-(trichloromethyl)-1H-benzimidazole which was used as such in the following step (0.3 g). Reference: Louvet, P.; Lallement, G.; Pemot-Marino, I.; Luu-Duc, C.; Blanchet, G. Eur. J. Med. Chem. 1993, 28, 71-75.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([N:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]1=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])c(OCc2ccccc2)ccn1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 4.68 g (30 mmol) of 2,4-dihydroxy-3-nitro-pyridine in 100 ml of dimethylformamide was combined batchwise at ambient temperature with 2.88 g (60 mmol) of a 50% suspension of sodium hydride in paraffin oil and stirred for 15 minutes. Then 8.91 ml (75 mmol) of benzylbromide were added and the mixture was stirred for 24 hours at 80° C. The solution was then carefully stirred into approx. 250 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and evaporated down in vacuo. The residue was triturated with diethyl ether, suction filtered and dried. The product thus obtained was further processed without any purification.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(OCC(C)C)=O.[CH3:38][N:39]1CCOCC1.CN>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH:39][CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at −10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stirred for 18 hours. The reaction mixture was concentrated in vacuo, suspended in water, filtered and washed with water, ethyl acetate and diethyl ether. 1H NMR (400 MHz, CD3OD) δ 8.03 (dddd, J=3.0, 6.4, 9.2 and 11.6 Hz, 1H), 7.81 (dd, J 3.0 and (0.2 Hz, 1H), 7.66 (q, J=10.4 Hz, 1H), 7.47 (t, J=12 Hz, 1H), 7.06 (t, J=12 Hz, 2H), 6.67 (s, 1H), 5.38 (s, 2H), 2.91 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.50 (1 F), −115.97 (1 F), −120.16 ppm. ES-HRMS m/z 481.0346 (M+H calcd for C21H17BrF3N2O3 requires 481.0369).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.Cl.[NH2:19][OH:20].N1C=CC=CC=1.Cl>CO>[OH:20][N:19]=[CH:1][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: NO
Reactant: COC(c1cc(C)no1)c1ccccc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(c1cc(C)no1)c1ccccc1C=NO
Yield: 81.2 %

Procedure:
To 1.39 g (6 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylisoxazole in 12 ml of methanol was added 0.83 g (12 mmol) of hydroxylamine hydrochloride and 1.07 ml (13.2 mmol) of pyridine and stirred under reflux for 2 hours. After completion of the reaction, 200 ml of 0.1 N hydrochloric acid was added and extracted twice with 100 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylisoxazole (1.20 g, 81.2%) as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 6.8 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 40 ml of tetrahydrofuran, 1 ml of triethylamine and 0.78 g of 3-fluorobenzenesulfonyl chloride. 0.1 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a cream solid melting at 195° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(C)=O>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:1][C:2]2[CH:14]=[CH:13][C:5]3[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=3[CH:3]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1cc2ccc(O)cc2o1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(OCCN3CCOCC3)cc2o1
Temperature: 60 °C
Reaction time: 72 h
Yield: 73.4 %

Procedure:
To a stirred solution of 267 (650 mg, 3.39 mmol) in a 1:1 mixture of DMF-acetone (20 mL) was added 4-(2-chloroethyl)morpholine (630 mg, 3.39 mmol) and potassium carbonate (937 mg, 6.78 mmol). The reaction mixture was stirred at 60° C. for 72 hours. The solvents were removed under reduced pressure and water (50 mL) was added to the residue. 2M Sodium carbonate solution (20 mL) was added and the resultant solution was extracted with ethyl acetate (2×40 mL). The organic phase was separated, dried with sodium sulfate and the solvents removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1:1 ethyl acetate-hexanes, then ethyl acetate, then 9:1 ethyl acetate-methanol. This afforded 268 as a clear oil (760 mg, 73% yield). 1H NMR: (DMSO) δ 7.67-7.63 (m, 2H), 7.32 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 4.14-4.16 (m, 2H), 3.85 (s, 3H), 3.57-3.55 (m, 4H), 2.88-2.86 (m, 2H), 2.72-2.70 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH2:30]([O:32][P:33]([O:37]CC)[O:34][CH2:35][CH3:36])[CH3:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:33]([O:34][CH2:35][CH3:36])([O:32][CH2:30][CH3:31])=[O:37])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Yield: 44.5 %

Procedure:
A solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%)/hexanes, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C as an oil (70 mg, 43%); 1H NMR (300 MHz, CDCl3)1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), (s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH:10]([OH:13])[O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]2[CH2:12][CH2:11][CH:10]([O:13][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CC[C@@H](COc2ccc(F)cc2)O1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(COc2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.47 g of (2S)-(4-fluorophenoxymethyl)-5-hydroxytetrahydrofuran 7 in 30 mL of CH2Cl2 was taken in an100 mL round bottom flask equipped with a magnetic stir bar and nitrogen inlet. That solution was cooled in an ice-water bath and 2.18 g (0.032 mol) of imidazole was added, followed by a solution of 3.6 g (0.024 mol) of tert-butyldimethylsilylchloride (TBDMSCl) in 30 mL of CH2Cl2. The reaction mixture then was stirred at room temperature for 3 hours, and the reaction then quenched with ice water, the organic layer separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using light petroleum ether:ethyl acetate (9:1) to yield (2S) (4-fluorophenoxymethyl)-5-(tert-butyldimethylsiloxy)-tetrahydrofuran) 8 as an oil (5.1 g, 95%). 1HNMR (200 MHz, CDCl3): γ 0.09 (s, 6 H), 0.88 (s, 9 H), 1.72-2.34 (m, 4 H), 3.76=4.08 (m, 2 H), 4.28-4.54 (m, 1 H), 5.47 (s, 1/3 H), 5.54 (d, J=4.5 Hz, 2/3 H), 6.75-7.0 (m, 4H).