Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][C:20]([O:23][CH2:24][CH3:25])=[N:21][CH:22]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH3:25])=[N:21][CH:22]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: CCOc1ncc(Br)cn1
Solvent: C1CCOC1
Product: CCOc1ncc(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cn1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.8 g, 8 mmol) and 5-bromo-2-ethoxy-pyrimidine (1.6 g, 8 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) are stirred for 1 hour at ambient temperature in the presence of sodium tert-butylate (4 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)-phenyl]palladium(II) (111 mg, 0.16 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is triturated in heptane to obtain the expected compound after filtration.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccc(Cl)cc1

Procedure:
To 2-bromobenzaldehyde (2.3 ml) and tetrakis(triphenylphosphine)palladium(0) (0.35 g) in toluene (50 mL), was added 4-chlorophenylboronic acid (4.0 g) and 2M Na2CO3 (70 ml). The mixture was heated under reflux for one hour. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers back-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. The crude material was purified by flash chromatography using 97.5/2.5 hexane/ethyl acetate.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.C(N(CC)CC)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4]/[C:9](=[CH:22]\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: O=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(=O)N/C(=C\c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol), which is compound (8) mentioned in Reference Example 3, was heated at 120°-130° C. in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol). After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml), and washed three times with brine. Any solid formed at this stage was filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NCC#Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-prop-2-ynylamine (2.5 g) in 50 mL of THF at room temperature was added a 1M solution of LiAlH4 in THF (30 mL) and the mixture was heated at reflux for 1 hr. It was cooled to room temperature, and to it was successively added 1.1 mL H2O, 1.1 mL of 15% aq. NaOH and 3.4 mL H2O. The precipitated solid was filtered off and the filtrate was concentrated and purified by chromatography to provide 1.45 g of 3-(4-chloro-phenyl)-allylamine. NMR (400 MHz, CDCl3) 7.26-7.21 (m, 4H), 6.42 (dt, J=16.0, 1.6 Hz, 1H), 6.29-6.22 (m, 1H), 3.44 (dd, J=5.6, 1.6 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The product from Step 4 above (60 mg, 0.1 mmol) was dissolved in 4 M HCI in dioxane (4 mL). Water (1 mL) was added and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was dissolved 20% aqueous acetonitrile and lyophylization yielded 4-chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as the hydrochloride salt. 1H NMR: (400 MHZ, DMSO-d6) δ 8.55 (d, J=6 Hz, 1 H), 8.45 (d, J=2 Hz, 1 H), 8.32 (d, J=2 Hz, 1 H), 8.18-8.15 (m, 1 H), 8.05 (d, J=2 Hz, 1 H), 7.95 (d, J=8.4 Hz, 1 H), 7.53 (m, 1 H), 2.20 (s, 3 H), 2.03 (s, 3 H). MS: (M+H)/z=504.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1>C1(C)C=CC=CC=1.[OH-].[K+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[O:19][CH:16]1[CH2:17][CH2:18][N:14]([CH3:13])[CH2:15]1
Reactant: CN1CCC(O)C1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(OC2CCN(C)C2)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 4-Fluoro-2-methoxy-1-nitrobenzene (Apollo Scientific; 4.28 g, 25 mmol) in toluene (20 mL) and 25% KOH aq. (20 mL), were added at room temperature, 1-methyl-3-pyrrolidinol (5.0 g, 50 mmol) and tetra-n-butylammonium bromide (1.66 g, 5 mmol). The mixture was heated at 60° C. for 18 hrs. The reaction mixture was cooled to room temperature, poured onto ice-water (200 mL) and extracted with Ethyl Acetate (3×100 mL). The organic layer was washed with 2 M HCl (250 ml) and then loaded onto a 50 g SCX-2 cartridge, washing with water and eluting with 7 N methanolic ammonia to give the title compound as a yellow oil, which solidified on standing (5.50 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].C(N(CC)C(C)C)(C)C>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([C:12]([C:13]#[N:14])([CH3:16])[CH3:15])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(C)(C)C#N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-amino-5-tert-butyl-2-methoxyphenyl)-2-methylpropanenitrile (0.050 g, 0.202 mmol) in THF (0.6 mL), 2,2,2-trichloroethyl chloroformate (0.052 g, 0.245 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.304 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 0.086 g (quantitative) of the captioned compound.
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]1.[NH2:21][NH2:22]>C(O)C>[I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:21][NH2:22])=[O:13])[CH2:7][CH2:6]1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2I)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccccc2I)CC1

Procedure:
Synthesized according to General Procedure C: 6{27} (4.87 g, 12.5 mmol, 1 equiv.), anhydrous hydrazine (1.2 mL, 37.6 mmol, 3 equiv.), ethanol (25.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{27} (4.08 g, 87%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.17 (br s, 1H), 7.82 (dd, 1H, J=1.2, 7.6 Hz), 7.37 (dd, 1H, J=1.6, 7.6 Hz), 7.29 (dt, 1H, J=1.2, 7.2), 6.91 (dt, 1H, J=1.6, 7.6 Hz), 3.85 (br s, 2H), 3.52 (s, 2H), 3.08 (s, 2H), 2.54 (br s, 8H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 140.2, 139.5, 130.2, 128.7, 128.0, 100.6, 61.2, 60.6, 53.7, 52.9.
Reaction SMILES: [Cl-].C[Al+]C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1.C([O:15][C:16]([C:18]1[CH:19]=[C:20]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[C:21]2[CH:25]=[CH:24][S:23][C:22]=2[CH:26]=1)=O)C>ClC(Cl)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:16]([C:18]2[CH:19]=[C:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=3)[C:21]3[CH:25]=[CH:24][S:23][C:22]=3[CH:26]=2)=[O:15])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2ccsc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3ccsc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Dimethylaluminum chloride (15.5 mmol, 15.5 ml of 1M in hexanes) was added to a solution of 2-amino-5-picoline (1.67g, 15.5 mmol) in dichloroethane (10 ml) at 0 C. The mixture was allowed to warm to room temperature, held 30 minutes at room temperature, then recooled to 0° C. and treated with 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester (0.58 g, crude product from previous step) in dichloroethane (5 ml). The mixture is allowed to warm to room temperature and held at room temperature for 8 h. The reaction was quenched by the drop wise addition of MeOH (2 mL) at 0 C, followed by 1M aqueous pH6 phosphate buffer (10 ml), then ethyl acetate (50 ml). Separation of the organic layer followed by evaporation yielded crude product (1.1 g). This was purified by silica gel chromatography (0-20% MeOH/CHCl3) to yield 0.35 g (59%) of 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85(s, 1H), 8.69 (s, 1H), 8.22(d, J=8.8, 2H), 8.10 (d, J=8.6, 1H), 8.03 (d, J=5.5, 1H), 7.94 (d, J=8.8, 2H), 7.76 (d, J=1.3, 1H), 7.67 (dd, J=9.0, 2.0, 1H), 7.38 (d, J=5.5, 1H), 7.26 (d, J=8.8, 2H), 3.21 (s, 3H0, 2.28 (s, 3H). LRMS for C22H18N2O4S2 m/z 439 (M+H)+. Anal. Calcd. for C22H18N2O4S2 C, 60.26;H, 4.14; N, 6.39; Found: C, 60.58; H, 4.23; N, 6.22.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:20]1([CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([NH:1][C:2]2[N:3]=[N:4][N:5]([CH2:7][CH2:8][CH3:9])[N:6]=2)=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCn1nnc(N)n1
Product: CCCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 124-125° and MS: (neg. ions): m/e=320.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-propyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][C:6]=1[Br:7].[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:7][C:6]1[CH:5]=[CH:4][O:3][C:2]=1[C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: Brc1ccoc1Br
Reactant: OB(O)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Brc1ccoc1-c1ccncc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A degassed mixture of 2,3-dibromofuran (11.3 g, 50 mmol), 4-pyridyl boronic acid (M. Lamothe et al, J. Med. Chem., 1997, 40, 3542) (6.15 g, 50 mmol) and potassium carbonate (55 g, 0.4 mol) in ethylene glycol dimethyl ether (300 ml) and water (150 ml) was treated with triphenylphosphine (1.31 g, 5 mmol) and palladium acetate (625 mg, 2.5 mmol) then heated under reflux for 18 hours. After cooling to room temperature, the mixture was filtered through filter aid and the filtrate diluted with water and ethyl acetate. The organic phase was separated, washed with water and brine, dried, concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (6.0 g, 54%); MS(ES+) m/e 224/226 [M+H]+.
Reaction SMILES: CN(C)[C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[C:13]=1[F:27].[OH-:30].[Na+]>CCO.O>[F:18][C:17]1[C:16]([F:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([F:26])=[C:13]([F:27])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:30])=[O:28]
Reactant: CN(C)C(=O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F

Procedure:
A mixture of N,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoro-4′-phenylanilino)phenylacetamide (2.7 g, 6.7 mmol) and NaOH (3.0 g, 72 mmol) in EtOH (100 mL) and water (20 mL) is heated at reflux temperature for 14 hours. After cooling to room temperature, most of the ethanol is removed by rotary evaporator. Ice water (250 mL) and ice cold Et2O (250 mL) are added and the organic phase is separated and washed with ice cold 1 N HCl (200 mL) and then brine (100 mL). The organic solution is dried (MgSO4) and evaporated by rotary evaporator taking care not to warm above 50° C. The title compound is obtained by trituration of the residue with hexane (m.p. 180–181° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[F:33].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:17][C:6]1[CH:5]=[C:4]([C:18]([OH:21])([CH3:19])[CH3:20])[CH:3]=[C:2]([F:1])[C:7]=1[C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[F:33]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)(C)O)cc2F)n1
Temperature: 120 °C

Procedure:
To a nitrogen purged mixture of 2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (1.53 g, 5.13 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.20 g, 5.13 mmol) and DIPEA (2.7 mL, 15 mmol) in 1,4-dioxane (20 mL) and water (1.2 mL), bis(tri-tert-butylphosphine)palladium (262 mg, 0.513 mmol) was added. The reaction mixture was heated at 120° C. for 40 min., then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate as a white powder, which was used without further purification.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:24])(=[O:3])[CH3:2].[OH:25]O.O>C(O)(=O)C>[C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[O:25])[CH2:6][C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C1C(=O)CC(CCS(=O)c2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 2.3 g of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione in 10 ml of acetic acid, 1.8 g of 30% H2O2 was dropped under cooling with ice-water bath. After stirring for 1 hour at room temperature, the reaction solution was poured into water and extracted with ethyl acetate. Removal of solvent afforded 1.83 g of 2-acetyl-5-[2-(4-trifluoromethylphenylsulfinyl)ethyl]cyclohexane-1,3-dione. m.p. 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cncc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cncc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-chloropyridin-3-yl)oxy]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[Si](C)(C)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl>[C:39]([NH:20][C:19]1[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])=[CH:22][N:15]([C@@H:13]2[O:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@@H:11]([OH:33])[CH2:12]2)[C:16](=[O:17])[N:18]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(N)nc2=O)C[C@@H]1O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The starting material (8) (10 g, 20.43 mmol) was azeotroped in dry pyridine (2×100 ml) then dissolved in dry pyridine (160 ml) under N2 atmosphere. Chlorotrimethylsilane (10 ml, 79.07 mmol) added drop wise to the solution and stirred for 2 hours at room temperature. Benzoyl chloride (2.6 ml, 22.40 mmol) was then added to solution and stirred for one further hour. The reaction mixture was cooled to 0° C., distilled water (50 ml) added slowly to the solution and stirred for 30 minutes. Pyridine and water were evaporated from mixture under high vacuum to yield a brown gel that was portioned between 100 ml of sat. aq. NaHCO3 (100 ml) solution DCM. The organic phase was separated and the aqueous phase extracted with a further (2×100 ml) of DCM. The organic layers were combined, dried (MgSO4), filtered and the volatiles evaporated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica gel (DCM:MeOH 99:1 to 95:5) to yield a light yellow crystalline solid (13) (8.92 g, 74%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.94 (m, 1H, H-2′), 2.27 (m, 1H, H-2′), 3.64 (d, 1H, J=11.6 Hz, H-5′), 3.75 (d, 1H, J=11.6 Hz, H-5′), 3.91 (m, 1H, H-4′), 4.09 (br m, 3H, CH2NH, H-3′), 5.24 (s, 1H, 3′-OH), 6.00 (m, 1H, H-1′), 7.39 (m, 2H, Ph), 7.52 (m, 2H, Ph), 7.86 (m, 1H, Ph), 8.0 (s, 1H, H-6), 9.79 (t, 1H, J=5.4 Hz, NHCH2), 12.67 (br s, 1H, NH). Mass (+ve electrospray) calcd for C27H33F3N4O6Si 594.67. found 595.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=[O:18].CO>[Pd]>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN1C(=O)CCc2cc(C(F)(F)F)ccc21

Procedure:
To a stirring mixture of 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid in Pd/C was added MeOH. The reaction mixture was placed under an atmosphere of hydrogen (balloon) for several hours. The product mixture was filtered through a plug of celite. The plug was washed several times with EtOAc. The mixture was concentrated under reduced pressure and the crude amine was taken directly to the next reaction without further purification. Retention time (min)=1.841, method [1], MS(ESI) 274.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1nc2c(Br)cc(N)cc2[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 4-bromo-2-methyl-6-nitro-1H-benzo[d]imidazole (35 g, 137 mmol) and Tin(II) chloride dihydrate (185 g, 822 mmol) in methanol (800 mL) was added conc. HCl (10 mL), and the mixture was stirred at 65° C. for 2 h. Then the solvent was removed in vacuo, and the residue was diluted with 1N Na2CO3 solution (600 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated to give the crude product (30.2 g, 97%) as a brown solid; LC/MS: MS (ES+) m/e 226 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 4.98 (s, 2H), 6.52 (d, J=1.5 Hz, 1H), 6.66 (d, J=1.5 Hz, 1H), 11.86 (s, br, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=CC)[CH3:2].C(O)(C(F)(F)F)=[O:22].O=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[O:22])[CH3:2]
Reactant: CC=CC(CC(=O)OCC)c1cnc2ccccc2c1
Reactant: O=C(O)C(F)(F)F
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CC(C=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 22-3 (1.0 g, 3.7 mmol), TFA (0.06 mL, 3.9 mmol), and sudan red (0.5 mg) in anhydrous CH2Cl2 (50 mL) was cooled to −78° and treated with O3 until the sudan red color disappeared (5 min). Solid Ph3P (1.4 g, 5.6 mmol) was added and the solution warmed to room temperature. After 30 min., the solution was washed with sat. NaHCO3, dried, filtered, and evaporated. Chromatography on silica gel (10% acetone/EtOAc) afforded 22-4 as colorless glass.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:27]=1[O:28][CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:27]=1[O:28][CH2:29][C:30]1([NH:33][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:32][CH2:31]1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1cccc(C)c1OCC1(N)CC1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(C)c1OCC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 191 mg (1 mmol) 1-(2,6-dimethyl-phenoxymethyl)-cyclopropylamine. Yield: 194 mg (49%, trifluoroacetate); mass spectroscopy: [M+H]+=399.