Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][N:4]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)#[N:11].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>O1CCCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10]#[N:11])[CH:8]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: N#Cc1ccccc1B(O)O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccccc1-c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 58 %

Procedure:
A suspension of 2,4-dichloropyridine hydrochloride (prepared according to Effenberger et al. in Chem. Ber., 1992, 125, 1131) (1.24 g, 6.75 mmol), 2-cyanophenylboronic acid (0.97 g, 0.98 mmol) and potassium carbonate (2.84 g, 20.5 mmol) in tetrahydrofuran (23 ml) and water (11 ml) was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)-palladium(0) (382 mg, 0.3 mmol) was then added and the mixture heated at reflux for 3 h then cooled to ambient temperature. The tetrahydrofuran layer was removed and the aqueous layer extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and adsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (10-50%) gave an oil. Trituration with diethyl ether afforded 2-(4-chloropyridin-2-yl)benzonitrile (122 mg) as a white solid: δH (400 MHz, CDCl3) 7.39 (1H, dd, J 5.3 and 1.8), 7.53-7.57 (1H, m), 7.69-7.73 (1H, m), 7.76-7.84 (3H, m), 8.68 (1H, d, J 4.7); m/z (ES+) 215, 217 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:29]2[S:28][N:27]=[CH:26][C:25]=2[CH:24]=[CH:23][C:22]=1[C:30]([OH:32])=[O:31]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[C:29]3[S:28][N:27]=[CH:26][C:25]=3[CH:24]=[CH:23][C:22]=2[C:30]([OH:32])=[O:31])=[C:4]([F:9])[CH:3]=1
Reactant: O=C(O)c1ccc2cnsc2c1F
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (1.05 g, 5.55 mmol) in anhydrous THF (20 mL) at −78° C. was added a 1.0 M solution of LHMDS in hexanes (8.3 mL, 8.3 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (547 mg, 2.78 mmol) in anhydrous THF (20 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 min, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous HCl (ca. 50 mL) and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, MeOH in DCM) to give the title compound as a brown solid (584 mg, 58%). LCMS (method B): RT=3.76 min, [M−H]−=365/367.
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1)=O.C(OO)(=[O:21])C>C1(C)C=CC=CC=1>[OH:21][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Reactant: CC(=O)OO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 79.8 %

Procedure:
While stirring a mixture of 25 g of (+)-butyl 2-(4-formylphenoxy)propionate ([α]D25 =+44.1°) and 75 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After the reaction at 50° C. for 2 hours, the reaction mixture was subjected to liquid separation with an addition of water. The toluene layer was separated and washed with water. To the toluene layer, 25 g of sodium hydrogen carbonate and water was added, and the mixture was reacted at 50° C. for 5 hours. Then, the reaction mixture was subjected to liquid separation. The organic layer was washed twice with water. The organic layer was concentrated by distilling off toluene, and then subjected to distillation under reduced pressure, whereby 19.0 g of (+)-butyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was 160° C./1 mmHg.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:32]=2[N:31]=1)([O:28][CH3:29])[C:4]1[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:10]([CH3:17])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2S(C1C=CC(C)=CC=1)(=O)=O.[O-]CC.[Na+]>CCO>[F:42][C:2]([F:1])([F:41])[C:3]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:32]=2[N:31]=1)([O:28][CH3:29])[C:4]1[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:10]([CH3:17])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(S(C)(=O)=O)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(S(C)(=O)=O)cc(C)c2[nH]ccc12)C(F)(F)F
Temperature: 60 °C

Procedure:
To (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (172 mg, 0.279 mmol) in EtOH (2.8 mL) was added sodium ethoxide (21% in EtOH, 2 mL, 5.58 mmol) and the mixture was stirred at 60° C. After 45 minutes the reaction was cooled to room temperature and purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84-13.00 (m, 1H) 11.59 (br. s., 1H) 8.47 (m) 8.00-8.19 (m) 7.94 (m) 7.61-7.72 (m, 1H) 7.50-7.61 (m) 7.27 (br. s., 1H) 5.45 (br. s., 1H) 3.39 (br. s., 3H) 3.21 (br. s., 3H) 2.57 (s, 3H). HRMS calcd. for C21H17F3N4O3S (M+H)+ 463.1052. found 463.1031.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[O:20][N:19]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.96 (d, J=1.0 Hz, 1H), 7.89-7.80 (m, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.5, 1.5 Hz, 1H), 5.84 (s, 2H), 2.91 (t, J=7.6 Hz, 2H), 1.76-1.47 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (ES) m/z 445 (M+1).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:8]=1.O>C(Cl)Cl>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Boron tribromide was added dropwise, under argon to an about -78° C. solution of about 12.16 g of 4-methoxy-1-tetradecyl-benzene in about 125 ml of methylene chloride. The reaction was stirred for about 21/2 hours at about -78° C., then water was added dropwise, the organic layer separated, washed with sodium bicarbonate solution and evaporated, giving about 11.8 g of the desired title compound, mp 70°-71° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCCC1.CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 23A (0.71 g, 2.28 mmol) in tetrahydrofuran (23 mL) and CH3OH (5.7 mL) was treated with 1N aqueous LiOH (5.7 mL, 5.7 mmol). After stirring overnight at room temperature, the organic solvents were removed under reduced pressure and the remaining aqueous solution was acidified to pH 1 with concentrated HCl. The acidified solution was extracted with ethyl acetate. The extracts were combined, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.06 (m, 4H), 7.69 (m, 2H), 7.38 (m, 2H), 1.29 (s, 9H); MS (ESI+) m/z 298 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16]>>[CH2:8]([N:6]1[C:5](=[O:13])[CH:4]=[CH:3][C:2]([C:23]2[CH:24]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:20]=[CH:21][CH:22]=2)=[CH:7]1)[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CCn1cc(Br)ccc1=O
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CC(C)CCn1cc(-c2cccc(NS(C)(=O)=O)c2)ccc1=O
Yield: 78 %

Procedure:
According to scheme 3 Method A: The title compound was prepared from 5-bromo-1-isopentylpyridin-2(1H)-one (1 eq, 0.41 mmol, 0.10 g) and 3-(methylsulfonamido)phenylboronic acid (1.5 eq, 0.61 mmol, 0.13 g) according to the procedure described for Example 2 Step 2. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using CH2Cl2/AcOEt (80/20) as the eluent to afford N-(3-(1-isopentyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methanesulfonamide (0.32 mmol, 0.11 g, 77%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]=[CH2:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2])[CH:10]=[CH2:11]
Reactant: C=CCOCCOCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOCCOCCO
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a stirred solution of ester (8) (9.77 g, 55.1 mmol, 1.0 equiv.) in THF (100 mL) was carefully added one portion of LAH (95%, 1.10 g, 27.5 mmol, 0.5 equiv.) at 0° C. After 30 min, another portion of LAH was carefully added and the reaction was stirred for an additional 30 min. The reaction was then carefully quenched with a Na2SO4-saturated aqueous solution. The resulting white aluminum salts were then filtered off over a short plug of Celite (EtOAc washings) and the filtrate was evaporated under reduced pressure. Purification was achieved by Kugelrohr distillation under reduced pressure and provided 7.99 g (99%) of alcohol (9) as a colorless oil; bp>200° C. (water tap vacuum). Spectroscopic data were consistent with those reported in the literature.26 1H NMR (400 MHz, CDCl3) δ 5.92 (m, 1H), 5.28 (m, 1H), 5.19 (m, 1H), 4.04 (m, 2H), 3.73 (m, 2H), 3.68 (m, 2H), 3.62 (m, 4H), 2.36 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (341 mg, 1.7 mmol), 1-(-2′,4′-difluoro-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol), and triethylamine (418 μL, 3 mmol) according to the procedure and in the same manner as described in Example 105, step c. The solid was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), and the product (473 mg, 78%) isolated as a white solid, m.p. 127.5-129° C.;
Reaction SMILES: O=[O+][O-].[C:4]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][CH:19]=C)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C[OH:22].C(Cl)Cl.[BH4-].[Na+]>CCOC(C)=O>[C:4]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][CH2:19][OH:22])[CH2:15][CH2:16]1)([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: C=CCOC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CO
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCCO)CC1
Reaction time: 0.08 h

Procedure:
Ozone was bubbled into a solution of 21-3 (1.5 g, 6.4 mmol) in 2:1 CH3OH/CH2Cl2 (102 mL) at -78° C. After 5 min no starting material remained so oxygen was bubbled through the solution for 15 min to remove excess ozone. NaBH4 (1.7 g, 45 mmol) was added and the cooling bath removed. After 1 h the reaction mixture was concentrated. The residue was diluted with H2O (30 mL) and then extracted with CHCl3 (300 mL). The organic phase was washed with brine (30 mL), dried (MgSO4), and concentrated. Flash chromatography (silica, EtOAc) gave 21-4 as a nearly colorless oil. Rf 0.42 (silica, EtOAc).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15]O[C:10]=3[CH:9]=2)[CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1.O[CH:22]1CN(C(=O)C2C=CC(OC)=CC=2)C(C(O)=O)C1>>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:4]([C:18]([O:20][CH3:22])=[O:19])[CH2:3]1
Reactant: COc1ccc(C(=O)N2CC(O)CC2C(=O)O)cc1
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Product: COC(=O)C1CC(O)CN1C(=O)c1ccc(OC)cc1
Yield: 40 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by the 4-hydroxy-1-(4-methoxy-benzoyl)pyrrolidine-2-carboxylic acid obtained in Example 57, the title product is obtained.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1OS(C(F)(F)F)(=O)=O)[C:9]([O:11][CH3:12])=[O:10])([CH:4]=[CH2:5])[CH3:3].[F:24][C:25]1[C:26](B(O)O)=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:25]1[C:26]([C:15]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=2[C:2]([CH3:1])([CH:4]=[CH2:5])[CH3:3])=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1
Reactant: C=CC(C)(C)c1cc(C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1cc(B(O)O)c(F)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: C=CC(C)(C)c1cc(C(=O)OC)ccc1-c1cc(OC)ncc1F
Temperature: 90 °C

Procedure:
The reaction mixture of T45.3 (0.45 g, 1.3 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid (0.55 g, 3.2 mmol), potassium phosphate (0.81 g, 3.8 mmol), S-phos (0.11 g, 0.26 mmol) and palladium acetate (0.03 g, 0.13 mmol) in DMF (1.5 mL) was purged with nitrogen three times. The resulting mixture was heated at 90° C. for 2 hours. The mixture was then purified by CombiFlash® silica gel chromatography, eluent with hexane/EtOAc, 9/1 to give T45.4. MS ESI (pos.) m/e: 330.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (1H, d, J=1.8 Hz), 7.95 (1H, s), 7.90 (1H, dd, J=7.8, 1.8 Hz), 7.06 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=4.9 Hz), 5.88-6.02 (1H, m), 4.75-4.85 (2H, m), 3.95 (3H, s), 3.94 (3H, s), 1.38 (3H, s), 1.36 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][OH:22])=[C:15]([Cl:23])[N:14]=1)(=[O:11])=[O:10].O1CCC[CH2:25]1>[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][O:22][CH3:25])=[C:15]([Cl:23])[N:14]=1)(=[O:11])=[O:10]
Reactant: COc1nc(CO)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: C1CCOC1
Agent: [Mn+4]
Agent: [O-2]
Product: COCc1nc(OC)c(NS(=O)(=O)c2cccc(Cl)c2Cl)nc1Cl
Reaction time: 20 h

Procedure:
To a stirred solution of 2,3-dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide (Example 127) (0.1 g) in tetrahydrofuran (3 mL) was added manganese dioxide (0.131 g) and the resulting suspension was stirred for 20 h, filtered and concentrated. The residue was taken up into methanol (3 mL) and acetic acid (0.1 mL). To this solution was added ethylamine hydrochloride (0.081 g) and sodium cyanoborohydride (0.051 g). The resulting mixture was stirred for 20 h and concentrated onto silical gel (1 g) and eluting with methanol/dichloromethane mixtures to afford the titled compound (0.029 g) as a white solid.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1([NH:20]C(=O)C(F)(F)F)[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=O.N>CO>[NH2:5][CH2:6][C:7]1([NH2:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1
Reactant: O=C(NCC1(NC(=O)C(F)(F)F)CCN(Cc2ccncc2)CC1)C(F)(F)F
Agent: N
Solvent: CO
Product: NCC1(N)CCN(Cc2ccncc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[1-pyridin-4-ylmethyl-4-(2,2,2-trifluoro-acetylamino)-piperidin-4-ylmethyl]-acetamide (200 mg, 0.49 mmol) in MeOH (10 ml) is added 30% aqueous ammonia solution (10 ml) and the reaction mixture is stirred at 60° C. for 3 h. The reaction mixture is concentrated in vacuo to obtain 4-Aminomethyl-1-pyridin-4-ylmethyl-piperidin-4-ylamine as a colourless gummy oil that is used without further purification; 1H NMR (DMSO-d6): 1.63-1.77 (4H, m), 2.45-2.54 (4H, m), 2.49 (2H, s), 3.57 (3H, s), 7.30 (2H, d, J=5.5 Hz), 8.68 (2H, d, J=5.5 Hz).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.C1([CH2:16][O:17]C2C=C([C@@H](O)CC3C(Cl)=C[N+]([O-])=CC=3Cl)C=CC=2OC(F)F)CC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:16]([C:8]1[CH:3]=[CH:4][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:17]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a solution of 2-(3-formylphenyl)acetic acid (394 mg, 2.4 mmol) in DMF (5 mL) was added (1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethanol (1.0 g, 2.4 mmol) followed by DMAP (147 mg, 1.2 mmol) and EDC.HCl (930 mg, 4.8 mmol). The mixture was allowed to stir a room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between DCM (10 mL) and waturated sodium bicarbonate solution (10 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM, to afford the title compound as an off-white solid (312 mg, 23%). 1H NMR (400 MHz, CDCl3): δ 10.00 (s, 1H), 8.04 (s, 2H), 7.81 (d, J=7.5 Hz, 1H), 7.72 (s, 1H), 7.52-7.42 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 6.91-6.85 (m, 2H), 6.62 (t, J=75.3 Hz, 1H), 6.05 (dd, J=9.9, 4.4 Hz, 1H), 3.85-3.76 (m, 2H), 3.72-3.59 (m, 2H), 3.49 (dd, J=14.0, 9.9 Hz, 1H), 3.18 (dd, J=14.0, 4.4 Hz, 1H), 1.32-1.19 (m, 1H), 0.70-0.63 (m, 2H), 0.40-0.34 (m, 2H). LCMS (Method 2): [MH+]=566 at 3.54 min.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=O)[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=C1NS(=O)(=O)c2cccc(F)c21
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(Cl)c2c(F)cccc21
Yield: 93.3 %

Procedure:
1.1 g of 4-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 2 g of thionyl chloride and a catalytic amount of DMF in 6 ml of dioxane are heated under reflux for 18 hours. Then additional 2 g of thionyl chloride are added and the mixture is heated for 8 hours. The mixture is concentrated and 1.12 g of a crude solid is obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[C:4](=[N:14][OH:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20]>O>[S:19](=[O:21])(=[O:20])([OH:23])[OH:22].[OH:16][C:3]1([C:2]([F:17])([F:18])[F:1])[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[N:14][OH:15]
Reactant: Cc1ccccc1CCC(=NO)C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cccc2c1CCC(=NO)C2(O)C(F)(F)F

Procedure:
cyclizing the 1,1,1-trifluoro-5-(2-methylphenyl)-2,3-pentanedione 3-oxime with 100% sulfuric acid or with aqueous sulfuric acid containing from 50 up to 100% by weight of sulfuric acid per volume of water, i.e. 50% up to 100% (w/v) aqueous sulfuric acid, to obtain 3,4-dihydro-1-hydroxy-5-methyl-1-(trifluoromethyl)-2(1H)-naphthalenone oxime;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:37]([O-:39])=[O:38].NN>C(O)C>[NH2:26][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[CH:4][C:3]([N+:37]([O-:39])=[O:38])=[C:2]([NH2:1])[N:7]=2)=[N:13][CH:14]=1
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)c4ccccc4C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Product: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]isoindoline-1,3-dione and 20 mmol of hydrazine were stirred in ethanol at 75° C. for two hours and the resulting product, [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine was purified by column chromatography eluting with 5-10% methanol/methylene chloride.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]=2[CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:18]([C:8]1[O:9][C:10](=[O:17])[C:11]2[C:16]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:19][CH3:20]
Reactant: CCCc1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 72.7 %

Procedure:
4-Phenyl-3-propyl-1H-isochromen-1-one (intermediate C20.3, 107 mg, 0.405 mmol), N-bromosuccinimide (86 mg, 0.486 mmol), benzoyl peroxide (25 mg, 0.1 mmol) were reacted in CCl4 (2 mL) at 100° C. for 2 hrs. The reaction mixture was then purified on Biotage 50 g silica gel cartridge with a gradient of hexane and EtOAc to give the title compound (101 mg, 72.7%) as a yellowish oil.
Reaction SMILES: C([N:9]1[CH2:18][CH2:17][C:16]2[N:15]=[C:14]([CH3:19])[O:13][C:12]=2[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)(=O)C1C=CC=CC=1>Cl.O1CCOCC1>[CH3:19][C:14]1[O:13][C:12]2[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=3[NH:9][CH2:18][CH2:17][C:16]=2[N:15]=1
Reactant: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccccc1)CC2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c(o1)-c1ccccc1NCC2
Yield: 83 %

Procedure:
6-Benzoyl-2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene from Example E5.8 (11.0 g, 3.25 mmol) was reacted with a 6M HCl/dioxan solution (100 ml) using an analogous procedure to that described for Example E5.9 to yield the title compound (540 mg, 82%).