Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 2-(3-bromo-5-chloro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (7.67 g, 17.5 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-chloro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.12 g, 42%) as a white solid: LC/MS m/e calcd for C20H21BrClNO2 M+: 422.8, observed: 422.0, 424.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[OH:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[Na+]>O.CO>[NH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:12]
Reactant: COc1cccc([N+](=O)[O-])c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(N)c1O
Temperature: 60 °C
Yield: 94 %

Procedure:
To a suspension of 4.72 g of 2-methoxy 6-nitrophenol in a mixture of 100 ml of water and 30 ml of methanol was added 29.3 g of sodium dithionite. The mixture was stirred at 60° C. until it became a uniform and colorless solution. To the reaction mixture was added a saturated aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give 3.65 g of crude 2-amino-6-methoxyphenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21]O.C(N(CC)CC)C.CS([Cl:46])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21][Cl:46]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (510 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (250 μL, 1.8 mmol ) was added to the mixture followed by methanesulfonyl chloride (100 μL, 1.3 mmol). Mixture was stirred at room temperature for 1.5 hours. Mixture was diluted with dichloromethane then washed once with water, twice with 1N hydrochloric acid, and once with brine. Organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 91% yield. MS m/e (M+H)+=491.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([NH:6][C:5]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(N)cc(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(NCc2ccccc2)cc(OC)c1
Reaction time: 0.04 h

Procedure:
N-benzyl-3,5-dimethoxyaniline was prepared using a system (FRX200, Syrris Limited) including a microflow reactor. For this purpose, 76 mg (0.5 mmol) of 3,5-dimethoxyaniline and 5 ml of dimethylformamide were added to the first storage unit of the system including the microflow reactor, and then 70 μl (0.5 mmol) of triethylamine was added thereto. Meanwhile, 60 μl (0.5 mmol) of benzyl bromide and 5 ml of dimethylformamide were added to the second storage unit of the system. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred through the third flow channel into the microflow reactor including microchannels. The first and second flow channels could transfer 360 μl (180 μl for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 250 μl, a temperature of 225° C. and a pressure of 8 bar. The reactants in the first and second storage units were set such that they were passed through the first to third flow channels at a flow rate of 0.05 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set at 2.5 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.CN(C=O)C>O>[Si:18]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2ncc(O)cc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(O[Si](C)(C)C(C)(C)C)cc2c1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A 500 mL flask, equipped with magnetic stirrer and septum, was charged with 16.6 g crude 16 (0.095 mole), 22.1 g TBDMS-Cl (97%, 0.142 mole), 13.1 g imidazole (99%, 0.19 mole) and 240 mL DMF (distilled, added by syringe). The mixture was stirred under argon for 8 hours and then poured into 1.0 L of water and extracted with ether (3×450 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give 36.4 g of crude (orange solid). Crystallization from Et2O-pentane (1:9) and chromatography of the mother liquor concentrate on silica gel (Et2O-pentane 1:2) gave 25.0 g of 17, 91% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc(Cl)c3)CC12
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 3-chlorophenylacetic acid (1.19 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (100 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(3-chlorophenyl)acetyl]-4-perhydroisoindolone (2.2 g) is obtained in the form of white crystals melting at 179° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>O>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[N:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:12](=[O:14])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC(c2ccccc2)CC(=O)N1c1ccncc1
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 19 g of 3-phenylglutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 2.5 g of methane sulfonic acid is refluxed on a water separator while stirring for 2 days. The hot solution is decanted from some insolubles, cooled, filtered and the residue triturated with hot isopropanol, to yield the 4-phenyl-1-(4-pyridyl)-piperidin-2,6-dione melting at 229°-230°; the analogously prepared 4-(p-methoxyphenyl)-1-(4-pyridyl)-piperidine-2,6-dione melts at 168°-169°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl>[Br:17][C:5]1[CH:4]=[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]([CH:16]=2)=[N:13][O:14][N:15]=3)[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: [Br-]
Reactant: Oc1ccccc1-c1ccc2nonc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1-c1ccc2nonc2c1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 5-(2-hydroxyphenyl)benzofurazan (11.2 g, 52.8 mmol), and tetrabutylammonium tribromide (25.5 g, 52.8 mmol) in dichoromethane (530 mL) is stirred at 18° C. for 18 h. The solvent is evaporated off under reduced pressure to yield a residue which is treated with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 5-(3-bromo-6-hydroxyphenyl)benzofurazan as a pale-yellow crystalline solid, m.p. 179-181° C.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:21]#[N:22].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29]>>[NH2:29][C:28]1[N:30]=[C:21]([NH2:22])[C:3]2[S:4][C:5]3[N:6]=[C:7]([N:14]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]4)[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[C:10]=3[C:2]=2[N:27]=1
Reactant: N=C(N)N
Reactant: CCCc1cc(N2CCC(O)CC2)nc2sc(C#N)c(N)c12
Agent: O=C(O)O
Product: CCCc1cc(N2CCC(O)CC2)nc2sc3c(N)nc(N)nc3c12
Temperature: 25 °C
Yield: 16.7 %

Procedure:
3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile (316 mg, 1.00 mol) (see Example 2) and guanidine carbonate (360 mg, 2 mmol) was mixed in a test tube. The mixture was heated to a melt for 15 min until the gas evolution stopped. After cooling to room temperature, the mixture purified by flash chromatography (35 g silica gel cartridge, 10% MeOH in dichloromethane, 30 mL/min for 15 min, Rf=0.25) to give the title compound as a yellow solid (120 mg, 33%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[S-:11][C:12]#[N:13].[NH4+]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:12]([NH2:13])=[S:11])=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)NNc1ccc(Cl)cc1

Procedure:
Fifty g of 4-chlorophenylhydrazine hydrochloride and 40 g of ammonium thiocyanate were added to 250 ml of denatured ethanol and the mixture was stirred under reflux for 16 hours. It was then filtered while still hot and the filter cake was washed with about 100 ml of hot ethanol. As the filtrate cooled, the product began to crystallize, and it was collected and recrystallized from denatured ethanol to obtain 32.7 g of the desired intermediate, m.p. 200°-201°.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([OH:10])([C:8]#[N:9])[CH2:5][C:4]([CH3:12])([CH3:11])[NH:3]1.S(=O)(=O)(O)O.[C:19](O)(=O)[CH3:20]>>[CH2:19]([CH:20]1[NH:9][CH2:8][C:6]2([CH2:5][C:4]([CH3:12])([CH3:11])[NH:3][C:2]([CH3:13])([CH3:1])[CH2:7]2)[O:10]1)[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)(C#N)CC(C)(C)N1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CC(C)CCCCCC1NCC2(CC(C)(C)NC(C)(C)C2)O1

Procedure:
182 g of 2,2,6,6-tetramethyl-4-hydroxy-4-cyanopiperidine, 284 g of isononyl-aldehyde and 200 g of concentrated sulfuric acid are stirred for 25 hours at 60° C. in 600 g of glacial acetic acid in a 2 liter apparatus with agitator. After cooling the main portion of the solvent is distilled off under reduced pressure. The residue is stirred with 500 ml of acetone and suction-filtered, thus yielding 292 g=69% of th. of the sulfuric acid salt of the intended compound.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[C:17]([CH3:33])=[C:16]([Cl:34])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[C:17]=1[CH3:33]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCOC1=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1N1CCOC1=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (6.3 mg, 0.032 mmol), 3-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-1,3-oxazolidin-2-one (10 mg, 0.03 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.057 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min, to give the desired. LCMS calculated for C23H21ClFN6O2 (M+H)+: m/z=467.1. found: 467.1.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]([OH:7])=O.[CH2:8]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C@H:15]1[CH2:19][N:18]([C:5](=[O:7])[CH2:4][O:3][CH3:2])[C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: COCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 43.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-methoxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 122, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide (12 mg, 43.2%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.56-7.59 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.94-7.02 (m, 4H), 4.50 (m, 1H), 4.04 (m, 1H), 3.60 (m, 1H), 3.28 (s. 3H), 3.18 (m, 2H), 2.65 (m, 3H), 1.90 (m, 2H). MS (EI) for C27H27FN2O4. found 463.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[N:27]([CH3:29])[CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[N:27]([CH3:29])[CH3:28]
Reactant: CN(C)c1ccc(B(O)O)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: CN(C)c1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 96.9 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.25 g (6.48 mmol) of 1-bromo-4,5-difluoro-2-[4(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.68 g (8.42 mmol) of 3-chloro-4-(N,N-dimethylamino)phenylboronic acid (Step 2). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 2.65 g (97%) of 2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-N,N-dimethylbenzenamine as a colorless solid: mp 129.0-130.0° C.; NMR (CDCl3) δ 2.81 (s, 6H), 3.05 (s, 3H), 6.76-6.91 (m, 2H), 7.08 (d, J=2 Hz, 1H), 7.17-7.26 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). MS (FAB): m/e 428 (M+Li). Anal. Calc'd for C21H18ClF2NO2S: C, 59.79; H, 4.30;N, 3.32. Found: C, 59.40; H, 4.29; N, 3.24.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]Cl)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NCCCCl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCCSc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 12 from 2-tert-butyl-4-[(3-chloropropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and thiophenol at 100° C. for 45 mins. The reaction mixture was filtered, evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 10-20% EtOAc in hexane as eluent to give the title compound (0.076 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.52-7.48 (m, 2H), 7.46-7.38 (m, 3H), 7.32-7.18 (m, 5H), 5.32 (t, 1H), 3.02-2.96 (m, 2H), 2.70 (t, 2H), 1.74 (s, 9H), 1.68-1.60 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.8, 135.6, 135.1, 131.8, 129.4, 129.9, 129.3, 128.9, 126.7, 125.1, 107.5, 61.8, 42.8, 31.0, 28.9, 27.9; Mass Spectrum: M+H+ 431.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29]>CN(C)C=O>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:6]1[C:5](=[O:8])[N:4]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[C:3](=[O:17])[C:2]([CH3:1])=[N:7]1
Reactant: COC(CCBr)OC
Reactant: Cc1n[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1nc(C)c(=O)n(C(=O)c2ccccc2)c1=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (P2, 90 mg, 0.389 mmol) in N,N-Dimethylformamide (DMF) (0.6 mL), potassium carbonate (64.6 mg, 0.467 mmol) and 3-bromo-1,1-bis(methyloxy)propane (commercially available from Aldrich, 0.071 mL, 0.467 mmol), were added and the mixture was stirred at rt overnight. The day after the reaction mixture was quenched with water and diluted with AcOEt. Organic phase was washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. Crude product was purified by flash chromatography (Cy 100% to Cy/AcOEt 6:4) affording the title compound 2-[3,3-bis(methyloxy)propyl]-6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (92 mg, 0.276 mmol, 70.9% yield) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Br:10])[N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:10][C:4]1[N:3]=[C:2]([NH:1][C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: COc1ccc(Br)nc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)nc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry reaction flask equipped with a nitrogen inlet and magnetic stirring bar was charged with 2-amino-6-bromo-3-methoxypyridine (33) (0.170 g, 0.84 mmol), pyridine (0.126 mL, 1.26 mmol) and CH2Cl2 (5 mL). To this at 0° C. was added pivaloyl chloride (0.113 mL, 0.92 mmol) and then the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (25 mL), extracted with CH2Cl2 (2×25 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to afford 6-bromo-2-(tert-butylcarbonyl)amino-3-methoxypyridine (34). LCMS: purity: 80%; MS (m/z): 287 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:14]
Reactant: CCNCC
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(CC)C1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
10.0 g of pseudosaccharine chloride are initially introduced in 150 ml of toluene. 3.7 g of diethylamine diluted with 25 ml of toluene are added dropwise at room temperature over the course of 30 minutes. After a further 30 minutes, 50 ml of pyridine in 25 ml of toluene are added and the mixture is subsequently stirred at room temperature for 2.5 hours. The solvent is then removed in vacuo and the residue is stirred up with 350 ml of water. The colorless precipitate is filtered off to give 10.1 g (84%) of 3-diethylaminobenzoisothiazole 1,1-dioxide.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]([CH3:40])[CH3:39])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]([CH3:39])[CH3:40])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5][CH2:4][NH:3]1.[C:18]1(=O)N(C2CCCNC2=O)C(=O)C2=CC=CC=C12>>[CH3:18][O:1][C:2]1[CH:6]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5][CH2:4][N:3]=1
Reactant: O=C1NCCCC1N1C(=O)c2ccccc2C1=O
Reactant: O=C1NCCC1N1C(=O)c2ccccc2C1=O
Product: COC1=NCCC1N1C(=O)c2ccccc2C1=O

Procedure:
By analogy with the method described in example 1 (step 1.1), using 2-(2-Oxo-pyrrolidin-3-yl)-isoindole-1,3-dione (prepared by analogy to the method described in (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin -2-one, the compound was obtained as a white powder.