Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][C:4]1[C:5]([CH3:20])=[N:6][N:7]([CH2:18][CH3:19])[C:8]=1[S:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:10]([S:9][C:8]2[N:7]([CH2:18][CH3:19])[N:6]=[C:5]([CH3:20])[C:4]=2[CH2:3][NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]([Cl:17])[CH:13]=1
Reactant: Nc1cccnc1
Reactant: CCn1nc(C)c(CCBr)c1Sc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(CNc2cccnc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 7.5 %

Procedure:
A mixture of 227 mg of 4-bromoethyl-5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole, 62 mg of 3-aminopyridine and 36 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 15 minutes. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol for the elution to give 17 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-ylmethyl]-pyridin-3-yl-amine as a brown gum. 1H NMR (DMSO-d6) 1.19 (t, 3H), 2.27 (s, 3H), 4.05-4.11 (m, 4H), 6.03 (t, 1H), 6.87 (d, 1H), 6.99 (m, 1H), 7.04 (d, 2H), 7.44 (t, 1H), 7.72 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH2:38]([O:40][CH:41]1[CH2:44][NH:43][CH2:42]1)[CH3:39]>>[CH2:38]([O:40][CH:41]1[CH2:44][N:43]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:42]1)[CH3:39]
Reactant: CCOC1CNC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: Cl
Product: CCOC1CN(Cc2ccc(C#Cc3ccc(C(=O)N(C)[C@@](C)(C(=O)NC)C(=O)NOC4CCCCO4)cc3)cc2)C1
Yield: 73.9 %

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.30 g) as obtained in Example 16-(1) and 3-ethoxyazetidine hydrochloride (0.11 g), there was obtained (2S)-2-{[4-({4-[(3-ethoxyazetidin-1-yl)methyl]phenyl}ethynyl)benzoyl](methyl)amino}-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.26 g, 74%) in the same manner as in Example 16-1-(3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[NH:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH3:16]C(C)([O-])C.[K+].COS(OC)(=O)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:16][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH:13]=[O:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(cc1C=O)NC(=O)CC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde 30 mg (0.146 mmol) was dissolved in 5 ml of anhydrous THF and the solution was cooled to 0° C. The reaction mixture was treated with 16 mg (0.146 mmol) of potassium t-butoxide whereupon it became yellow in color. After stirring for 30 minutes, the mixture was treated with 14 μl (0.146 mmol) dimethylsulfate and slowly warmed to room temperature while stirring for 16 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to an oil. The residue was chromatographed on silica gel eluting with 6/4 ethyl acetate/hexane to afford 16 mg (50%) as a white solid. MS APCI m/e 220 (p+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
4-Bromo-4'-hydroxybiphenyl (2.49 g) was added over 30 minutes to a stirred suspension of sodium hydride (0.42 g of 60% dispersion in mineral oil) in dimethylformamide (10 ml) whilst keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at a temperature below 10° C. for a futher 5 minutes. Ethyl iodide (1.87 g) was added over 10 minutes and stirring continued at room temperature for 2 hours. Water (200 ml) was added to the mixture and the mixture extracted with diethyl ether (3×50 ml). The ether extracts were combined, washed with 1M sodium hydroxide solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to give a residue which was crystallised from hexane to give, as a colourless solid, 4-bromo-4'-ethoxybiphenyl (2.15 g), m.p. 139° C.; NMR (CDCl3): 1.4(3H, t), 4.0-4.1(2H, q), 6.9(2H, d) and 7.35-7.55(6H, m).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:36])=[N:22][N:23]3[CH:28]=[CH:27][C:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][Zn+])=[CH:41][CH:40]=1.O1CCCC1>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>[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:36])=[N:22][N:23]4[CH:28]=[CH:27][C:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][C:24]=34)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:41][CH:40]=1
Reactant: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Br)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Reactant: Clc1ccc(C[Zn+])cc1
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
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Cc4ccc(Cl)cc4)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A mixture of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine (0.907 g, 1.53 mmol) and bis(tri-t-butylphosphine)palladium(0) (39.0 mg, 0.0764 mmol) in a 40 mL vial was evacuated under low vacuum and backfilled with nitrogen four times. 4-Chlorobenzylzinc chloride in tetrahydrofuran (0.50 M, 7.0 mL, 3.5 mmol) was added and the solution was again evacuated under low vacuum and backfilled with nitrogen twice. The solution was heated to 60° C. for 4 hours. The reaction mixture was cooled to rt, quenched with water, adjusted to ˜pH 6 with acetic acid, and extracted with EtOAc (2×). The organic layers were combined, washed with water, brine, dried over Na2SO4, filtered and evaporated to give a crude residue which was purified by column chromatography on silica gel column using EtOAc/hexane (0/100 to 40/60) as an eluant to give a solid product (0.806 g, 85% pure by 1H-NMR, yield 70.5%). LCMS: (FA) ES+ 639, 641. 1H NMR of pure fraction (400 MHz, CDCl3) δ: 8.36-8.39 (m, 2H), 8.27 (s, 1H), 7.45-7.47 (m, 2H), 7.23-7.25 (m, 2H), 6.99-7.01 (m, 1H), 5.54 (s, 2H, 5.50 (s, 1H), 4.67 (s, 2H), 3.66-3.74 (m, 4H), 3.57-3.62 (m, 2H), 2.74 (s, 3H), 1.26-1.30 (m, 6H), 0.95-0.99 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.O[CH:25]([CH2:35][CH3:36])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:29][C:28]([NH:27][CH2:26][CH:25]([O:23][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:10]2[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=2[N:12]=[CH:13][N:14]=1)[CH2:35][CH3:36])=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCC(O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Product: CCC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)OC)c(C)c12

Procedure:
Synthesized analogously to example 9.1 using methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate and tert-butyl 2-hydroxybutylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:26][CH3:27])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:29]1[S:30][CH:31]=[CH:32][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:26][CH3:27])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Temperature: 100 °C
Yield: 50 %

Procedure:
To a solution of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (120 mg) in ethylene glycol dimethyl ether (0.586 ml) was added 2-bromo-1,3-thiazole (0.040 ml, 1.5 eq.), Cesium carbonate (144 mg, 1.5 eq.), N-[2′-(dicyclohexylphosphino)-1,1′-biphenyl-2-yl]-N,N-dimethylamine (16 mg, 0.14 eq.) and Tris(dibenzylideneacetone)dipalladium (19 mg, 0.7 eq.). The reaction mixture was heated at 100° C. for 16 h, poured into saturated sodium bicarbonate (50 ml), extracted 2×50 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Purification via MPLC chromatography eluting with 10–30% ethyl acetate/heptane provided the title compound as an amorphous solid (77 mg, 50%): 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34, 7.28–7.23, 6.53, 5.30, 4.92, 4.27, 4.02, 3.82–3.72, 3.55, 3.46, 2.72, 2.48, 1.33–1.27, 1.16; IR (liq.) 2972 (s), 2934, 2335 (w), 1564 (s), 1539 (s), 1494 (s), 1470 (s), 1396 (s), 1357, 1350, 1201, 1141, 1121 (s), 1101, 610 cm−1 HRMS (ESI) calcd for C23H27N5OSCl2+H1 492.1391. found 492.1378.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:29]=[C:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[CH3:24][C:19]1[CH:18]=[C:17]([CH:15]2[CH2:14][CH:13]([C:25]3[O:26][N:34]=[C:30]([CH:31]([CH3:33])[CH3:32])[N:29]=3)[CH2:12][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:16]2)[CH:22]=[CH:21][C:20]=1[CH3:23]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C
Reactant: CC(C)C(N)=NO
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C

Procedure:
80 mg (0.210 mmol) of the compound from Example 132A and 33 mg (0.315 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 47 mg (51% of theory)
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][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][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.Cl.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[OH:1][CH2:2][C:3]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]=[C:6]([O:10][CH2:11][CH2:12][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][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cn(-c2ccccc2)c(CO)cc1=O

Procedure:
5.0 g (12 mMole) 2-hydroxymethyl-5 octadecyloxy-4-pyranone are suspended in 90 mL water and 2 mL concentrated hydrochloric acid and mixed with 4.0 g (43 mMole) aniline. The mixture is heated under reflux for 24 hours, cooled and the precipitate formed is separated from the aqueous solution and recrystallized from ethyl acetate, an almost colorless product being obtained; m.p. 67°-72° C. In a manner analogous to that described in Example 30, there is obtained the following compound:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)[S:5][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](#[N:36])C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([C:34]#[N:36])[N:3]=2)[CH2:8]1
Reactant: C[C@@H]1CN(c2nc(Br)cs2)C[C@H](C)O1
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H]1CN(c2nc(C#N)cs2)C[C@H](C)O1
Temperature: 140 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A mixture of Intermediate 1 (52.8 g, 190.49 mmol), triphenylphosphine (4.99 g, 19.05 mmol), zinc cyanide (22.37 g, 190.49 mmol) and dry acetonitrile (360 mL) was introduced in a pressure tube and was degassed with nitrogen for 5 min. Tetrakis(triphenylphosphine)palladium (11 g, 9.52 mmol) was added and the mixture was further degassed for 5 min. The tube was sealed and the reaction mixture was stirred at 140° C. for 3 h. The suspension was evaporated and taken up in water/DCM. The combined organic layer was separated, filtered on a plug of diatomaceous earth, dried on MgSO4, filtered off, and evaporated. The residue was purified on an 800 g EasyVarioPrep (Merck) column (eluent: DCM). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 50° C. overnight, yielding 25.6 g (60%) of Intermediate 2 as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 93, Part A (26.5 mg, 0.05 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 93, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H) 7.86 (d, J=7.72 Hz, 2H) 7.55-7.78 (m, 5H) 7.50 (t, J=6.25 Hz, 1H) 7.38 (d, J=2.57 Hz, 1H) 7.16-7.21 (m, 1H) 6.58 (s, 1H) 5.69 (d, J=7.72 Hz, 1H) 4.19 (d, J=4.78 Hz, 2H) 3.48 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12](Cl)=[CH:13][C:14]=1[Cl:15].C([Sn](CCCC)(CCCC)[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C)C=O.O1CCOCC1.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:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:13][C:14]=1[Cl:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ncccn2)nc1Cl

Procedure:
14.6 g (0.047 mol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab), 20.0 g (0.051 mol) of 2-tri-n-butylstannylpyrimidine and 1.1 g (0.94 mmol) of tetrakistriphenylphosphinepalladium(0), dissolved in 70 ml of dimethylformamide and 50 ml of 1,4-dioxane, were kept at 110° C. for 10 h. After removal of the volatile components under reduced pressure, the product was purified on silica gel using cyclohexane/ethyl acetate. Yield 2.0 g of yellow crystals (m.p. 147° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](Cl)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=1[NH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCCn1c(Cl)nc2cccc(Br)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(Br)c21
Temperature: 150 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
A mixture of ethyl 4-(7-bromo-2-chloro-1H-benzimidazol-1-yl)butanoate (1.57 g, 4.54 Mmol), 2,4-di-chloroaniline (2.21 g, 13.6 mmol), p-toluenesulfonic acid monohydrate (930 mg, 4.89 mmol) and xylene (8.0 mL) was stirred at 150° C. for 3 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.61 g, 3.42 mmol, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[C:47]([CH3:48])=[C:46]([S:49](Cl)(=[O:51])=[O:50])[C:45]([CH3:53])=[N:44]1>C(#N)C>[CH3:42][N:43]1[C:47]([CH3:48])=[C:46]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:51])[C:45]([CH3:53])=[N:44]1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C)c(C)c1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 27.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0316 g, 0.0685 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 1,3,5-trimethyl-1H-pyrazol-4-sulfonyl chloride (0.0407 g, 0.195 mmol) to obtain 4-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0118 g, yield 27%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[C:15]([F:39])=[C:16]([N:21](COCCOC)[S:22]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[F:20])=[N:4]1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C([NH2:55])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:55][C:12]1[CH:13]=[C:8]([C:6]2[C:5]([C:14]3[C:15]([F:39])=[C:16]([NH:21][S:22]([C:25]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=4[F:32])(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=3[F:20])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[CH:9]=[CH:10][N:11]=1
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(COCCOC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: CC(C)(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2ccnc(N)c2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide (123 mg, 0.217 mmol) was dissolved in dry DCM, mCPBA (75 mg, 2 eq) was added and the reaction mixture was stirred at room temperature for 3 hours. A further addition of mCPBA was made (50 mg) and the mixture was stirred for 2 more hours. It was then diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude intermediate N-oxide (130 mg) was dissolved in dry trifluoromethylbenzene (1.5 mL), the solution was cooled to 0° C. and t-butyl amine (0.118 mL 1.12 mmol, 5 eq) was added. Tosylanhydride (150 mg, 0.448 mmol, 2 eq) was then added in portions. After 1 h stirring at 0° C., further additions of t-butyl amine (0.03 mL, 1.25 eq) and tosylanhydride (40 mg, 0.5 eq) were made and the reaction mixture was stirred at 0° C. for 30 more minutes. Trifluoroacetic acid (1.5 mL) was then added and the mixture was hated to 70° C. and stirred at this temperature for 1.5 h. The solvent was evaporated and the residue taken up with DCM and water. The aqueous phase was neutralized with 32% aq. NaOHand extracted 3 times with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (DCM/MeOH 95:5) to give 46 mg of N-{3-[4-(2-amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10](I)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B:22](OCCCC)([O:28]CCCC)[O:23]CCCC.[Li]CCCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([B:22]([OH:28])[OH:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(nc1OC)c(I)cn2C(=O)OC(C)(C)C
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(nc1OC)c(B(O)O)cn2C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 16.6 g of 1-t-butyloxycarbonyl-3-iodo-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine in 300 cm3 of anhydrous tetrahydrofuran, under an inert atmosphere of argon at a temperature in the region of −100° C., are added dropwise 14.41 cm3 of tributyl borate followed by 41 cm3 of n-BuLi (1.6M in hexane). The reaction medium is stirred at this same temperature for 90 minutes. The cooling bath is removed. The temperature rises to −5° C. 100 g of ice are added, followed by 100 cm3 of water and 300 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluents, argon). The fractions containing the product are concentrated under reduced pressure. 8.32 g of 1-t-butyloxycarbonyl-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridin-3-boronic acid are thus obtained with the following characteristics: