Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:26]=[N:25][N:24]([CH:27]([CH3:29])[CH3:28])[C:16]=2[N:17]=[C:18]([NH:20]CC=C)[CH:19]=1)=[O:13].CS(O)(=O)=O>C(O)C.C(Cl)Cl.[Pd]>[NH2:20][C:18]1[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[C:15]2[CH:26]=[N:25][N:24]([CH:27]([CH3:29])[CH3:28])[C:16]=2[N:17]=1
Reactant: C=CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 10% Pd/C (0.200 g, 0.188 mmol) and N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-propen-1-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.200 g, 0.507 mmol) was suspended in ethanol (10 mL) and stirred. Added next was methanesulfonic acid (0.033 mL, 0.507 mmol), and the stirring contents were heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through Celite. The filter pad was washed with 10% MeOH/DCM. The filtrate was pre-adsorped onto silica gel, and the crude product purified by silica gel chromatography (dry loaded, eluent: gradient of 5-80% Dichloromethane/Chloroform containing 10% 2M Ammonia (in methanol)). The collected product was dried in vacuum oven at 45° C. overnight. The final product was collected as 0.065 g (36%). LCMS E-S (M+H)=355.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.82 Hz, 6 H), 2.12 (s, 3 H), 2.21 (s, 3 H), 4.31 (d, J=5.05 Hz, 2 H), 4.85-5.00 (m, 1 H), 5.89 (s, 1H), 6.49-6.68 (m, 3 H), 7.85 (s, 1 H), 8.46 (t, J=5.05 Hz, 1 H), 11.54 (br. s., 1 H).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.OS(O)(=O)=O>O>[CH:11](=[C:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1

Procedure:
90 Parts by weight of xylitol (75 wt% aqueous solution), 42 parts by weight of benzaldehyde, 60 parts by weight of methanol, 6 parts by weight of conc. H2SO4 and 6 parts by weight of water were reacted with refluxing for two hours. After cooling, the solidified product was ground and washed with water and, then, neutralized with 10 wt% sodium hydroxide aqueous solution followed by washing with water and drying to obtain benzylidenexylitol.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.[F:12][C:13]([F:21])(S(F)(=O)=O)C(O)=O>C(#N)C.[Cu]I>[F:12][CH:13]([F:21])[O:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(CO)CCC1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(=O)C1(COC(F)F)CCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
To a stirred solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (0.2 g, 1.264 mmol) in acetonitrile (2 mL) was added CuI (0.120 g, 0.632 mmol) and the reaction mass was heated to 50° C. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.196 mL, 1.896 mmol) added dropwise to the solution and the reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled to RT and extracted with EtOAc (3×15 mL). The combined organic layer was washed with a 10% aqueous solution of NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 223A as a brown oil (0.2 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.94-6.39 (m, 1H), 4.16-3.99 (m, 4H), 2.41-2.17 (m, 2H), 2.08-1.73 (m, 4H), 1.26-1.09 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(O)C1CCN(Cc2ccc(I)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 2-piperidin-4-ylpropan-2-ol. Yield: 1.01 g (67% of theory); C15H22INO (M=359.25); calc.: molecular ion peak (M+H)+: 360; found: molecular ion peak (M+H)+: 360; Rf value: 0.4 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15](=[O:20])[CH3:14])[C:17](=[O:19])[CH3:18]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(C)=O

Procedure:
A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.00 g of 2,4-pentanedione in 10 ml of tetrahydrofuran was saturated with gaseous hydrogen chloride. After standing over night at 5° C. the product was filtered and washed with ether. Yield 1.2 g (50%), m.p. 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:23])([CH3:22])[O:14][C:15]=3[C:16]([C:18]([O:20]C)=O)=[CH:17][C:8]=2[N:7]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:22])([CH3:23])[O:14][C:15]=3[C:16]([C:18]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=3)=[O:20])=[CH:17][C:8]=2[N:7]=1
Reactant: COC(=O)c1cc2nc(NCc3ccccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(F)(F)F)c3)cc3nc(NCc4ccccc4Cl)[nH]c23)O1
Yield: 24.3 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-((2-chlorobenzyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-52, 0.200 g, 0.519 mmol), 3-trifluoromethyl aniline (0.167 g, 1.038 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL). The obtained crude was purified by column chromatography eluting with 0.5% DCM:MeOH to afford 0.0650 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.16 (s, 2H), 7.00 (d, J=6 Hz, 2H), 7.30-7.42 (m, 2H), 7.44-7.64 (m, 6H), 7.72 (d, J=7.8 Hz, 1H), 8.35 (s, 1H), 9.96 (s, 1H), 10.90 (s, 1H); [M+H]+: 515.19.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:6]1[OH:20])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:26]2=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:31]3[C:25]4[C:26](=[N:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:29]([S:41]([C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)(=[O:42])=[O:43])[CH:30]=3)[N:13]=2)[CH:6]1[OH:20])=[O:4]
Reactant: COC(=O)C1(C)CCCC(Nc2nc(Cl)ncc2F)C1O
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1O
Temperature: 25 °C

Procedure:
To a solution of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66e, (0.65 g, 2.05 mmol) and 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.32 g, 3.05 mmol) in THF (20 mL) was added aqueous Na2CO3 (3.52 mL of 2 M solution, 7.04 mmol). The solution was degassed with N2 for 20 minutes. Tetrakis triphenylphosphane palladium (O) (0.14 g, 0.12 mmol) was added and the mixture was refluxed overnight. LCMS showed good conversion, but some starting materials remained. More degassed 2 N Na2CO3 was added followed by another portion of Tetrakis triphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction was refluxed for another 4 hours. The mixture was cooled to room temperature, extracted with EtOAc. The organic phase was washed by brine and dried over Na2SO4. After evaporation of solvent the crude mixture was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100) to provide 1.0 g of racemic methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f. LCMS: 588.26 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: Oc1cccc(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3cccc(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenol to give [1-(3-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N

Procedure:
A sealed tube was charged with suspension of 1 (330 mg, 1.15 mmol) and Lindlar catalyst (245 mg, 10 mol %) in methanol (5 mL) then placed on a Parr shaker. Reaction purged with H2 at 60 psi for 1 h. Solids filtered through Celite and washed with methanol, then concentrated to give 2 as a brown semi-solid. Taken on without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[CH2:36]([S:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:40])=[O:39])[CH3:37]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: CCS(=O)(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available ethanesulfonyl chloride (Aldrich) via the parallel synthesis described above. MS-base peak at m/z=570 by positive ion Cl, mp=232-234° C.
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:15]=2[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Clc1cccc(CBr)c1Cl
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1cccc(Cl)c1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 68, and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 29.1 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). 1H NMR (CDCl3, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1H, br s); 6.92-7.89 (10H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.[NH2:26][CH2:27][C@H:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:40]([O:39][C:37]([NH:36][C@@H:28]([CH2:27][NH:26][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: COC(=O)COc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
420 mg (0.002 mol) of 4-(methoxycarbonylmethyloxy)benzoic acid, 270 mg (0.002 mol) of 1-hydroxybenzotriazole and 588 mg (0.002 mol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were dissolved in 5 ml of dimethylformamide. The solution was cooled to 0° C. and treated with 453 mg (0.0022 mol) of N,N′-dicyclohexylcarbodiimide and then stirred at 0° C. for 10 min and at room temperature for 2 h. For working-up, the urea was filtered off and the filtrate was concentrated to dryness. The pure compound was obtained by chromatography of the crude product on silica gel (dichloromethane/acetonitrile 20/1). Yield: 820 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of 2-(4′-Amino-3′-iodophenyl)-6-methoxybenzathiazole (5) (8.0 mg, 0.02 mmol) in CH2Cl2 (2.0 mL) was injected 1 M BBr3 solution in CH2Cl2 (0.20 ml, 0.20 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 18 hrs. After the reaction was quenched with water, the mixture was neutralized with NaHCO3. The aqueous layer was extracted with ethyl acetate(3×3 mL). The organic layers were combined and dried over MgSO4. The solvent was then evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:ethyl acetate=7:3) to give 2-(3′-iodo-4′-aminophenyl)-6-hydroxybenzothiazole 6 (4.5 mg, 58%) as a brown solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][C:14]1([CH3:21])[C:18]([CH3:20])([CH3:19])[O:17][BH:16][O:15]1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[O:15]2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
To a degassed mixture of methyl 2-iodo-6-methylbenzoate (220 mg, 0.9 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.16 mL, 1.1 mmol), TEA (0.4 mL, 2.7 mmol) in 2 mL dioxane was added Pd(PPh3)2Cl2 (20 mg, 0.03 mmol). The mixture was stirred at 165° C. for 10 min in a microwave oven. The mixture was diluted with EtOAc, washed with sat. NH4C1, H2O and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by HPLC to afford 65 mg (35%) of Intermediate 296.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:21][CH:22]=3)[C:17]([C:28]3[N:29]=[C:30]4[C:36]([C:37]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][N:34]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:31]4=[N:32][CH:33]=3)=[N:16]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:40]([NH:39][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:19]=4)[N:15]([CH2:14][CH:10]4[O:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:16]=3)[N:29]=2)[N:34]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:35]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: [H][H]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CNCCO4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a stirred solution of 2-(1-((4-benzylmorpholin-2-yl)methyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (see Example 340, 130 mg, 181 μmol) in ethyl acetate (2 mL) and methanol (1 mL) was added palladium on carbon (19.2 mg) and the mixture hydrogenated using a balloon filled with hydrogen gas. After stirring at room temperature for 15 h, the mixture was transferred to a Parr hydrogenator and shaken under 40 psi for 1 h. The mixture was filtered, concentrated in vacuo and then purified by chromatography (silica, 24 g Analogix column, 0-100% ethyl acetate in hexanes followed by 5% methanol in ethyl acetate) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(morpholin-2-ylmethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.10 g 88%). MS (M+H)+=630.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 4-benzyl-2-hydroxymethylmorpholine (118.8 g.) in dry pyridine (250 ml.) toluene-p-sulphonyl chloride (120.2 g.) is added gradually at 18°-25° C. The mixture is stirred for 20 hours at ambient temperature (ca. 20° C.) and the pyridine is removed under diminished pressure. The residue is diluted with water, the mixture made alkaline by the addition of sodium hydroxide solution, and the product is then extracted into ether. The ethereal solution is dried (MgSO4) and filtered, the ether is evaporated and the residual solid is crystallised from cyclohexane or petroleum ether (b.p. 60°-80° C.) to give 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine, m.p. 78°-79° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2B(O)O)[CH:28]=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>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.COCCOC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:34]=2[N:25]=[CH:26][CH:27]=[CH:28]3)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cccc2cccnc12
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: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cccc3cccnc23)cc1
Yield: 91.5 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method 14; 200 mg, 0.5 mmol), 8-quinoline boronic acid (104 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol), 1,2-dimethoxyethane (3 ml) and a saturated aqueous solution of sodium hydrogen carbonate (3 ml) were stirred at 80° C. under an atmosphere of argon for 20 hours. The mixture was allowed to cool before being partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by flash column chromatography, eluting with methanol/dichloromethane (0-10%), to give the title compound (201 mg, 84%); NMR Spectrum: (DMSO-d6): 1.47 (s, 9H), 7.20 (m, 2H), 7.60 (m, 4H), 7.73 (t, 1H), 7.84 (t, 3H), 8.06 (d, 2H), 8.47 (d, 1H), 8.68 (s, 1H), 8.93 (m, 1H), 9.91 (s, 1H), Mass Spectrum: M+H+: 440.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]([O:24]C2C=CC=CC=2)=O)[CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][S:6]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH2+:14])=[O:11])(=[O:8])=[O:7].[C:31]1([CH3:49])[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=[C:39]([C:45]([F:48])([F:47])[F:46])[N:38]=2)[CH:32]=1>C(#N)C.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]([NH:44][CH2:43][C:42]2[C:37]([C:33]3[CH:32]=[C:31]([CH3:49])[CH:36]=[CH:35][CH:34]=3)=[N:38][C:39]([C:45]([F:48])([F:46])[F:47])=[CH:40][CH:41]=2)=[O:24])[CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][S:6]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:7])=[O:8]
Reactant: [CH2+]C(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
2-(N-(2-Fluoro-4-(phenoxycarbonylamino)benzyl)sulfamoylcarbamoyloxy)-2-methylpropan-1-ylium (100 mg, 0.225 mmol) was dissolved in acetonitrile. (2-m-Tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (60 mg, 0.225 mmol) and 4-dimethylaminopyridine (27 mg) were added to the solution. The reaction mixture was stirred for overnight at 50° C. The mixture was extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave tert-butyl N-(2-fluoro-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)sulfamoylcarbamate (70 mg, 51%).