Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:34])[CH2:28][O:29][CH2:30][C:31]([O-:33])=[O:32])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[OH-].[Na+].C([O-])(=O)COCC([O-])=O.C1(=O)OC(=O)COC1>O.ClCCl>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:34])[CH2:28][O:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:18][CH2:19]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])COCC(=O)NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])COCC(=O)[O-]
Agent: O=C1COCC(=O)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)COCC(=O)NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
A 1.02 gram (2.10 millimoles) sample of sodium {2-[6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetate (prepared as described in Example XIII) and 7.3 milliliters of 5 N aqueous NaOH is heated under reflux temperature for 1.5 hours to obtain 6-piperidinohexamine and diglycolate in the reaction mixture; the mixture is then diluted with 25 milliliters of water and extracted with ether. The ether solution is washed with aqueous NaCl, dried with Na2SO4, and concentrated to obtain as residue, 6-piperidinohexamine. To a solution of 0.685 grams (1.96 millimoles) of the thus prepared 6-piperidinohexamine in 14 milliliters of dichloromethane is added drop by drop during about 10 minutes, a warm solution of 0.227 (1.95 millimole) of diglycolic anhydride in 26 ml. of dichloromethane. After the addition, the mixture is stirred at a temperature range of 25°-30° C. for two hours to obtain the desired {2-[6-(4-benzhydrylpiperidino)hexyl]amino-2 -oxoethoxy}acetic acid; the latter is isolated by volatilization of the solvent.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][C@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][C@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: CCCC[C@H](N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Boc-Gly-OH (4.4 g, 0.025 mol.) and Nleu-OEt (3.2 g, 0.02 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. on a water-ice bath. BOP (11 g, 0.025 mol.) was added to the solution. Triethylamine was used to adjust the pH of the solution to about 9. The solution was stirred overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 300 ml ethyl acetate. The ethyl acetate solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again. The organic layer was dried by Na2SO4 and the ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product (5.9 g, 94%). TLC Rf=0.52 (developing solvents: E/H, 2:1). 1H-NMR (360 MHz, DMSO-d6) δ6.74 (m, Gly-NH), 6.68 (m, Gly-NH), 4.18 (s, Nleu-α), 4.12 (q, ethyl ester-CH2), 4.04 (q, ethyl ester-CH2), 3.94 (s, Nleu-α), 3.79 (d, Gly-α), 3.65 (d, Gly-α), 3.07 (m, Nleu-β), 1.79 (m, 1H, Nleu-γ), 1.34 (s, 9H, Boc-CH3), 1.16 (m, ethyl ester-CH3), 0.87 (d, Nleu-δ), 0.78 (d, Nleu-δ).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([O:15][CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: OC1(c2ccc(Br)cc2)CCCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ambient suspension of NaH (332 mg, 8.30 mmol, 60 wgt % in mineral oil) in N,N-dimethylformamide (2 mL) was added dropwise a solution of Example 30A (1.0 g, 4.15 mmol) in N,N-dimethylformamide (1 mL). After 30 min., bromoacetic acid (577 mg, 4.15 mmol) in N,N-dimethylformamide (13 mL) was added, dropwise. The solution was stirred at room temperature for 16 h and then heated to 50° C. for 3 h. The reaction was cooled to room temperature and was quenched by the addition of water (10 mL). The solution was basicified to pH 10 by the addition of 2.5 M NaOH. The aqueous was extracted with ethyl acetate (2×10 mL), and the organics discarded. The aqueous was acidified to pH 1 with 6 M HCl, and then extracted with ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated, under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66-1.72 (m, 2 H), 1.74-1.85 (m, 4 H), 2.02-2.15 (m, 2 H), 3.56-3.60 (m, 2 H), 7.33-7.39 (m, 2 H), 7.49-7.56 (m, 2 H), 12.37 (s, 1 H).
Reaction SMILES: C([Li:5])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][C:15]1([CH3:46])[CH2:24][CH:23]=[C:22]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[C:21]2[CH:20]=[C:19](/[CH:33]=[CH:34]/[C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH:18]=[CH:17][C:16]1=2>CCCCC.C1COCC1.[Cl-].[Cl-].[Zn+2].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>[Li:5][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:46][C:15]1([CH3:14])[CH2:24][CH:23]=[C:22]([O:25][S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[C:21]2[CH:20]=[C:19](/[CH:33]=[CH:34]/[C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:44][CH:45]=3)[CH:18]=[CH:17][C:16]1=2
Reactant: Cc1ccc(Br)cc1
Reactant: [Li]C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: [Cl-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: [Li]c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-lithiotoluene was prepared at −78° C. by the addition of 130.7 mg of t-butyllithium (2.04 mmol; 1.20 ml of a 1.7M solution in pentane) to a solution of 374.5 mg (2.20 mmol) of 4-bromotoluene in 2.5 ml of THF. After 30 minutes a solution of 313.4 mg (2.30 mmol) of ZnCl2 in 2.0 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 1.25 hour and then added via canula to a solution of 285.0 mg (0.590 mmol) of ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethenyl]-benzoate (Compound P) and 29.0 mg (0.025 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF. The resulting solution was stirred at room temperature for 1 hour and then at 55° C. for 2 hours. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the combined extracts were washed with 5% aqueous NaOH, saturated aqueous NaCl, and dried over Na2SO4 before being concentrated under reduced pressure. The title compound was isolated by column chromatography (10% EtOAC/hexanes) as a colorless solid. 1H NMR (CDCl3): δ 7.96 (2H, d, J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.43-7.16 (7H, m), 7.07 (1H, d, J=16.3 Hz), 6.93 (1H, d, J=16.3 Hz), 5.97 (1H, t, J=4.7 Hz), 4.39 (2H, q, J=7.0 Hz), 2.41 (3H, s), 2.33 (1H, d, J=4.7 Hz), 1.38 (3H, t, J=7.0 Hz), 1.33 (6H, s).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]([N:16]1[C:28]2[CH:27]=[C:26]([C:29]([OH:31])=O)[CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:15])[CH3:14].C(=O)(O)O.[NH2:36][C:37]([NH2:39])=[NH:38]>CN(C=O)C>[NH2:38][C:37]([NH2:39])=[N:36][C:29]([C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:13]([CH3:15])[CH3:14])[C:28]=2[CH:27]=1)=[O:31]
Reactant: N=C(N)N
Reactant: CC(C)n1c2ccccc2c2ccc(C(=O)O)cc21
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1c2ccccc2c2ccc(C(=O)N=C(N)N)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A 134 mg portion of CDI was added to 4 ml DMF solution of 140 mg 9-isopropyl-9H-carbazole-2-carboxylic acid, followed by stirring at 50° C. for 1 hour. After spontaneous cooling to room temperature, 238 mg of guanidine carbonate was added thereto, followed by stirring overnight at room temperature. After evaporation of the solvent, water was added thereto and the thus precipitated solid was purified by a silica gel column chromatography (Chromatorex (registered trademark), methanol/chloroform) to obtain 157 mg of N-(diaminomethylene)-9-isopropyl-9H-carbazole-2-carboxamide as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)(=[O:7])=[O:6].Br[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:35]=[C:34]([CH:36]3[CH2:38][CH2:37]3)[NH:33][N:32]=2)[C:27]([C:39]#[C:40][Si](C)(C)C)=[CH:26][N:25]=1.C1(C2NN=C(NC3C(C#C)=CN=C(C4C=C(S(N)(=O)=O)C=CC=4)N=3)C=2)CC1>[Pd]>[CH:36]1([C:34]2[CH:35]=[C:31]([NH:30][C:28]3[C:27]([C:39]#[CH:40])=[CH:26][N:25]=[C:24]([C:10]4[CH:9]=[C:8]([S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=4)[N:29]=3)[NH:32][N:33]=2)[CH2:38][CH2:37]1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC1(C)OB(c2cccc(S(=O)(=O)NCCO)c2)OC1(C)C
Agent: [Pd]
Agent: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Product: C#Cc1cnc(-c2cccc(S(=O)(=O)NCCO)c2)nc1Nc1cc(C2CC2)n[nH]1
Yield: 22 %

Procedure:
3-(4-(3-Cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl)-N-(2-hydroxyethyl)benzene sulfonamide (Compound 122) (100 mg, 22%) was prepared from N-(2-hydroxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 2-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine using the same Pd cataliysed condition as described in Compound 110. LC-MS (m/z)=425.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.81-0.83 (m, 2H), 0.96-0.98 (m, 2H), 1.91-1.98 (m, 1H), 2.83 (q, J=6.0 Hz, 2H), 3.37 (q, J=6.0 Hz, 2H), 4.70 (t, J=5.6 Hz, 1H), 4.91 (s, 1H), 6.46 (s, 1H), 7.71 (t, J=5.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 8.52 (d, J=7.6 Hz, 1H), 8.62 (s, 1H), 8.73 (s, 1H), 8.76 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[OH-].[Na+].CO>C1COCC1>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (140 mg, 0.44 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred for 5 h at r.t. The resulting mixture was concentrated to approximately one-third of its original volume and then placed in an ice bath. Hydrochloric acid (1 M) was added until pH ˜2, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 132 mg of the title compound as a white solid. MS: (−) m/z 305.26 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:28]
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cc(F)cc(C(F)(F)F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-5-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.55 (d, J 7.1, 3H), 4.36 (m, 2H), 4.53 (q, J 7.1, 1H), 7.29 (m, 2H), 7.49 (d, J 8.7, 1H), 7.80 (t, J 7.8, 1H), 7.93 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.31 (d, J 6.4, 1H), 8.60 (d, J 6.2, 1H), 8.73 (t, J 5.8, 1H), 9.56 (s, 1H).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[CH:23]12[CH2:30][CH:27]([CH2:28][CH2:29]1)[C:26](=[O:31])[CH2:25][C:24]2=[O:32].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:25]2[C:26](=[O:31])[CH:27]3[CH2:30][CH:23]([CH2:29][CH2:28]3)[C:24]2=[O:32])[CH:19]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: O=C1CC(=O)C2CCC1C2
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (16.34 g, 28.80 mmol) in chloroform (160 ml) is added bicyclo[3.2.1]octane-2,4-dione (3.61 g, 26.10 mmol) and 4-dimethylaminopyridine (16.63 g, 131 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (40 ml) is added, and the mixture is stirred at 80° C. for 1 hour (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 1M hydrochloric acid, and the organic phase separated. The aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a crude oil, which is purified by flash column chromatography on silica gel (30% to 50% ethyl acetate/iso-hexane eluant ratio, then 10% methanol/dichloromethane eluant ratio). The resulting gum is then recrystalised from dichloromethane/hexane to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (4.62 g, 55%) as a cream coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-])=O)=[CH:5][CH:4]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([NH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2CCN(C)CC2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(N)c(N2CCN(C)CC2)n1

Procedure:
1.30 g (0.0052 mol) of the product 1-(6-methoxy-3-nitropyrid-2-yl)-4-methylpiperazine synthesized according to the above procedure, 25 ml of ethanol, 5 ml of cyclohexene and 0.6 g of palladium-on-charcoal were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][C:26]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)(=[O:30])=[O:31])=[CH:25][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)N5CCN(C)CC5)cc4)nnc3c2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (1.0 equiv., 0.75 mmol), 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine (1.5 equiv., 1.125 mmol), Xantphos (0.1 equiv., 0.074 mmol), palladium acetate (0.05 equiv., 0.0375 mmol), and potassium-tert-butoxide (2.0 equiv, 1.5 mmol) were dissolved in 20 mL of dioxane and bubbled with argon. The reaction was stirred in an oil bath at 100° C. for 18 h under an argon blanket. The reaction was cooled to room temperature and filtered to remove inorganics, concentrated under reduced pressure, then brought up in EtOAc and extracted using saturated NaHCO3 and brine. The organics were dried over Na2SO4 and concentrated under reduced pressure then precipitated using EtOAc/Hexanes (1:5 v/v) to afford brown solid (182.3 mg, 45% yield). MS (ES+): m/z=540 LC retention time: 2.67 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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]>[CH3:24][N:23]1[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=[C:19]1[C:17]#[N:18]
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCCC1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reaction time: 16 h
Yield: 8.3 %

Procedure:
According to general procedure B, 1-[(4-bromophenyl)sulfonyl]piperidine (121 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 1-methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile (11 mg, 8%) was provided after purification. MS (ESI) m/z 329. HPLC purity 100.0% at 210-370 nm, 11.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH3:25])[S:8]([C:11]1[C:12]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:13]=2[S:14][C:15]=1[C:16]([O:18]C)=O)(=[O:10])=[O:9])=[O:5])C.C[O-].[Na+]>CO>[CH3:25][N:7]1[C:6]([C:4]([O:3][CH3:1])=[O:5])=[C:16]([OH:18])[C:15]2[S:14][C:13]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:12]=3[C:11]=2[S:8]1(=[O:10])=[O:9]
Reactant: CCOC(=O)CN(C)S(=O)(=O)c1c(C(=O)OC)sc2cc(C)ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Yield: 51 %

Procedure:
Prepared analogous to Example 1(e) from methyl 3-{[(ethoxy-carbonyl-methyl)methylamino]sulfonyl}-6-methyl-benzo[b]thiophene-2-carboxylate by reaction with sodium methylate in anhydrous methanol with a yield of 51% of theory.
Reaction SMILES: Br.[NH+]1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([S:22][CH3:23])[CH:11]=1.[OH-].[K+]>O.CCO>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[C:12]([S:22][CH3:23])[CH:11]=1
Reactant: COc1ccc(C2CCNCC2)c(SC)c1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1cc(O)ccc1C1CCNCC1
Temperature: 225 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
A mixture of pyridinium hydrobromide (20.76 g) and 4-[4-methoxy-2-methylthiophenyl]piperidine (6.16 g) was heated at 225° C. for 18 h. The reaction mixture was cooled, dissolved in 200 mL H2O, adjusted to pH 7 with 1N KOH, and extracted with hexane (4×50 mL). The aqueous layer was concentrated under reduced pressure to give an oil which was dissolved in 200 mL EtOH and stirred for 0.5 h. The precipitate was filtered and washed with EtOH (2×40 mL). The filtrate and all washes were combined and concentrated under reduced pressure. The crude product was purified by chromatography (9:1 DCM:MeOH) to give 6.06 g of 4-[4-hydroxy-2-methylthiophenyl]piperidine as the hydrobromide salt. 1H NMR (DMSO d6) δ 9.44 (s, 1H), 8.49 (m, 2H), 6.97 (d, 1H), 6.66 (d, 1H), 6.58 (dd, 1H), 3.43-3.30 (dm, 2H), 3.13-2.95 (m, 3H), 2.42 (s, 3H), 1.91-1.61 (m, 4H); MS m/z 225 (M+H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[Cl:5][C:6]1[C:15]2[O:14][CH2:13][CH2:12][CH:11]([N:16]3[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=[CH:17]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.[N+:25]([O-])([OH:27])=[O:26]>>[N+:1]([O-:4])([OH:3])=[O:2].[Cl:5][C:6]1[C:15]2[O:14][CH2:13][CH2:12][CH:11]([N:16]3[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=[CH:17]3)[C:10]=2[CH:9]=[C:8]([N+:25]([O-:27])=[O:26])[CH:7]=1
Reactant: COC(=O)c1cncn1C1CCOc2c(Cl)cccc21
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C1CCOc2c(Cl)cc([N+](=O)[O-])cc21
Yield: 20 %

Procedure:
A solution of 31 parts of methyl 1-(8-chloro-2,3-dihydro-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate mononitrate in 260 parts of a nitric acid solution 60% was stirred for 45 minutes at room temperature (exothermic reaction). The reaction mixture was poured into crushed ice and the whole was made alkaline. The product was extracted with trichloromethane. The undissolved product was filtered off (the trichloromethane layer was set aside) and dried, yielding a first fraction of 7 parts (20.0%) of methyl 1-(8-chloro-2,3-dihydro-6-nitro-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate mononitrate. The trichloromethane layer, which was set aside (see above), was washed with water, dried, filtered and evaporated. The residue was converted into the nitric acid salt. The product was filtered off and dried, yielding a second fraction of 21 parts (60.2%) of methyl 1-(8-chloro-2,3-dihydro-6-nitro-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate mononitrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:18]=[C:19]1[C:24]2=[CH:25][NH:26][C:27]([CH:28]=O)=[C:23]2[CH2:22][CH2:21][O:20]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12](=[CH:28][C:27]4[NH:26][CH:25]=[C:24]5[C:19](=[O:18])[O:20][CH2:21][CH2:22][C:23]=45)[C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(-c3ccc(F)cc3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-(4-Fluoro-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.