Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:46]([O:48]C)=[O:47])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([CH2:21][N:22]([CH3:41])[CH2:23][CH2:24][N:25]([CH3:40])[CH2:26][CH2:27][CH2:28][S:29](=[O:39])(=[O:38])[NH:30]C(=O)OC(C)(C)C)[CH2:18][C:17]4[CH:42]=[CH:43][CH:44]=[CH:45][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[K+].Cl>C(Cl)Cl>[NH2:30][S:29]([CH2:28][CH2:27][CH2:26][N:25]([CH3:40])[CH2:24][CH2:23][N:22]([CH2:21][CH:19]1[CH2:18][C:17]2[CH:42]=[CH:43][CH:44]=[CH:45][C:16]=2[C:15]2=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]3[CH:9]=[CH:10][C:11]([C:46]([OH:48])=[O:47])=[CH:12][C:13]=3[N:14]2[CH2:20]1)[CH3:41])(=[O:39])=[O:38]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)Cc1ccccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCS(N)(=O)=O)CCN(C)CC1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 13-cyclohexyl-6-(2,5,13,13-tetramethyl-9,9-dioxido-11-oxo-12-oxa-9-thia-2,5,10-triazatetradec-1-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate was dissolved in DCM (0.1 M) and TFA (44 eq.) was added. After stirring at RT for 1 h all volatiles were evaporated in vacuo and the residual material was coevaporated three times with toluene. (MS (ES+): 595.6). The material was dissolved in MeOH (0.05 M) and 1 M KOH solution (10 eq.) was added and the mixture was stirred at 70° C. for 3 h. After cooling 1N hydrochloric acid was slowly added until neutral pH. The mixture was extracted three times with EtOAc, washed with water and brine. After drying the organic phase over Na2SO4 all volatiles were evaporated in vacuo. The residual material was used without further purification in the next reaction. (ES+) m/z 581 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:18]([CH3:20])[CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)I
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)cc1C=O
Yield: 98.7 %

Procedure:
To a solution of 5-bromosalicylaldehyde (5.0 gm, 0.025 mol) in DMF (40 mL) were added powdered potassium carbonate (5.15 gm, 0.037 mol) and 2-iodopropane (3.5 mL, 0.035 mol) dropwise with stirring. The mixture was stirred overnight at room temperature, partitioned between diethyl ether and water. The aqueous was extracted with ether, and the combined organic layers were washed with water, saturated brine solution, dried (Na2 SO4), and evaporated to afford 6.0 gm of pure title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]=[CH:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].[CH3:24][N+:25]([O-:27])=[O:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH:20]([CH2:24][N+:25]([O-:27])=[O:26])[CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Product: CCOC(=O)c1c[nH]c2c1C(=O)CC(C[N+](=O)[O-])CC2
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (6.81 g, 21.3 mmol) is dissolved in CH3NO2 (50 ml), Triton B (40% aqueous, 2.5 mL) is added quickly. The reaction mixture was kept at 80° C. for 8 h. The mixture is cooled and the solvent removed under reduced pressure. The residue is taken into 50 ml CH2Cl2 and 25 ml H2O. The aqueous phase is adjusted to slightly basic with 1N HCl and sat. NaHCO3, and extracted with CH2Cl2 (30 mL×4). Organic phases are combined, dried (Na2SO4), and evaporated. Flash chromatography (1:1 hexanes/EtOAc) provides the title compound (5.6 g, 93%) as white solid. 1H NMR (400 MHz, CD3OD) δ 7.21 (1H, s), 4.45 (2H, d), 4.20 (2H, q), 2.97-2.62 (5H, m), 2.04 (1H, m), 1.65 (1H, m), 1.27 (3H, t). MS (ES+) 281 (M+1) Step 2: Dimethylaminomethyl4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester.
Reaction SMILES: [K].N1C=CN=C1.FC(F)=C(F)F.FC(F)(F)C(OCC)=O.[F:22][C:23]([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)(F)[CH:24]([F:26])[F:25]>O1CCCC1>[F:22][C:23]([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[C:24]([F:26])[F:25]
Reactant: FC(F)C(F)(F)n1ccnc1
Agent: CCOC(=O)C(F)(F)F
Agent: FC(F)=C(F)F
Agent: [K]
Solvent: C1CCOC1
Product: FC(F)=C(F)n1ccnc1
Temperature: -78 °C
Yield: 55 %

Procedure:
Into a 50 ml autoclave were poured 0.20 g (5 mmol) of metallic potassium and tetrahydrofuran (10 ml), and the inside of the autoclave was cooled to −78° C., and evacuation and replacement of atmosphere in the autoclave with nitrogen gas were carried out three times. Then thereto was added a solution obtained by dissolving 1.36 g (20 mmol) of imidazole in tetrahydrofuran (10 ml) at 10° C. over 30 minutes under pressurized nitrogen atmosphere. Thereafter tetrafluoroethylene (TFE) was introduced until the inside pressure of the system reached 0.1 MPa·G. Then the temperature of the reaction system was increased to 100° C., and TFE was further introduced to maintain the inside pressure of the reaction system at 0.3 to 0.5 MPa·G. Supply of TFE was stopped when the amount of TFE reached 1.1 equivalents (2.2 g=22 mmol) to imidazole, and stirring was continued at 100° C. Eight hours after starting of the stirring, the inside of the reaction system was brought to room temperature, followed by evacuation to terminate the reaction. To this crude reaction product was added 1.42 g (10 mmol) of ethyl trifluoroacetate, and it was confirmed by a 19F-NMR analysis based on ethyl trifluoroacetate that 1-(1,1,2,2-tetrafluoroethyl)imidazole had been produced at yield of 55% and 1-(1,2,2-trifluoroethenyl)imidazole had been produced at yield of 23%. Also according to gas chromatography, it was confirmed that the remaining imidazole was 9%.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(OC(C)(C)C)=O>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCNc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 N HCl in dioxane (3.2 mL) was added in a stream to a solution of 2-[[2-(Boc-amino)ethyl]amino]pyridine (148.4 mg, 0.63 mmole) in anhydrous CH2Cl2 (3.2 mL) at 0° C., then the reaction was warmed to RT. After 2 hr, the mixture was suction filtered to collect the precipitated solid, which was washed with anhydrous Et2O and dried to afford the title compound (132.8 mg, quantitative) as a yellow solid: 1H NMR (400, CD3OD) δ 7.99-8.07 (m, 1H), 7.92-7.98 (m, 1H), 7.19 (d, J=9.1 Hz, 1H), 6.98-7.04 (m, 1H), 3.76 (t, J=6.2 Hz, 2H), 3.27 (t, J=6.2 Hz, 2H, partially obscured by residual solvent signal); MS (ES) m/e 138 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=2)=[O:20])[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=[NH:43])(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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]>[NH2:43][C:23]1[CH:22]=[C:21]([C:19]([C:7]2[CH:8]=[C:9]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]=2[O:28][CH3:29])=[O:20])[CH:26]=[CH:25][N:24]=1
Reactant: COc1ncccc1-c1cc(C(=O)c2ccnc(Cl)c2)c(OC)c(C(C)(C)C)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncccc1-c1cc(C(=O)c2ccnc(N)c2)c(OC)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
step 3—A flask containing 42 (106 mg, 0.259 mmol), benzophenone imine (0.070 mL, 0.417 mmol), Pd2(dba)3 (11.5 mg, 0.013 mmol), racemic BINAP (23.8 mg, 0.038 mmol), and sodium tert-butoxide (35 mg, 0.364 mmol) was purged with argon 3 times before toluene (5 mL) was added. The reaction was heated overnight at 80° C. then cooled to RT. The reaction mixture was diluted with EtOAc, filtered through CELITE, and the filtrate was concentrated. The residue was taken up in a mixture of MeOH (5 mL) and hydroxylamine (50% wt solution in water, 0.5 mL) and stirred overnight at RT before it was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (25 to 75% EtOAc) to afford (2-amino-pyridin-4-yl)-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-methanone (44) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH:15]([CH2:16][CH3:17])[CH2:14]1>CC(O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:14][CH:15]([OH:13])[CH2:16][CH3:17])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CCC1CO1
Solvent: CC(C)O
Product: CCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Yield: 43.3 %

Procedure:
A solution (6 ml) of 4-methanesulfonylbenzylamine (3.0 g) and 1,2-epoxybutane (1.1 g) in 2-propanol was heated under reflux for 12 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (1.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C[Sn](C)(C)[C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39]#[N:40].[Li+].[Cl-].[NH4+].[Cl-]>O1CCOCC1.CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:34]2[CH:38]=[CH:37][S:36][C:35]=2[C:39]#[N:40])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: C[Sn](C)(C)c1ccsc1C#N
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccsc2C#N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 38 h
Yield: 38 %

Procedure:
A mixture of N-(2,6-dichlorobenzoyl)-O-(trifluoromethane sulfonyl)-L-tyrosine methyl ester (361 mg), trimethyl(2-cyano-3-thienyl)tin (393 mg), Pd(PPh3)4 (42 mg) and LiCl (93 mg) in dioxane (8 mL) was stirred at 100° C. under N2 for 38 h. The mixture was diluted with AcOEt and treated with 10% NH4Cl aqueous solution (6 mL). After stirring at room temperature for 1 h, the mixture was filtered through Celite and washed with AcOEt. The combined organic layers were washed successively with water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel chromatography to afford N-(2,6-dichlorobenzoyl)-4-(2-cyano-3-thienyl)-L-phenylalanine methyl ester (126 mg). ESMS m/z 481 (M++Na), 459 (MH+), 457 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH2:16]([N:23]1[CH:27]=[C:26]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[C:26]([CH2:28][N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])[CH:25]=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(Cc3ccccc3)c1)c1ccc(C(C)C)cc1)CCC2
Yield: 45.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (2.22 g) as starting materials, N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.64 g) was obtained.
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:13][C:14](=O)[CH3:15].C([O-])([O-])=O.[K+].[K+]>>[CH3:15][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][CH:13]=1
Reactant: CC(=O)CCl
Reactant: NC(=O)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1coc(/C=C/c2ccccc2)n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 1.8 %

Procedure:
Cinnamamide (2.0 g, 14 mmol), chloroacetone (0.93 mL, 16 mmol), and K2CO3 (940 mg, 6.8 mmol) were combined under argon and the mixture was heated in a 120° C. oil bath. The reaction mixture solidified and stirring stopped upon heating. After 16 h, the cooled reaction mixture was quenched by the addition of water (20 mL) and then diluted with ethyl acetate (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 90:10 hexane:ethyl acetate. The product that was obtained (280 mg) showed some close running impurities by thin layer chromatography (TLC). The material was further purified by preparative TLC via multiple elutions with 95:5 hexane:ethyl acetate. Isolation of the middle of the main band afforded 4-methyl-2-[(E)-2-phenylethenyl]-1,3-oxazole (47.0 mg, 2% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.53-7.32 (m, 7H), 6.91 (d, J=16.4 Hz, 1H), 2.21 (s, 3H). MS (ESI) 185.7 (M++H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH:37]=[O:38])[CH2:31][CH2:30]1.C[Si](C)(C)[C:41]([F:44])([F:43])[F:42].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][CH:37]([OH:38])[C:41]([F:44])([F:43])[F:42])[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC=O)CC2)c2ncnn12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)(F)F)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4′-({5-Oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.31 g) and trimethyl(trifluoromethyl)silane (0.12 g) were dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (0.74 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 16 hr. 1 M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.054 g, 15%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([CH:43]=[O:44])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:42]=[N:41][C:40]([CH:43]=[O:44])=[CH:39][CH:38]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
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: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.1 g, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (0.064 g, 0.274 mmol) and Pd(PPh3)4 (0.013 g, 0.011 mmol) in 1,4-dioxane (2 mL) was purged with argon for 10 min. A solution of 2M Na2CO3 (0.087 g, 0.820 mmol) was then added to it and argon again purged for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1H-indazole-4-carboxamide (0.1 g, 94.3%).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[C:4]2[CH:9]=[CH:8][N:7]([CH3:10])[C:6](=[O:11])[C:5]=2[O:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.IC1C(=O)C2C=CN[C:26](=[O:30])C=2OC=1C1C=CC=CC=1.BrCCO>>[OH:30][CH2:26][CH2:10][N:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:20])[C:2]([I:1])=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:5]=2[C:6]1=[O:11]
Reactant: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Agent: OCCBr
Product: O=c1c(I)c(-c2ccccc2)oc2c(=O)n(CCO)ccc12
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-iodo-7-methyl-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione, 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted with 2-bromoethanol to give the title compound (45.2 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.76-7.73 (m, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.62-7.58 (m, 3H), 6.64 (d, J=7.3 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.06 (t, J=5.4 Hz, 2H), 3.67 (q, J=5.4 Hz, 211).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9][C:8]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9](=[O:27])[C:8]=2[C:17]#[N:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CC1=C(c2ccccc2)Nc2ccccc2S1
Solvent: ClCCl
Product: N#CC1=C(c2ccccc2)Nc2ccccc2S1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-phenyl-4H-1,4-benzothiazine-2-carbonitrile (0.10 g) and 3-chloroperbenzoic acid (0.17 g, purity 80%) in dichloromethane (8 ml) was stirred at 0° C. for 30 min. The mixture was filtered and the filter cake was washed with dichloromethane and dried to give the title compound as pale crystals. Yield 66 mg; mp 182-184° C.; 1H-nmr(DMSO) δ (ppm): 12.31 (br, 1H), 8.09-7.99 (m, 1H), 7.83-7.60 (m, 7H), 7.60-7.48 (m, 1H); IR(KBr) ν (cm−1): 3211, 3161, 2985, 2935, 2850, 2193 (C≡N ), 1603, 1548, 1502, 1463, 1429, 1004, 771, 703; MS m/e (rel. intensity): 250 (86%; M+−16), 249 (87%), 218 (39%), 211 (100%), 190 (11%), 146 (23%), 108 (43%), 69 (43%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.CN.[CH:22]([N:25](C(C)C)CC)(C)C>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([NH:25][CH3:22])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:5]=1
Reactant: CCOC(=O)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc(Cl)nc(NC)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of ethyl 1-(4,6-dichloro-1,3,5-triazin-2-yl)-4-piperidinecarboxylate (1.0 g, 3.3 mmol, 1.0 equiv) in dichloromethane (20 ml) at room temperature, a premixed solution of methylamine (1.6 ml, 3.3 mmol, 1.0 equiv) and diisopropylethylamine (DIEA, 1.7 ml, 9.8 mmol, 3.0 equiv) in dichloromethane (10 ml) was added dropwise. The reaction was stirred for 3 h at room temperature. The solvent was removed under reduced pressure to afford 983 mg (100%) of the title compound. MS (ES+): m/e 300.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.B1([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)OCCCO1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.ClCCl.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:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH:16]=[N:15][CH:14]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccc(Br)cc1
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: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(-c2cccnc2)cc1

Procedure:
Under a nitrogen atmosphere a mixture of N-[(1S)-1-(4-bromophenyl)ethyl]-6-chloropyrazin-2-amine (0.117 g, 0.37 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (67 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol) and toluene (4 mL) was treated with 2M aqueous sodium carbonate solution (0.2 mL). The resulting mixture was stirred vigorously whilst being heated under reflux for 24 hours. Upon cooling, the solution was diluted with methanol and dichloromethane and the mixture dried (MgSO4) and filtered. Removal of solvent in vacuo then yielded the crude product which was purified by column chromatography using dichloromethane-diethyl ether (90:10) then dichloromethane-methanol (99:1) as eluent (50 mg).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:30]=2)=[O:18])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1

Procedure:
3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (2) (100 mg, 0.32 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (47 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 75-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 36 mg (29%). 1H-NMR: 8.65-8.61 (m, 1H), 8.50 (s, 1H), 8.42-8.35 (m, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.95-7.88 (m, 2H), 7.75-7.68 (m, 2H), 7.64 (d, J=8.5 Hz, 1H) 7.39-7.32 (m, 1H), 7.25-7.18 (m, 1H), 7.12-7.05 (m, 2H), 3.88-3.81 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 1.68-1.60 (m, 2H).