Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(OC)C=CC=1B(O)O.Cl.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]3[C:30]4=[C:31]([CH2:33][CH2:34][CH2:35][N:29]4[CH2:28][C@@H:27]4[CH2:36][NH:37][CH2:38][C@@H:26]34)[CH:32]=2)=[C:19]([C:39](F)(F)F)[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]3[C:30]4=[C:31]([CH2:33][CH2:34][CH2:35][N:29]4[CH2:28][C@@H:27]4[CH2:36][NH:37][CH2:38][C@@H:26]34)[CH:32]=2)=[C:19]([CH3:39])[CH:18]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1
Agent: COc1ccc(B(O)O)c(C)c1
Agent: Cl
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C)c1

Procedure:
Using 2-methyl-4-methoxyphenyl boronic acid and following procedures described in EXAMPLE 34, (±)-trans tert-butyl 2-bromo-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 36 as a yellow semi-solid. 1H NMR (500 MHz, CDCl3) δ 1.26 (s, 1H), 1.95 (m, 1H), 2.01 (m, 1H), 2.16 (m, 1H), 2.28 (s, 3H), 2.70-2.90 (m, 4H), 2.98 (t, 1H, J=7 Hz), 3.22 (m, 1H), 3.30 (m, 4H), 3.38 (t, 1H, J=7 Hz), 3.60 (s, 3H), 6.58 (s, 1H), 6.74 (d, 1H, J=8.4 Hz), 6.77 (s, 2H), 7.12 (d, 1H, J=8.4 Hz). LRMS (ES)+: 335 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.Br[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH3:21]>>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH3:21]
Reactant: CCC/C=C\CBr
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Product: CCC/C=C\CC(C#C[Si](C)(C)C)OC1CCCCO1

Procedure:
Reaction of trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)silane and (Z)-1-bromohex-2-ene according to General Procedure 11.A provided (Z)-trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)non-5-en-1-ynyl)silane.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].Cl[CH2:16][C:17]([NH2:19])=[O:18].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]2[CH:8]=[C:16]([C:17]([NH2:19])=[O:18])[O:12][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc2cc(C(N)=O)oc2c1
Yield: 68 %

Procedure:
When 4-diethylaminosalicylaldehyde is reacted with chloroacetamide and potassium hydroxide in dimethylformamide at ambient temperature or with potassium carbonate instead of potassium hydroxide at refluxing temperature, the above benzofuran derivative is obtained in a similarly good yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH2:6]2)=[CH2:2].B1C2CCCC1CCC2.C1C[O:25]CC1>>[OH:25][CH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH2:6]2
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(c1)CCCO2
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc2c(c1)CCCO2
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of the 6-vinylchroman intermediate (0.12 g, 0.27 mmol) in anhydrous THF (1 mL) was cooled to 0° C. and treated with 9-BBN (0.60 mL, 0.5 M in THF, 0.3 mmol). The reaction mixture was heated to reflux for 8 h. The reaction was quenched with water (1.5 mL) and treated with NaBO3.4H2O and the resulting slurry was stirred overnight. Diethyl ether (4 mL) and the reaction mixture were extracted with CH2Cl2 (2×20 mL). The organic layers were concentrated to a clear oil that was purified by silica gel chromatography eluting with ethyl acetate (50%, v/v) in hexane. This yielded the desired 6-(2-hydroxyethyl)chroman intermediate as a colorless oil (30 mg, 24%). 1H-NMR (CDCl3/TMS, ppm): 0.87 (m, 12H, 4a′-, 8a′-, 12a′-, 13′-CH3), 1.0-1.6 (m, 24H, 4′-, 8′-, 12′-CH, 1′-, 2′-, 3′-, 5′-, 6′-, 7′-, 9′-, 10′-, 11′-CH2, 2a-CH3), 1.81 (m, 2H, 3-CH2), 2.17, 2.24, 2.28 (3×s, 9H, 5a-, 7a-, 8a-CH3), 2.68 (t, J=6.8 Hz, 2H, 4-CH2), 3.01 (t, J=7.5 Hz, 2H, Ar—CH2), 3.74 (t, J=7.5 Hz, 2H, OCH2); 13C-NMR (CDCl3, ppm): 12.0, 15.1, 16.0 (5a-, 7a-, 8a-CH3), 19.6, 19.7 (CH3), 20.6, 21.0 (CH2), 22.6, 22.7 (CH3), 23.8 (2a-CH3), 24.4, 24.8 (CH2), 28.0 (CH), 31.2 (3-CH2), 32.7, 32.8 (CH), 37.3, 37.4, 37.5, 39.4, 40.0 (CH2), 62.2 (OCH2), 72.6 (2-C), 116.8, 122.3, 124.9, 132.4, 133.9 (aryl C), 150.1 (aryl C—O); HRMS (CI, m/z): 458.412154 (M+H+, Calc. for C31H54O2 458.412384).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1I)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1.CN(C=O)C.CCN(CC)CC>O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:25]#[C:24][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(I)c(C#N)c2ccc(OC)cc21
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(C#Cc2ccc(F)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) was added to a sealable tube and alternatively evacuated and flushed with N2. To the tube was then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction was heated at 80° C. for 20 h and then cooled to room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were washed with H2O (3×) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix was absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][C:38]2[CH:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][NH2:51])[CH:45]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:33][CH2:32]1.C(N(CC)CC)C.ClCCl>CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([NH:51][CH2:50][C:46]3[CH:45]=[C:44]([C:40]4[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][CH:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH:39]=4)[CH:49]=[CH:48][CH:47]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1cccc(-c2cccc(CC3CCN(C)CC3)c2)c1

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (0.080 g, 0.198 mmol), (({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine, triethylamine (0.080 mL, 0.575 mmol) and dichloromethane (DCM) (3 mL) was stirred at room temperature overnight. The LC-MS suggested that the reaction was complete. The reaction was diluted with EtOAc and washed in turn with sat. aq. NaHCO3, then saturated aqueous NaCl. The organic phase was dried (Na2SO4) and evaporated to give a residue (175 mg). This residue was purified on a Gilson HPLC on RP column CH3CN—H2O (0.1% TFA) gradient [10-80%]. Fractions containing the desired product were combined and evaporated to a small volume, then treated with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2×) and the combined extracts were washed with saturated aqueous NaCl and dried (Na2SO4), then evaporated to a glassy solid (52.2 mg). LC-MS m/z 680.7 (M+H)+, 0.76 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([CH3:25])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[NH2:18]>>[CH3:16][C:17]([NH:18][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[CH3:25]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(Br)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (Example 33d) as starting materials; MS (EI) 455.1 (M+H)+.
Reaction SMILES: N1(CC[C@@H](NC2C=CC(S(N)(=O)=O)=CC=2S(C(F)(F)[F:33])(=O)=O)CSC2C=CC=CC=2)CCOCC1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([F:33])(=[O:45])=[O:44]
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=S(=O)(F)c1ccccc1F

Procedure:
Scheme 2 shows two routes used to make 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). One route involves reacting commercially available 2-fluorobenzenesulfonyl chloride (11) with TBAF (tetra-n-butylammonium fluoride) to provide 2-fluorobenzenesulfonyl fluoride (12). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 2-Fluorobenzenesulfonyl fluoride (12) can be converted to 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) by reaction with Ruppert's reagent (CH3SiCF3) catalyzed by (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF. The reaction is typically performed at about room temperature in a solvent such as but not limited to tetrahydrofuran, dichloromethane, toluene, dimethoxyethane, or mixtures thereof. 1-Fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) can be reacted with chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14). The reaction is typically performed at an elevated temperature before cooling for the addition of SO2Cl2, used to quench the chlorosulfonic acid. 4-Fluoro-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (15) can be prepared from 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14) by reacting the latter with aqueous ammonium hydroxide. The reaction is typically performed in a solvent such as acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl alcohol, isopropyl acetate, dimethoxyethane, dichloromethane, toluene, or mixtures thereof. (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine (16), prepared as described in U.S. Pat. No. 7,390,799 B2, can be reacted with 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (15) in the presence of a base such as but not limited to triethylamine, to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). The reaction is typically performed at elevated temperatures in a solvent such as but not limited to ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:3][CH:2]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccncc2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
1.121 g of 4-pyridylboronic acid, 2.35 g of methyl 3-bromobenzoate, 7.5 g of cesium carbonate and 530 mg of tetrakistriphenyl phosphine palladium were dissolved in 40 ml of N,N-dimethylformamide, and the mixture was stirred at 120° C. overnight in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column, to give 1.325 g of the title compound in the 4:3 hexane-ethyl acetate fraction.
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 88%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15]/[C:16](=[CH:19]\[CH2:20][C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])/[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15]/[C:16](/[CH3:17])=[CH:19]/[CH2:20][C:21]2[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=2[CH3:29])=[CH:8][CH:7]=1
Reactant: COC(CSc1ccc(O)cc1)OC
Reactant: CC1=C(C/C=C(\C)CO)C(C)(C)CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(CSc1ccc(OC/C(C)=C/CC2=C(C)CCCC2(C)C)cc1)OC
Yield: 85 %

Procedure:
By the method of example 13, 4-((2,2-dimethoxyethyl)thio)phenol (example 64) and (E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenol (Chem. Abstr., 94, 65904 h) are coupled in the presence of triphenylphosphine and diethyl azodicarboxylate to provide (E)-1-((2,2-dimethoxyethyl)thio)-4-(2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenyloxy)benzene as a colorless oil after chromatography (85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[C:10](=O)[CH3:11])=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)([O-:3])=[O:2].[NH2:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1>C(O)(C)C>[C:13]([C:9]1[CH:8]([C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:18]([F:19])([F:20])[F:21])[C:24]2[C:25](=[O:29])[NH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
1.28 g (4.24 mmol) of 3-[4-nitro-2-(trifluoromethyl)benzylidene]pentane-2,4-dione and 484 mg (4.24 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 25 ml of isopropanol and heated under reflux under argon for 12 h. Cooling is followed by filtration, and the remaining solid is washed with diethyl ether (40 ml). 990 mg (58% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[CH:21]=[N:20][C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[C:9]([OH:11])=O)=[CH:4][C:3]=1[F:32].CCN=C=NCCCN(C)C.C(Cl)(Cl)Cl.[CH:48]([NH:50][NH2:51])=[O:49]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[CH:21]=[N:20][C:19]([NH:25][CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[C:9]([NH:51][NH:50][CH:48]=[O:49])=[O:11])=[CH:4][C:3]=1[F:32]
Reactant: O=C(O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=CNNC(=O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
To a solution of 46 (270 mg, 0.582 mmol) and EDCI (139 mg, 0.728 mmol) and CHCl3 (10 mL) was added formohydrazide (41.9 mg, 0.698 mmol) and the reaction was stirred at RT for 2 h. Water was added and the mixture was extracted with DCM. The organic layer was separated and concentrated. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (6 to 8% MeOH) to afford 119 mg (36.4%) of N-(1-(4-chloro-3-fluorophenyl)-2-(2-formylhydrazinyl)-2-oxoethyl)-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (48).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)c(C)c2)cc1
Yield: 89.2 %

Procedure:
4-Bromo-2-methyl-benzoic acid (2.15 g, 10 mmol), 4-methoxy-phenylboronic acid (1.52 g, 10 mmol) and sodium carbonate (3.24 g, 30 mmol) in a mixture of toluene, water and ethanol (15 mL:6 mL:3 mL) was sparged with nitrogen for 5 minutes. To this was added palladium acetate (0.014 g). The mixture was heated at reflux, under a static pressure of nitrogen, for 24 hours. The sample was diluted with water and ethyl acetate (50 mL each) and the pH was adjusted to 1. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined and washed with water and brine. The sample was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate/hexanes to yield the title compound (2.16 g) as a white solid, m.p 199-201° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20](=[O:22])(=[O:21])[N:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18](=[O:27])[CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20](=[O:22])(=[O:21])[N:19]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:18](=[O:27])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CCN)cc2)S1(=O)=O
Yield: 100 %

Procedure:
2-[4-(2-tert-Butyl-1,1,3-trioxo-2,3-dihydro-1H-1λ6-isothiazol-5-yl)-phenyl]-ethyl-carbamic acid tert-butyl ester (200 mg, 0.490 mmol) was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (2 mL) and the reaction was stirred for 2 h. The reaction was chromatographed on a 21 mm Luna C18 column using a 10–90% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 12.5 mL per minute over a 15 minute period. The major fraction was lyophilized to give a white powder (207 mg, 100%). 1H NMR (500 MHz, CDCl3): δ 7.90 (m, 2H), 7.52 (m, 2H), 3.25 (t, J=6.5 Hz, 2H), 3.06 (t, J=7.4 Hz, 2H), 1.73 (s, 9H); LCMS found for C17H22F3N2O5S (M+H)+: m/z=309.2.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[CH3:32][N:33]1[C:37]([CH3:38])=[CH:36][C:35]([CH2:39][N:40]2[C:48]3[CH:47]=[CH:46][CH:45]=[C:44]([NH2:49])[C:43]=3[C:42]([CH2:50][CH3:51])=[N:41]2)=[N:34]1>CN1C(=O)CCC1.[OH-].[Na+].CCOC(C)=O>[CH3:32][N:33]1[C:37]([CH3:38])=[CH:36][C:35]([CH2:39][N:40]2[C:48]3[C:43](=[C:44]([NH:49][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:12])[CH:45]=[CH:46][CH:47]=3)[C:42]([CH2:50][CH3:51])=[N:41]2)=[N:34]1
Reactant: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (45.1 mg, 0.278 mmol) in NMP (5 mL) was added 2,4,6-trichlorobenzoyl chloride (43.5 μL, 0.278 mmol) and triethylamine (38.8 μL, 0.278 mmol). The reaction mixture was stirred for 30 minutes. 1-((1,5-Dimethyl-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-amine (50 mg, 0.186 mmol) was added to the reaction mixture, which was heated to 87° C. for 3 hours. The mixture was cooled to ambient temperature, and diluted with 10% NaOH aqueous solution (5 mL) and EtOAc (20 mL). The organic phase was washed with water and brine, then concentrated under reduced pressure. The residue was triturated with Et2O to give final product (35 mg). MS (ES+APCI) m/z=414 (M+H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:36][CH3:37])[CH2:5][CH2:6][N:7]([CH3:35])[C:8]([C:10]1[S:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14](CC3C=CC(OC)=CC=3)[C:13](=[O:32])[C:12]=2[C:11]=1[O:33][CH3:34])=[O:9])[CH3:3].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[CH2:36]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]([CH3:35])[C:8]([C:10]1[S:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13](=[O:32])[C:12]=2[C:11]=1[O:33][CH3:34])=[O:9])[CH3:37]
Reactant: CCN(CC)CCN(C)C(=O)c1sc2c(c1OC)c(=O)n(Cc1ccc(OC)cc1)c1ccccc21
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN(C)C(=O)c1sc2c(c1OC)c(=O)[nH]c1ccccc12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 0 %

Procedure:
A mixture of the compound of Example 48 (4.10 g, 8.08 mol), trifluoroacetic acid (34 mL) and trifluoromethanesulfonic acid (6.6 mL) was stirred at room temperature for 5 hr and at 80° C. for 2.5 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and ethyl acetate and 1N aqueous sodium hydroxide solution were added to the residue. The mixture was extracted with ethyl acetate and the extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=1/2) to give the title compound (1.50 g, 48%) as a white powder.