Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:23])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:24][C:25]([F:36])([F:35])[CH2:26]OS(C(F)(F)F)(=O)=O>C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([CH2:26][C:25]([F:36])([F:35])[F:24])[C:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(CC(F)(F)F)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a suspension of 60% sodium hydride (0.678 g, 16.97 mmol) in THF (100 mL) at room temperature was added malonic acid dibenzyl ester (4.825 g, 16.97 mmol) to give a clear solution after 30 min. Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (3.52 g, 15.43 mmol) was added and reaction mixture was stirred at 50° C. for 48 h. The reaction mixture was concentrated, partioned between ethyl ether and washed with saturated ammonium chloride solution and acidified with 1N HCl. The mixture was extracted with ethyl ether (2×), dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 0 to 0% ethyl ether/hexanes) to give a colorless oil (3.844 g, 68%). 1H NMR (300 MHz, CDCl3): δ 7.4-7.2 (m, 10H), 5.15 (s, 4H), 3.75 (t, J=6.9 Hz, 1H), 2.9-7.7 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:32]#[N:33])[C:11]([CH3:31])=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)[C:13]=2[N:14]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15]2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>Cl>[NH2:28][C:24]1[CH:23]=[C:22]([C:12]2[C:13]([N:14]3[CH2:18][CH2:17][C@H:16]([N:19]([CH3:20])[CH3:21])[CH2:15]3)=[C:7]3[O:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[N:9][C:8]3=[C:10]([C:32]#[N:33])[C:11]=2[CH3:31])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2cccc([N+](=O)[O-])c2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)C)nc2c1C#N
Agent: Cl
Product: Cc1c(-c2cccc(N)c2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)C)nc2c1C#N
Reaction time: 3 h
Yield: 17.1 %

Procedure:
2-tert-Butyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-(3-nitrophenyl)-1,3-benzoxazole-4-carbonitrile (I-22) (30.7 mg, 68.6 μmol) was dissolved in 4 N hydrogen chloride (ethyl acetate solution, 2 ml) and the solvent was concentrated under reduced pressure. The residue was dissolved in methanol (8 ml), followed by catalytic hydrogenation at room temperature under normal pressure for 3 hours in the presence of 5% palladium-carbon (50% wet, 30 mg). The catalyst was separated by filtration, the filtrate was concentrated under reduced pressure, aqueous 10% sodium carbonate solution and ethyl acetate were added to the residue followed by stirring. The organic layer was collected by liquid-liquid separation, concentrated and purified by preparative TLC (developing solvent, chloroform:methanol=10:1) to obtain the entitled compound (4.9 mg) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](CC#N)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:22][C:21]([OH:19])=[O:23])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CCO
Reactant: Cc1ccc(CC#N)c(OCc2ccccc2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CC(=O)O)c(OCc2ccccc2)c1
Yield: 88 %

Procedure:
A solution of crude 2-(4-methyl-2-phenylmethoxyphenyl)acetonitrile (15 g, 63 mmol) in ethanol (200 ml) and water (50 ml) containing 10 g (0.25 mol) NaOH was heated under reflux overnight, and the ethanol was removed under vacuum. The residue was diluted with water and washed with benzene. The aqueous layer was then acidified with dilute HCl to give an oil which was extracted into ethyl acetate to give (4-methyl-2-phenylmethoxyphenyl)acetic acid (14.2 g, 88%) as an oil which solidified on standing. A solution of this crude (4-methyl-2-phenylmethoxyphenyl)acetic acid in ethanol was hydrogenated over palladium on charcoal to give (2-hydroxy-4-methylphenyl)acetic acid. Anal (C9H10O3) C,H.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.C[N:9](C1C=CC=CC=1)[S:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:25]=[C:20]3[C:19](=[O:34])[C:18]=2[CH:35]=1)(=[O:12])=[O:11].N1C=CC=C(N)C=1>CS(C)=O.O>[CH3:31][N:29]1[CH:30]=[C:26]([C:24]2[CH:25]=[C:20]3[C:19](=[O:34])[C:18]4[CH:35]=[C:14]([CH2:13][S:10]([NH:9][C:3]5[CH:1]=[N:2][CH:6]=[CH:5][CH:4]=5)(=[O:12])=[O:11])[CH:15]=[CH:16][C:17]=4[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=2)[CH:27]=[N:28]1
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Reactant: CN1CCCC1=O
Agent: Nc1cccnc1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)Nc5cccnc5)cc4c(=O)c3c2)cn1
Temperature: 180 °C
Reaction time: 2.25 h

Procedure:
N-Methyl-2-pyrrolidinone (3 ml) was added to N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide (150 mg, 0.319 mmol) and pyridin-3-amine (150 mg, 1.594 mmol) in a vial. The vial was sealed and the resulting solution was heated to 180° C. with stirring. After 2.25 h., the reaction was cooled to room temperature and diluted in DMSO and water. The resulting solution was filtered and purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a brown solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.52 (d, 1H); 8.48 (s, 1H); 8.33 (d, 1H); 8.16 (d, 1H); 8.15 (s, 1H); 8.07 (s, 1H); 7.77 (d, 1H); 7.68 (dd, 1H); 7.52 (m, 1H); 7.35 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.77 (s, 2H); 3.89 (s, 3H). LRMS (APCI) calculated for C24H19N5O3S [M+H]+, 458.1. found 458.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.ClCCl.[I-].C(OC([N:35]1[CH2:38][CH:37]([Zn+])[CH2:36]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:35]1[CH2:38][CH:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(C3CNC3)cc1OCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
Following the procedure for 419, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazole (313.4 mg, 0.803 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (32.8 mg, 0.04 mmol) and copper(I) iodide (15.3 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (279.8 mg, 0.80 mmol) in 2.8 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted tert-butyl 3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 370 (33.3 mg, 11% yield, M=1 367.1)
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[CH:14]=[C:15]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16][C:11]=2[C:10]=1[CH2:27][CH2:28][CH3:29])C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[CH:14]=[C:15](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16][C:11]=2[C:10]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=CC(=O)OCC)oc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCc1c(O)ccc2c(=O)cc(/C=C/C(=O)OCC)oc12
Yield: 69.2 %

Procedure:
A solution of ethyl 3-(7-benzyloxy-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl)acrylate (6.0 g) in dichloromethane (150 ml) at -60° C. was treated with an excess of BCl3. After 3/4 hour the solution was poured onto ice and stirred. After 12 hours the mixture was extracted with ethyl acetate. The organic layer was separated, washed well (water), dried (MgSO4) and evaporated to afford a pale yellow solid. The latter was crystallised from aqueous ethanol to yield trans ethyl 3-(7-hydroxy-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl)acrylate (3.2 g) mp 203°-204° C.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15][OH:16].[ClH:17]>C(Cl)Cl.O1CCOCC1>[ClH:17].[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11](=[NH:12])[O:16][CH3:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: N#CC(O)c1cccc(OC(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=N)C(O)c1cccc(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 131A (1.83 g, 9.2 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added MeOH (2.24 mL) and 4.0 N HCl in dioxane (9.2 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. Solvent was removed to give methyl 2-(3-(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude prouduct was purified by silica gel chromatography to give 131B (700 mg, 33% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H) 5.22 (s, 1H) 6.82 (t, J=74.04 Hz, 1H) 7.09 (dd, J=7.91, 2.20 Hz, 1H) 7.23 (s, 1H) 7.28-7.34 (m, 1H) 7.38 (t, J=7.91 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])[CH3:2].[Cl:25][C:26]1[C:27]([F:33])=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[C:27]=1[F:33])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: Nc1cccc(Cl)c1F
Solvent: O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(Cl)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate C and 3-chloro-2-fluoroaniline. The reaction was stirred at rt for 1.5 h. The reaction mixture was diluted with H2O and extracted. The organic layers were washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (hexane/EtOAc, 90:1→65:35). The residue was then triturated in CH2Cl2 to give the title compound as white foam. tR: 1.45 min (LC-MS 2); ESI-MS: 542.0/544.0/546.0 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[Na+]>[Pd].CN(C=O)C.O.CO>[CH3:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:28][CH2:27][CH2:26]4)=[CH:23][CH:24]=3)[N:9]=2)[N:12]=[CH:13][CH:14]=1
Reactant: COc1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1ccnn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.075 g, 0.14 mmol) and 5% palladium on carbon (0.007 g) in DMF (1 mL) was added a solution of sodium formate (0.074 g, 1.09 mmol, 8.0 eq) in water (0.2 mL). The resulting mixture was stirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered through a membrane filter, and the solids were washed with MeOH (1 mL). The resulting solution was diluted with EtOAc (25 mL), washed with water (2×25 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure to give tert-butyl {1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate approximately 75% purity (0.058 g, 90%):
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:34])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[ClH:35].CCOC(C)=O>>[ClH:35].[ClH:35].[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:34])[C:18]([NH:20][CH:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1

Procedure:
A solution of tert-butyl 4-({[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}amino)piperidine-1-carboxylate (Example 181, 2.5 g, 5.29 mmol) in 4 M HCl-EtOAc solution (20 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (2.94 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C@H:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[O:23][N:22]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[C:24]([C:21]1[CH:20]=[C:19]([NH:18][C:15]([C@@H:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:17])[O:23][N:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)[C@@H]1CCCC(=O)N1c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCC(=O)N2c2ccc(Cl)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold slurry of (S)-1-(4-Chloro-phenyl)-6-oxo-piperidine-2-carboxylic acid (0.2 g; 0.788 mmol) and 5-amino-3-tert-butylisoxazole (0.110 g; 0.788 mmol) in pyridine (0.956 mL; 11.820 mmol) is added phosphorous oxychloride (0.088 mL; 0.946 mmol). The mixture is stirred at 0° C. for 30 minutes and then diluted with water and extracted with ethyl acetate several times. The organics are combined and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC affords title compound, m/z 376 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][C:29]([CH2:32]O)=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)([Cl:36])=O.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:36][CH2:32][C:29]1[N:28]=[CH:27][C:26]([S:23]([NH:22][C:13]2[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CO)nc2)cc(OC)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCl)nc2)cc(OC)c1
Yield: 108.3 %

Procedure:
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(hydroxymethyl)pyridine-3-sulfonamide (90 mg; 0.19 mmol; 1 eq.) is dissolved in CHCl3 (10 ml) at rt. Thionyl chloride (0.05 ml; 0.39 mmol; 2 eq.) is added and reaction mixture is stirred for 1 h30. Water and aqueous NaHCO3 are added and the product is extracted with DCM. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to afford 100 mg (108%) of the title compound as a powder. It was used as such in the next step. HPLC (max plot) 35%; Rt 4.78 min, LC/MS: (ES+) 486.22, (ES−) 484.22.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH3:35])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:35][N:34]([CH2:33][C:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[S:29][CH:30]=1)[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)cs4)cc23)CC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN(C)C)cs4)cc23)CC1
Yield: 15.3 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide trifluoroacetate, substituting dimethylamine (0.5 mL) for 2 M methylamine to afford 9 mg of the title compound (15.3%).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)O)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CC(C)CCCCCCCO
Reactant: C=C(C)C(=O)OC
Agent: CCN(O)CC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCCCCCCC(C)C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Four hundred seventy four grams (3.0 moles) of isodecyl alcohol, 750 g (7.5 moles) of methyl methacrylate (MMA), 1.75 g (3.0 millimol) of hafnium actylacetonate, and 50 mg diethylhydroxylamine and 25 mg phenothiazine free radical polymerization inhibitors, are added to a 3 liter flask equipped with an agitator, thermometer, and a 10-plate Oldershaw fractional distillation column. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of MMA and methanol was removed from the upper part of the fractionating column. The reaction was continued in this manner for approximately 90 minutes while the temperature at the top of the column was 65°-67° C. and the temperature in the pot was 106°-124° C. Excess MMA was removed under vacuum and the resulting IDMA was isolated (660 grams, 99.0% yield) and analyzed. Gas-liquid chromatographic (GLC) analysis showed >99.9% conversion of isodecanol to IDMA of 99.8% purity.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][N:15]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=3[N:13]=2)[CH:17]=[N:16]1
Reactant: CSc1ncc2ccc(Cl)nc2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CSc1ncc2ccc(-c3cnn(C)c3)nc2n1
Yield: 34.6 %

Procedure:
A suspension of 7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 57, 31 mg, 0.146 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43 mg, 0.21 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol) and CsF (67 mg, 0.44 mmol), in DME/MeOH (3/1 mL) was stirred at 150° C. under microwave irradiation for 30 minutes. The reaction mixture was filtered, concentrated in vacuo onto silica gel and purified by Biotage silica gel column chromatography eluting with 80% EtOAc in cyclohexane to afford title compound as an yellow oil (13 mg, 35%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)[N:14]2[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]12
Reactant: CI
Reactant: N#Cc1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile (Ex. 19) and 220 mg of 60% sodium hydride dispersed in mineral oil in 50 ml of N,N-dimethylformamide was stirred at room temperature under nitrogen for 3 1/2 hours. Then one ml of iodomethane was added and the reaction mixture was stirred under nitrogen for 16 hours. The mixture was evaporated in vacuo and gave an oil. The oil crystallized upon trituration in n-hexane to give the product which was recrystallized from ethyl acetate:n-hexane (1:4) and this gave the desired product as yellow crystals, mp 120°-122° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][N:12]1[C:17](=[O:18])[C:16]2[N:19]=[CH:20][N:21](C(OC(C)(C)C)=O)[C:15]=2[CH:14]=[N:13]1.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl.O.N>O1CCCC1>[Cl:29][C:20]1[NH:21][C:15]2[CH:14]=[N:13][N:12]([CH3:11])[C:17](=[O:18])[C:16]=2[N:19]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cn1ncc2c(ncn2C(=O)OC(C)(C)C)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2[nH]c(Cl)nc2c1=O
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
8.4 ml of lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) was added dropwise over one hour to a 300-ml tetrahydrofuran solution containing 1.68 g of t-butyl 5-methyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-carboxylate and 4.15 g of hexachloroethane under a nitrogen atmosphere at 0° C. The resulting mixture was stirred for 30 minutes. 2N ammonia water was added to the solution, and the mixture was stirred for three hours. Then, the reaction solution was concentrated to 50 ml, and washed with 20 ml of t-butyl methyl ether. The solution was acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, and washed successively with 10 ml of water and 10 ml of t-butyl methyl ether. Thus, 1.03 g of the title compound was obtained.