Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: COc1ccnc(N)c1C#N
Reactant: O=CC(Br)CC(F)(F)F
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Temperature: 156 °C
Yield: 19 %

Procedure:
A mixture of compound D3 (3.31 g, 22.19 mmol) and D4 (6.2 g, 21.86 mmol) in EtOH (10 ml) was subjected to microwave heating at 156° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was treated with Et2O and a solid precipitated. The solid was filtered off, washed with EtOAc and dried in vacuo to yield compound D5 (1 g, 18%).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]=1[C:7]1[S:11][C:10]2[CH2:12][CH:13]([NH:16]C(OC)=O)[CH2:14][CH2:15][C:9]=2[CH:8]=1.[OH-].[K+]>CO.O>[N:1]1[NH:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]=1[C:7]1[S:11][C:10]2[CH2:12][CH:13]([NH2:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)NC1CCc2cc(C3=NNC(=O)CC3)sc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1CCc2cc(C3=NNC(=O)CC3)sc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In 10 ml of methanol was dissolved 1.01 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-6-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene, and 560 mg of potassium hydroxide dissolved in 5 ml of water was added thereto. The mixture was stirred at room temperature for 3 hours. Methanol was removed from the reaction mixture, the residue was extracted with ethyl acetate and dried, and the the solvent was removed to obtain 0.5 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-6-amino-4,5,6,7-tetrahydrobenzo-[b]thiophene as crystals.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[C:24]=4C)=[O:19])=[CH:13][C:12]=3[CH3:36])=[CH:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O>O>[CH3:36][C:12]1[CH:13]=[C:14]([NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[CH:24]=2)=[O:19])[CH:15]=[N:16][C:11]=1[C:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)cnc1C1=CCC2(CC1)OCCO2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2)cnc1C1=CCC(=O)CC1
Yield: 28.9 %

Procedure:
N-[6-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)-5-methylpyridin-3-yl]-5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (823 mg), trifluoroacetic acid (9 ml) and water (catalytic amounts) was stirred at room temperature overnight. After the reaction, water was added, extracted with chloroform, the aqueous layer was neutralized under cooling by the addition of a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and saturated brine respectively and dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting residue was purified with a silica gel column chromatography (chloroform/methanol), washed with ethanol and the resulting solid was dried at 60° C. in vacuo to give N-[5-methyl-6-(4-oxocyclohex-1-en-1-yl)pyridin-3-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (210 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH:13]([OH:17])[NH:14][C:15](=O)[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[SiH](C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][NH:14][C:13](=[O:17])[CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(O)C2CN(Cc3ccccc3)CC12
Agent: C[SiH](C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCC2CN(Cc3ccccc3)CC12
Temperature: 3 °C
Reaction time: 16 h

Procedure:
5-Benzyl-3-hydroxyhexahydropyrrolo[3,4-c]pyrrole-1-one, (7 g; 30 mmol) in suspension in dichloromethane (50 ml) is placed in a 1000 ml three-necked flask and is then cooled in an ice bath. Trimethylsilane (7.1 g; 60 mmol) is run in slowly at 3° C. The reaction mixture is homogeneous and is left to react at 25° C. for 10 minutes, and is then cooled to 3° C. in order to run in trifluoroacetic acid (50 ml). The reaction mixture is agitated at 20° C. for 16 hours and then evaporated under reduced pressure. The residue is taken up in a mixture of ethyl acetate (100 ml) and 4 N aqueous sodium peroxide (50 ml), separated by settling out and washed with water (100 ml). After drying over magnesium sulfate and evaporation under reduced pressure, a yellow-colored oil is isolated, which is purified by chromatography on silica gel (silica: 40-63 μm, eluent: 90/10 ethyl acetate/methanol). The fractions containing the expected compound are combined and then evaporated under reduced pressure, giving 5-benzyl-hexahydropyrrolo[3,4-c]pyrrole-1-one, (7.2 g) which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>O1CCOCC1>[OH:27][CH:24]1[CH2:25][CH2:26][N:21]([C:4]2[N:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]3[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=3)[C:6](=[O:18])[N:5]=2)[CH2:22][CH2:23]1
Reactant: CSc1nc(C)n(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Reactant: OC1CCNCC1
Solvent: C1COCCO1
Product: Cc1nc(N2CCC(O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 99.9 %

Procedure:
To a 1,4-dioxane solution (1.0 mL) of 6-methyl-4-(methylthio)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (321 mg, 1.00 mmol) synthesized in Reference Synthesis Example 292, 4-piperidinol (202 mg, 2.00 mmol) was added and the resultant mixture was stirred under reflux by heating for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0→10/1) to obtain the title compound (374 mg, yield 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: COCCn1cc(-c2ccccc2)n(C(=O)c2ccccc2)c1=O

Procedure:
Approximately 21.8 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 14.5 g. of benzoyl chloride and 20 g. of tri-n-butylamine are refluxed together in 60 ml. of xylene for sixteen hours. The solvent is distilled off under reduced pressure and the remaining viscous oil is dissolved in 300 ml. of benzene. The benzene solution is washed with water (2×100 ml.), dried over sodium sulfate, and the solvent removed to give a semisolid. Recrystallization from ether gives the title compound as a pale yellow solid; m.p. 114°-117° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:26][CH3:27])[CH2:1][CH3:2])=[C:8]([C:16](=[O:25])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C(=O)C=Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCN(CC)CCOc1ccc(N)cc1C(=O)C=Cc1ccccc1
Reaction time: 2 h

Procedure:
To 5.00 g (13.6 mmol) of 1-[2-[2-(diethylamino)ethoxy]-5-nitrophenyl]-3-phenyl-2-propen-1-one in 50 mL of ethanol add 9.20 g (40.8 mmol) of tin(II) chloride dihydrate and heat the mixture to reflux with stirring for two hours. After cooling remove the solvent in vacuo. Add water and adjust the pH to 12 with potassium hydroxide. Add ethyl acetate and filter the mixture through celite. Separate the layers of the filtrate and extract the aqueous layer twice with ethyl acetate. Wash the combined organic layers with water, saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Remove the solvent in vacuD to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:21])=[O:20])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:30](N)[CH2:31][NH2:32].[S]>O>[Cl:29][C:23]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([CH2:18][NH:17][CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:32][CH2:31][CH2:30][N:2]=2)=[CH:8][CH:7]=1)(=[O:21])=[O:20]
Reactant: N#Cc1ccc(CCC(=O)NCCCNCS(=O)(=O)c2cccc(Cl)c2Cl)cc1
Reactant: NCCN
Agent: [S]
Solvent: O
Product: O=C(CCc1ccc(C2=NCCN2)cc1)NCCCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
A solution of 0.7 g (1.54 mmol) of 3-(4-cyanophenyl)-N-{3-[(2,3-dichloro-benzenesulphonyl)methylamino]propyl}propionamide, 3 ml of ethylenediamine and 0.10 g (3.12 mmol) of sulphur was stirred at 100° C. for 15 minutes. Water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on alumina (mobile phase: dichloromethane/methanol 100:1) and then crystallized from ethyl acetate/diethyl ether.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[CH:11]=2)[C:6]2[N:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[C:31]1([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:31]1([C:37]2[N:41]([CH2:2][C:3]3[C:8](=[O:9])[N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]5[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=5)[CH:11]=4)[C:6]4[N:27]=[CH:28][CH:29]=[CH:30][C:5]=4[N:4]=3)[CH:40]=[CH:39][N:38]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-n2c(=O)c(Cn3ccnc3-c3ccccc3)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Yield: 16.2 %

Procedure:
The solution of 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (285 mg) and 2-phenylimidazole (734 mg) in N,N-dimethylformamide (30 ml) was stirred for 3 hours at 80° C. The mixture was poured into aqueous sodium hydrogencarbonate (150 ml) and extracted by ethyl acetate (150 mg). The organic layer was evaporated and chromatographed to obtain 2-[(2-phenylimidazol-1-yl)methyl]-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (52 mg) in brown powder form.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[C:6](=[O:19])[NH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9][C:10]=2[CH:11]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[C:6](=[O:19])[NH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:15])[CH3:16])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2cc(CBr)c3ccccc3c2c(=O)[nH]1

Procedure:
To a solution of N-(6-methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.76 g, 5.7 mmoles) in dry benzene (150 ml) was added N-bromosuccinimide (1.01 g, 5.7 mmoles) and dibenzoyl peroxide (15 mg). The mixture was heated to reflux under a nitrogen atmosphere for 2.5 hours. After cooling, benzene was removed under reduced pressure, and the residue was purified on a silica gel column eluting with chloroform to give N-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as an off-white solid. (1.4 g, 57%) 1H NMR (DMSO-d6, 200 MHz) δ: 1.27(s, 9H, t-butyl); 5.26(s, 2H, CH2Br); 7.63-7.81(m, 3H, Ar); 8.26(dd, J=7.6, 2.0 Hz, 1H, Ar); 9.81(dd, J=7.8, 2.0 Hz, 1H, Ar); 11.27(s, 1H, NH); 12.33(s, 1H, NH). Anal. Calculated for C18H18BrN3O2 : C, 55.68 H, 4.67; N, 10.82. Found C, 55.48; H, 4.84; N, 10.57.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:30])[C:18]([C:21]1[O:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@H:17]([CH3:30])[C:18]([C:21]3[O:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=3)([CH3:20])[CH3:19])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: COC(=O)c1coc(C(C)(C)[C@@H](C)N)n1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(C(C)(C)[C@@H](C)Nc2c(C(N)=O)cnn3cc(Br)cc23)n1
Temperature: 50 °C
Reaction time: 52 h
Yield: 25.9 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 0.729 mmol) in DMF (15 mL) was added (R)-methyl 2-(3-amino-2-methylbutan-2-yl)oxazole-4-carboxylate hydrochloride (217 mg, 0.874 mmol) and potassium carbonate (302 mg, 2.186 mmol) at RT and the reaction mixture was allowed to stir at 50° C. for 52 h. It was then quenched with water (150 ml) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. Crude product was purified by combiflash (12 g silica column, 60% EtOAc: Pet-Ether) to get desired product as yellow solid (85 mg, 25.9%). 1H NMR (400 MHz, DMSO) δ ppm: 1.23-1.25 (d, J=8.0 Hz, 3H), 1.42-1.44 (d, J=8.0 Hz, 6H), 3.79 (s, 3H), 4.61-4.62 (d, J=4.0 Hz, 1H), 7.09-7.10 (d, J=4.0 Hz, 1H), 7.892-7.896 (d, J=1.6 Hz, 1H), 8.22 (s, 1H), 8.75 (s, 1H), 10.91-10.95 (t, J=16.0 Hz, 1H). LC retention time: 1.680 min (analytical HPLC Method P).
Reaction SMILES: [CH3:1][C:2]1(C)[C:6](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[C:21]([N:42]2[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43]2)=[C:22]2[C:28]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]2=[N:24][CH:25]=1>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:32]1([C:30]([NH:29][C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:2]([CH3:6])=[CH2:1])[C:21]=3[N:42]3[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49](=[O:50])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])[CH2:43]3)[NH:26][CH:27]=2)=[O:31])[CH2:34][CH2:33]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)C2CC2)cn3C(=O)OC(C)(C)C)C1
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: C=C(C)c1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 62.1 %

Procedure:
4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (436 mg, 2.59 mmol), PS-tetrakis(triphenylphosphine)palladium (786 mg, 0.0864 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (1296 μL, 2.59 mmol) were added to (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (500 mg, 0.864 mmol; Example 107, Step A) in degassed dioxane (1 mL). The reaction was heated to 120° C. for an hour under microwave irradiation. The reaction was then heated to 150° C. for 30 minutes. The reaction was filtered and extracted with DCM. The organic layer was concentrated, and the resulting residue was purified by reverse phase chromatography (Gilson, C-18, 5-95% CH3CN/water) to yield (R)-tert-butyl 1-(3-(cyclopropanecarboxamido)-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (236 mg, 62% yield).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][SH:34]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:34][CH2:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: SCCc1ccccn1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(SCCc3ccccn3)C(=O)O2)cc1Cl
Yield: 5 %

Procedure:
The title compound was prepared analogously to Example F(7), Step 6, substituting 3-chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.201 g, 0.52 mmol, described below) in place of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione, and 2-Pyridin-2-yl-ethanethiol in place of 2-mercaptothiazole.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:41]=[CH:40][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:23]=2)=[O:20])=[CH:40][C:41]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:132-133° C.; 1H NMR (300 MHz, CDCl3) δ: 9.53 (1 H, s), 8.10 (1 H, s), 8.00 (2 H, m), 7.85-7.87 (1 H, d, J=6.0 Hz), 7.66-7.69 (1 H, d, J=9.0 Hz), 7.43-7.45 (1 H, d, J=6.0 Hz), 7.33-7.36 (1 H, d, J=9.0 Hz), 6.58-6.61 (1 H, d, J=9.0 Hz), 5.56 (1 H, s), 4.23-4.25 (1 H, m), 3.64 (2 H, s), 2.61 (8 H, brs),2.44 (3 H, s), 2.43 (2 H, m), 1.91-1.97 (2 H, m), 1.81-1.86 (1 H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H31ClF3N6O: 583.2194. found: 583.2174.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[I:14][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: O=I(=O)Cl
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COc1cc(OC)c([N+](=O)[O-])cc1I
Temperature: 25 °C

Procedure:
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial acetic acid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirred at room temperature under an atmosphere of argon. Additional benzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hours and again after 24 hours. Additional zinc chloride (0.5 g) and glacial acetic acid (15 mL) is added after 24 hours. The mixture is permitted to stir at room temperature for 3 days and is then filtered, diluted with 5% aqueous sodium bisulfite, and extracted three times with ethyl acetate. These pooled organic extracts are washed successively with 5% aqueous sodium bisulfite, saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is triturated with hexanes to provide the desired product as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CS(C)=O>[F:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[C@@H:20]1[CH2:4][C@H:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1c(F)ccc2nn(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a suspension of sodium hydride (0.793 g, 18.2 mmol) in dimethyl sulfoxide (100 mL) was added a solution of trimethylsulfoxonium iodide (4.00 g, 18.2 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(5-fluoro-2-methyl-2H-indazol-4-yl)acrylate (4.10 g, 16.5 mmol) in dimethyl sulfoxide (130 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.00 g, yield 46%).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]CCCCCCC.C(C=O)=O.[C:36]([OH:55])(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C1(C)C=CC=CC=1.C(O)C>[C:48]1([CH3:47])[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=1[NH:31][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:12][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[C:36]([OH:55])(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: Cc1ccccc1-c1c[nH]nn1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=CC=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1NCCCCCCCC/C=C\CCCCCCCCc1c[nH]nn1
Yield: 343.6 %

Procedure:
Approximately 53 grams (0.4 mole) tolyltriazole, 111 grams (0.4 mole) oleyl amine, 100 ml ethanol, and 100 ml toluene were charged to a 1 liter flask equipped with an agitator, Dean-Stark apparatus, and dropping funnel. This mixture was stirred to a homogeneous mixture. Glyoxal (29 grams, 0.2 mole, 40% in water) was added dropwise and then stirred at room temperature for 12 hours. Water was then azeotropically removed by heating to reflux temperatures of approximately 100°-120° C. While maintaining a temperature of less than or equal to 60° C., 56 grams (0.2 mole) oleic acid was added slowly. The reaction mixture was stirred at 60° C. for 1 hour. The orange product (243 grams) was isolated by filtration and removal of solvent under reduced pressure.