Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[ClH:13].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][C:40]([C:43](N4CCN(C5C=CC=CC=5)CC4)=[O:44])=[CH:39][CH:38]=3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]>C(OCC)C>[ClH:13].[ClH:13].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([N:9]4[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:12])[CH2:11][CH2:10]4)=[O:44])=[CH:41][CH:42]=3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: CN(C)CCCN1CCNCC1
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: Cl
Solvent: CCOCC
Product: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from intermediate product A1 and 1-(3-dimethylaminopropyl)piperazine as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 248° C. (with decomposition).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[C:27]([CH2:28]C)=[CH:26][C:25]([NH:30][C:31]([C:33]3[CH:34]=[N:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=4)[C:37]=3[CH3:38])=[O:32])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[NH:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[N:23]=[CH:24][C:25]([NH:30][C:31]([C:33]3[CH:34]=[N:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:41][N:40]=4)[C:37]=3[CH3:38])=[O:32])=[CH:26][C:27]=2[CH3:28])[CH2:17][CH2:16]1
Reactant: CCc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCNCC1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (4.0 ml) was added at room temperature to a solution of 4-[3-ethyl-5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]azepan-1-carboxylic acid tert-butyl ester (1.1 g) described in Example D291 in dichloromethane (20 ml), and stirred at the same temperature for 4 hours. After completion of the reaction, 4N aqueous solution of sodium hydroxide was added to adjust the solution to pH 11 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated to give N-[6-(azepan-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70]>CN(C=O)C>[CH2:70]([O:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH3:59]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) in suspended under argon in absolute DMF (50 mL) and the mixture is heated to 55° C. A solution of dodecyl bromide (49.4 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. The mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture extracted with ethyl acetate (3×40 mL). The combined organic fractions are dried (Na2SO4) and the solvent evaporated. The product is isolated by chromatography on a column (300 g) of silica. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.), di-substituted compound (trans-isomer) with toluene:ethyl acetate (15:1 by vol.), di-substituted compound (cis-isomer) with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) with toluene:ethyl acetate (5:1 by vol). Solvent is removed in vacuo and the residue dried at high vacuum to give product as a violet solid.
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (331 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (276 mg, 89%) as a white solid.
Reaction SMILES: [N:1]([O-])=[O:2].[Na+].C(O)(=O)C.[N+:9]([C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([N:1]=[O:2])[CH:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])=[CH:29][CH:30]=1)([O-:11])=[O:10]
Reactant: O=C(O)C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1C(=O)O
Reaction time: 1 h

Procedure:
The H2O (300 mL) solution of NaNO2 (cont. 98.5%) (6.66 g) was added to the acetic acid (864 mL) solution of piperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester (26.72 g) under a nitrogen atmosphere at 0° C. for 0.5 h and stirred for 1 h. In addition, the H2O (132 mL) solution of NaNO2 (cont. 98.5%) (2.41 g) was added to the solution at 0° C. for 0.5 h and stirred for 1 h. The solution was concentrated under reduced pressure and H2O (500 mL) was added to the residue. The solution was extracted with AcOEt (5 times) and organic layer was washed with brine. The mixture was dried over MgSO4, filtered and concentrated under reduced pressure to afford crude 4-nitrosopiperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester as pale brown amorphous (27.83 g (gross), 25.77 g (net), 88.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(CCNC(C)=O)c1

Procedure:
In close analogy to the procedure described above, 2-(3-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]1([C:31]#[C:32][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Product: C(#Cc1ccc2cc[nH]c2c1)c1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
6-Bromoindole (3.84 g, 19.6 mmol) was dissolved in triethylamine (40 ml.). A catalytic amount of phenothiazine was added, and the solution was degassed by bubbling argon through it. Phenylacetylene (8.60 mL, 78.3 mmol) was added via syringe. Bis(triphenylphosphine)palladium(II) chloride (0.69 g, 0.98 mmol) was added, and the reaction mixture was heated at 75°-85° C. for 5 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica gel to give 6-phenylethynylindole (2.55 g, 60%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+]>ClC(Cl)C.[Au]>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:16]([CH3:20])[CH:15]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cccc(Br)c1
Agent: [Au]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
To a suspension of AlCl3 (20.3 g, 152 mmol) in dichloroethane (250 mL, DCE) was added ethyl chlorooxoacetate (16.8 g, 123 mmol) at room temperature. To the resulting gold solution was added 3-bromotoluene (20.0 g, 117 mmol) and the dark solution was stirred at room temperature for 4 h. The reaction was cooled to 0° C. and saturated aqueous ammonium chloride was slowly added. The phases were separated and the DCE layer was washed with additional ammonium chloride, dried (Na2SO4), filtered, and the DCE removed in vacuo to give the crude product as a gold oil. Flash chromatography (SiO2; 0-3% Et2O/Hexanes) gave ethyl (4-bromo-2-methylphenyl)-(oxo)acetate (16.2 g; 33%) as a gold oil. 1H NMR (CDCl3) δ 1.41 (t, 3H, J=7.0 Hz), 2.58 (s, 3H), 4.43 (q, 2H, J=7.0 Hz), 7.44-7.48 (m, 2H), 7.58 (d, 1H, J=8.0 Hz); EI/MS 271 m/e (M+). Ethyl (4-bromo-2-methylphenyl)-(methoxyimino)ethanoate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:21][NH2:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[NH:22][N:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NN
Reactant: COc1ccc(C#CC(=O)c2cc(Cl)cc(Cl)c2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)n[nH]2)cc1

Procedure:
To a solution of the intermediate from step A (1.13 g, 3.7 mmol) in DMF (20 mL) was added hydrazine (0.37 mL, 4.07 mmol, 35% aqueous solution). After 2 hours the reaction mixture was concentrated in vacuo. The residue was suspended in H2O (20 mL). A white precipitate crashed out. The aqueous layer was extracted with ethyl acetate (2×). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. An off-white solid was obtained. This material was used in the next step without any further purification. 1H NMR (CDCl3, 500 MHz): δ 7.7 (d, J=1.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.35 (s, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.8 (s, 1H), 3.91 (s, 3H). LC-MS: 2.92 min. (M+H)=319.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1>>[CH:12]1([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(CCO)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 69 %

Procedure:
Following general procedure A1, 4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.100 g, 0.40 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.066 g, 0.48 mmol) to afford the title compound (0.097 g, 69%) as a white solid. MW=351.37. 1H NMR (DMSO-d6, 500 MHz) δ 9.93 (s, 1H), 7.68-7.54 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.92 (s, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.63-3.56 (m, 2H), 3.19 (quin, J=8.0 Hz, 1H), 2.70 (t, J=7.0 Hz, 2H), 2.05-1.96 (m, 2H), 1.89-1.60 (m, 6H); APCI MS m/z 352 [M+H]+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]=[C:10]1[NH:14][C:13](=[O:15])[CH:12]=[C:11]1[OH:16]>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]=[C:10]1[NH:14][C:13](=[O:15])[C:12](=[N:1][OH:3])[C:11]1=[O:16]
Reactant: O=C1C=C(O)C(=Cc2cccc(Cl)c2)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2cccc(Cl)c2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(3-chlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(3-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 50%, with a melting point of 185° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:42]([CH3:45])([CH3:44])[CH3:43])/[CH:30]=[CH:31]/[P:32](=[O:41])([O:37][CH:38]([CH3:40])[CH3:39])[O:33][CH:34]([CH3:36])[CH3:35])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].[NH4+].[Cl-]>CO>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:42]([CH3:45])([CH3:44])[CH3:43])/[CH:30]=[CH:31]/[P:32](=[O:41])([O:37][CH:38]([CH3:39])[CH3:40])[O:33][CH:34]([CH3:35])[CH3:36])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](/C=C/P(=O)(OC(C)C)OC(C)C)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)OP(=O)(/C=C/[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C)OC(C)C
Reaction time: 0.05 h

Procedure:
To a solution of (R,E)-diisopropyl (3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate, 17a, (1.0 g, 1.51 mmol) in methanol (30 mL) was added sodium methoxide (8.2 mL of 25% wt solution in MeOH). After 3 minutes, the mixture was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-15% MeOH/CH2Cl2 gradient) to afford 724 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.76 minutes (M+H) 508.13.
Reaction SMILES: [CH2:1]([C:8]1([O:14][C:15]([NH:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](OC)=[O:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:30]1([P:36](=[CH:49][C:50]#[N:51])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:50]([C:49](=[P:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:19]([C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])#[N:51]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCCC1)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To 1.90 g (5.26 mmol) of methyl(2S)-2-({[(1-benzylcyclohexyl)oxy]carbonyl}amino)hexanoate in 18 mL of tetrahydrofuran:water (1:1) was added 308.8 mg (7.36 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 15 mL of dichloromethane, then 19.0 mg (155.4 μmol) of 4-dimethylaminopyridine was added. To this solution was added 983.4 mg (3.26 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 658.8 mg (3.42 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 16 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 1.29 g (39%) of 1-benzylcyclohexyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.32 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.74-7.70 (m, 3H), 7.62-7.50 (m, 12H), 7.22-7.12 (m, 5H), 6.90 (d, J=8 Hz, 1H), 4.60-4.52 (m, 1H), 3.23 (ABq, JAB=13 Hz, ΔνAB=40 Hz, 2H), 2.19 (d, J=13 Hz, 1H), 1.95 (d, J=16 Hz, 1H), 1.86-1.68 (m, 1H), 1.60-1.10 (m, 13H), 0.90 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](C=O)[CH:5]=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cccc(Br)n1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC(OC)c1cccc(Br)n1

Procedure:
The procedure in Example 6: step b was followed using 6-bromo-pyridine-2-carbaldehyde (600 mg, 3.23 mmol), trimethyl orthoformate (8 mL), and toluenesulfonic acid (100 mg) in MeOH (50 mL). Analogous aqueous workup yielded the product (743 mg) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(O)=O>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(C#N)cc1
Temperature: 90 °C
Yield: 97.2 %

Procedure:
Pd/C (0.6 g, 10%, 50% water wet) was added to a solution of ethyl (2E)-3-(4-cyanophenyl)-2-propenoate (2.7 g, 13.42 mmol) in ethyl acetate (40 mL) under an argon atmosphere. It was mixed with TEA (3.74 mL, 26.8 mmol) and formic acid (2.57 mL, 67.1 mmol). The reaction mixture was refluxed at 90° C. under argon for 1 h. It was filtered through a Celite pad. The filtrate was then washed with water, 5% NaHCO3 solution and brine, dried over Na2SO4, and concentrated to provide the title compound as a pale yellow oil (2.65 g, 97% yield). LCMS: rt=2.94 min, [M+H+]=204.0
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)=[O:7].[CH3:21][NH2:22].CO>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([S:17]([NH:22][CH3:21])(=[O:19])=[O:18])[C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)=[O:7]
Reactant: CN
Reactant: O=C(CCCCCl)c1cc2c(c(S(=O)(=O)Cl)c1)OCC2
Solvent: CO
Product: CNS(=O)(=O)c1cc(C(=O)CCCCCl)cc2c1OCC2

Procedure:
Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonyl chloride (5.06 g) obtained in Reference Example 69 and a 40% mehtylamine-methanol solution (2.6 g) according to the same method as that of Reference Example 66, the title compound was obtained as colorless crystals (4.82 g) having a melting point of 120 to 121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:14].[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:14])=[CH:19][CH:18]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CN(C)S(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)c(F)c1
Reaction time: 16 h
Yield: 28.1 %

Procedure:
According to general procedure B, 4-bromo-3-fluoro-N,N-dimethylbenzenesulfonamide (166 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N,N-dimethylbenzenesulfonamide (51 mg, 28%) was provided after purification. HRMS: calcd for C14H14FN3O2S, 307.07907; found (EI, M+.), 307.0786. HPLC purity 99.3% at 210-370 nm, 8.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH:10]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[C:2]1([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:25][CH:24]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(NCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(NCC2CN(c3ccccc3)CCN2)cc1

Procedure:
In a manner similar to Example 1, react N-[4-[[[4-phenyl-1-(phenylmethyl)piperazin-2-yl]methyl]amino]phenyl]methanesulfonamide hydrochloride (2.05 g, 4.22 mmol) with H2 over 10% palladium on activated carbon (0.19 g). Remove the catalyst by filtration and evaporate the solvent. Dissolve the residue in methanol and adjust thepH to 8 with 4M aqueous NaOH. Remove the solvent in vacuo. Triturate the residue with methylene chloride. Remove the solid by filtration. Recrystallize the residue from methylene chloride to obtain the title compound.