Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Br:20][C:21]1[C:22]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: Nc1scc(Br)c1-n1nccn1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Br)c1-n1nccn1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.31 g, 1.14 mmol) and 4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g, 1.42 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=6.9, method [7], MS (ESI) 498.0 (M+H). 1H NMR (CDCl3) δ 10.56 (s, 1H), 7.90-7.89 (m, 2H), 7.86 (s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.9 Hz, 2H), 5.16 (s, 2H).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([O:15][C:16]2[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+].[CH2:36](I)[CH3:37]>O.O1CCOCC1>[CH2:36]([S:22]([C:20]1[C:19]([O:26][CH3:27])=[CH:18][C:17]([CH:28]([CH3:30])[CH3:29])=[C:16]([CH:21]=1)[O:15][C:11]1[C:12]([NH2:14])=[N:13][C:8]([NH2:7])=[N:9][CH:10]=1)(=[O:24])=[O:23])[CH3:37]
Reactant: CCI
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Temperature: 80 °C
Yield: 19.6 %

Procedure:
To a solution of sodium sulfite (541 mg, 4.29 mmol) in water (20 mL) was added 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonyl chloride (400 mg, 1.07 mmol) and the reaction was heated at 80° C. for 1 hour. Sodium bicarbonate (361 mg, 4.29 mmol-dissolved in 5 mL water), dioxane (20 mL), and ethyl iodide (0.10 mL, 1.29 mmol) were added and the reaction was heated at 80° C. for 2 hours. The reaction was concentrated, extracted with dichloromethane (150 mL) and water (20 mL). The dichloromethane layer was dried using anhydrous sodium sulfate, concentrated, and purified via silica gel column chromatography (95/5/0.1 dichloromethane/methanol/ammonium hydroxide) to yield 5-(5-ethanesulfonyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (77 mg, 20%) as white solid, MS (M+H)=367.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1([CH:42]2[CH2:47][C:46](=[O:48])[NH:45][C:44](=[O:49])[CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[O:48]=[C:46]1[CH2:47][CH:42]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:43][C:44](=[O:49])[N:45]1[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Reactant: O=C1CC(c2ccccc2)CC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)CC(c2ccccc2)CC1=O
Temperature: 15 °C
Reaction time: 8 h

Procedure:
9.3 g (42.3 mmol) N-(4-hydroxy-butyl)-3-pyridin-3-yl-acrylamide, 11.1 g (42.3 mmol) triphenylphosphine and 8.0 g (42.3 mmol) 4-phenyl-piperidin-2,6-dione are suspended in 120 ml THF, thereafter 6.7 ml (42.3 mmol) azodicarboxylic acid diethyl ester dissolved in 60 ml THF are added dropwise within three hours under protective atmosphere and light cooling (to ca. 15° C.). The mixture is left standing overnight without further cooling at RT. Subsequently, the solvent is removed under vacuum and the residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and, after withdraw of the solvent, crystallized from acetic acid ethyl ester: Colorless crystals with MP. 160–161° C.; Yield 3.8 g (23%).
Reaction SMILES: Cl.COCCCOC(C1C=CC=CC=1)C1CCCNC1.CSC(SC)=C[N+]([O-])=O.C(N(C(C)C)CC)(C)C.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][O:44][CH:45]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH:46]1[CH2:51][CH2:50][CH2:49][N:48](/[C:52](/SC)=[CH:53]/[N+:54]([O-:56])=[O:55])[CH2:47]1.[NH2:65][C@@H:66]([CH2:76][CH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1)[CH2:67][NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:73])[CH3:72]>C(#N)C>[CH3:39][O:40][CH2:41][CH2:42][CH2:43][O:44][CH:45]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:52]([NH:65][C@@H:66]([CH2:76][CH:77]2[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82]2)[CH2:67][NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:72])[CH3:73])=[CH:53][N+:54]([O-:56])=[O:55])[CH2:47]1
Reactant: COCCCOC(c1ccccc1)C1CCCN(/C(=C/[N+](=O)[O-])SC)C1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)CC1CCCCC1
Agent: COCCCOC(c1ccccc1)C1CCCNC1
Agent: CSC(=C[N+](=O)[O-])SC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCCOC(c1ccccc1)C1CCCN(C(=C[N+](=O)[O-])N[C@H](CNC(=O)OC(C)(C)C)CC2CCCCC2)C1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
3-((3-Methoxypropoxy)(phenyl)methyl)piperidine hydrochloride (177 mg, 0.59 mmol), 1,1-bis(methylthio)-2-nitroethene (117 mg, 0.71 mmol, 1.2 equiv), and diisopropylethylamine (500 μL, 2.8 mmol, 5 equiv) were dissolved in acetonitrile (5 mL) and put on a shaker for 2 h. LC-MS indicated the presence of 3-((3-methoxypropoxy)(phenyl)methyl)-1-((Z)-1-(methylthio)-2-nitrovinyl)piperidine. Tert-butyl (S)-2-amino-3-cyclohexylpropylcarbamate (˜300 mg, 1.17 mmol, 2 equiv) was added to the mixture and shaking was continued overnight. The mixture was concentrated and purified by prep HPLC to afford tert-butyl (S)-2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinylamino)-3-cyclohexylpropylcarbamate (22 mg, 6.6%). LC-MS (3 min) tR=1.92 min. m/z 589 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][OH:25].O>CO.CN(C=O)C>[Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11](=[NH:12])[O:25][CH3:24])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2
Reactant: CO
Reactant: N#Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: O
Solvent: CN(C)C=O
Product: COC(=N)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
2,5,6-Trichloro-3-cyano-1-(β-D-ribofuranosyl)indole (4.4, 107 mg, 0.28 mmol) was dissolved in dry MeOH (10 mL) which was cooled to 0 C in an ice bath. Hydrogen chloride gas was slowly bubbled through the solution for 2 h, then the reaction vessel was tightly capped, and the resulting solution was stirred at room temperature for 24 h. The acidic solution was diluted with Et2O (20 mL) and evaporated to dryness. The residual solid was suspended in 10% aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL, with vigorous shaking). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid which was dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield 64 mg (58%) of 4.34 as a white crystalline solid: mp 248-249 C; Rf 0.6 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.43 (s, 1H, D2O exch.), 7.96 (s, 1H), 5.98 (d, 1H), 5.39 (d, 1H, D2O exch.), 5.37 (t, 1H, D2O exch.), 5.24 (d, 1H, D2O exch.), 4.41 (q, 1H), 4.14 (s, 1H), 3.98 (d, 1H), 3.85 (s, 3H), 3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 161.40, 132.01, 128.23, 125.67, 124.82, 124.50, 121.32, 115.19, 106.29, 88.73, 86.08, 71.40, 69.50, 60.99, 52.45. HRMS (EI) m/z calcd. for C15H15Cl3N2O5 408.0047, found 408.0043. Anal calcd for C15H15Cl3N2O5: C, 43.98; H, 3.69; N, 6.84. Found: C, 43.97; H, 3.81; N, 6.75.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[O:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Oc1ccc(-c2cc(Cn3ccnc3)on2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc(-c3cc(Cn4ccnc4)on3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(5-imidazol-1-ylmethyl-isoxazol-3-yl)-phenol (150 mg, 0.62 mmol) and potassium carbonate (172 mg, 1.25 mmol) were placed in 10 ml of DMF, to which solution was added dropwise 3-fluorobenzyl bromide (89 μl, 0.75 mmol), and the mixture was stirred at room temperature for 4 hours. The completion of the reaction was confirmed by LC, and then DMF was distilled off under reduced pressure. A crude solid compound was extracted with ethyl acetate and water, and the organic solvent was distilled off under reduced pressure to obtain a white solid compound. The compound was purified by silica chromatography (methylene chloride:MeOH=20:1) to obtain 3-[4-(3-fluoro-benzyloxy)-phenyl]-5-imidazol-1-ylmethyl-isoxazole as a desired white solid compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: Nc1ccccc1
Product: CC(=O)Nc1ccccc1

Procedure:
A process according to claim 5, wherein acetic acid is reacted with aniline to produce acetanilide.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1
Reactant: OC(CCl)CCCl
Reactant: NC(=O)c1ccc(O)cc1
Product: NC(=O)c1ccc(OCC(O)CCCl)cc1
Yield: 25 %

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-hydroxybenzamide to give white title compound, m.p. 150°-153° C. in 25% yield. The recrystallizing solvent was 95% ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(CC)CC)C>ClCCl>[O:10]=[C:9]([NH:11][CH2:12][CH2:13][S:14](=[O:16])(=[O:15])[NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)CCNC(=O)OCc1ccccc1

Procedure:
A cold (0° C.) mixture of sulfonyl chloride from Step 1 (5.54 g, 20 mmol) and glycine methyl ester hydrochloride (2.7 g, 21.5 mmol) in dichloromethane (125 mL) was treated with triethylamine (6.0 mL, 43 mmol). The resultant mixture was stirred at 0° C. for 2 hours. The product mixture was diluted with dichloromethane and was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the intermediate methyl 3-oxo-1-phenyl-2-oxa-7-thia-4,8-diazadecan-10-oate 7,7-dioxide.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14].[OH-].[Li+]>O.CO>[F:24][C:22]([F:23])([F:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])(=[O:15])=[O:14]
Reactant: COC(=O)CCCC1CCCCN1S(=O)(=O)c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCC1CCCCN1S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
4-(1-(2-(Trifluoromethyl)phenylsulfonyl)piperidin-2-yl)butanoic acid methyl ester (3.5 g, 8.9 mmol, 1 eq.) was dissolved in water (25 ml) and methanol (35 ml). Lithium hydroxide (1 g, 44.5 mmol, 5 eq.) was added, while stirring. The mixture was stirred at room temperature for 24 h.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13])(C)C.[F:15][C:16]1[CH:23]=[CH:22][C:21](I)=[CH:20][C:17]=1[CH:18]=[O:19].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:15][C:16]1[CH:23]=[CH:22][C:21]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1cc(I)ccc1F
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2ccc(F)c(C=O)c2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
Combine 5-trimethylsilanylethynyl-nicotinonitrile (1.30 g, 11.5 mmol), (prepared as described in PREPARATION 3), 2-fluoro-5-iodobenzaldehyde (3.45 g, 13.8 mmol, (prepared essentially as described in Tet. Lett., 33, 7499, (1992)), bis(triphenylphosphine)palladium (II) dichloride (404 mg, 0.575 mmol), copper (I) iodide (219 mg, 1.15 mmol), and triethylamine (22.4 mL, 161 mmol) in tetrahydrofuran (9 mL). Cool the suspension to −78° C. and treat with a 1.0 M solution of tetrabutylammonium fluoride (11.5 mL) in tetrahydrofuran. After 10 min, heat to 60° C. for 2 h. Cool to room temperature and filter through diatomaceous earth washing with ethyl acetate. Purify the crude product by silica gel chromatography, eluting with a gradient from 80:20 to 60:40 hexanes:ethyl acetate, to give the title compound as an off-white crystalline solid (1.3 g, 45%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:36]=[O:37])[CH2:24][C:25](=[N:31][NH:32][C:33]([NH2:35])=[O:34])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:36]=[O:37])[CH2:24][C:25](=[N:31][NH:32][C:33]([NH2:35])=[O:34])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
1-Methylindole-2-carboxylic acid (70 mg, 0.4 mmol) and 3(S)-(Leucinyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (131 mg, 0.4 mmol) were dissolved in methylene chloride (2 mL) and both DMAP (49 mg, 0.40 mmol) and EDAC (107 mg, 0.56 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 3 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution. The ethyl acetate solution was washed successively with 5% KHSO4 solution, saturated with sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated in vacuo to give a crude solid. Trituration of the solid with ether afforded the title product as a white powder (156 mg, 80%). TLC: (methanol/methylene chloride: 5/95, silica gel): Rf=0.42; 1H NMR (CDCl3+CD3OD): δ8.18 (s, 1H), 7.66-7.11 (m, 6H), 6.97 (s, 1H), 6.32 (d, J=7.7, 1H), 4.95-4.88 (m, 1H), 4.70-4.62 (m, 1H), 4.03 (s, 3H), 2.82-2.56 (m, 2H), 1.87-1.58 (m, 3H), 1.38 (9H), 1.00 (t, J−6.3, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1C=Nc1ccccc1
Yield: 32.7 %

Procedure:
A mixture of 4-chloro-2-methylbenzaldehyde (3.5 g, 22.6 mmol) and aniline (2.11 g, 22.6 mmol) in toluene (40 ml) was heated at reflux in a Dean-Stark apparatus for 1 hour. The mixture was cooled and evaporated in vacuo to leave an oily residue. The residue was redissolved in ether, washed with 5% sodium bicarbonate solution. The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford an oily residue which was purified by distillation via a Kugelrohr apparatus (oven temperature 160° C., 0.5 mm) to provide the title compound (4.0 g, 7.4 mmol, 77%) as a viscous oil; pmr(CDCl3) δ 2.5 (3H, s), 6.3~7.5 (7H, m), 7.95 (H, d), 8.6 (H, s).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[C:11]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=[C:8]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:7]=1.[OH-].[Na+]>CO>[CH3:4][O:5][C:6]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[C:8]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:7]=1
Reactant: COc1nc(OCC(F)(F)F)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(OCC(F)(F)F)ccc1CN
Temperature: 50 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
Hydrazine monohydrate (0.13 mL, 2.74 mmol) is added to a solution of 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.83 mmol, Step-3) in methanol (20 mL) and stirred at 50° C. for 20 hours. The reaction mixture is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.41 g (95% yield) of the title compound as white solid. This material is used for the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:24][CH2:23][C:18]4([CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:24][CH2:23][C:18]4([CH2:22][N:21]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2nccc(NC3CCC4(CCNC4)CC3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(Nc2nccc(NC3CCC4(CC3)CCN(C(=O)CC#N)C4)n2)cn1
Temperature: 45 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine (80 mg, 0.24 mmol) and 2-cyanoacetic acid (22 mg, 0.26 mmol) in DCM (3 mL) and DMF (2 mL) were added EDCI (49 mg, 0.26 mmol) and HOAT (17 mg, 0.12 mmol). The mixture was stirred at 45° C. for 1 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (13 mg, 13%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][CH:23]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[CH:18]=[CH:17][C:16]([NH:19][C:30](=[O:31])/[CH:29]=[CH:28]/[C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:34])[F:20])=[CH:27][CH:26]=3)=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cccc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1cccc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=414.93.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[N:46]1([CH2:52][CH:53]([N:57]2[CH:61]=[C:60]([C:62]3[C:63]4[CH:70]=[CH:69][N:68](COCC[Si](C)(C)C)[C:64]=4[N:65]=[CH:66][N:67]=3)[CH:59]=[N:58]2)[CH2:54][C:55]#[N:56])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C1COCC1.O.C(OCC)(=O)C>[F:13][CH:2]([F:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:49]2[CH2:48][CH2:47][N:46]([CH2:52][CH:53]([N:57]3[CH:61]=[C:60]([C:62]4[C:63]5[CH:70]=[CH:69][NH:68][C:64]=5[N:65]=[CH:66][N:67]=4)[CH:59]=[N:58]3)[CH2:54][C:55]#[N:56])[CH2:51][CH2:50]2)=[O:9])=[C:5]([F:12])[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=C(O)c1ccc(C(F)F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCC(CN1CCN(C(=O)c2ccc(C(F)F)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
4-(Difluoromethyl)-2-fluorobenzoic acid (10.1 mg, 0.0532 mmol) was dissolved in THF (0.39 mL). Triethylamine (29.7 uL, 0.213 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0426 mmol) were added, followed by 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol, prepared as in Example 12, step 2). The reaction was stirred for 30 minutes. Ethyl acetate and water were added, shaken, and layers separated. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS (eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as the free base (7 mg, 39%). 1H NMR (300 MHz, d6-dmso): δ 12.06 (br s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.60 (d, 1H), 7.57-7.43 (m, 3H), 7.07 (t, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.63-3.55 (m, 2H), 3.25-3.18 (m, 2H), 3.317-3.10 (m, 2H), 2.91-2.77 (m, 2H), 2.66-2.26 (m, 4H); LCMS (M+H)+: 509.2.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)=[CH:19][CH:18]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:26]2[CH2:25][CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Product: CC(=O)N1CC(CCN2CC=C(c3ccc(Cl)cc3)CC2)c2ccccc21

Procedure:
In the manner described in Example 1, reaction of 1-acetyl-3-(2-bromoethyl)indoline with 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine gives white crystals, m.p. 116°-118°C., after recrystallization from dilute methanol.