Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[CH3:34][O:35][CH2:36][CH2:37][NH:38][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: COCCN
Product: COCCNC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 35.4 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (200 mg, 0.45 mmol) and 2-methoxyethylamine (5 ml, 57.2 mmol) was heated at reflux for 18 hours. The reaction mixture was evaporated, the residue dissolved in methanol and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 90:10). The purified product was triturated with diethylether and the resulting solid collected by filtration to give the title compound (78 mg, 36%).
Reaction SMILES: ClC1C=CC2OC(NC[C@@H]3[C@H](C)CCCN3C(OCC=C)=O)=NC=2C=1.[NH2:26][CH2:27][C@@H:28]1[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)=[O:36].Cl[C:51]1[O:52][C:53]2[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:54]=2[N:55]=1>>[F:60][C:57]1[CH:58]=[CH:59][C:53]2[O:52][C:51]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:36])=[N:55][C:54]=2[CH:56]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc2oc(Cl)nc2c1
Agent: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(F)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-5-fluorobenzo[d]oxazole. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.O.Cl.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>C(O)(=O)C.FC(F)(F)C(O)=O>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH:5]=2)=[CH:12]1
Reactant: Cn1ccc2ccccc21
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C2=CCNCC2)c2ccccc21
Yield: 47 %

Procedure:
To a solution of 4-piperidone. H2O.HCl (50 g, 0.32 mol) in 100 ml of acetic acid and 150 ml of trifluoroacetic acid was added dropwise a solution of 1-methylindole (11.5 ml, 0.09 mol) in 100 ml of acetic acid at room temperature. After stirring for 1h the reaction mixture was concentrated (in vacuum , temp. ca. 30° C.), water was added , the mixture was made basic with potassium carbonate and extracted with ethyl acetate. The organic layer was separated, dried and purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide =84/15/1) to give 9 g (47%) of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH:10][C:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)C1
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
1.04 g (5.02 mole) of 3-cyclopentyloxy-4-methoxyaniline, 0.51 g (5.02 mmole) of 1,3-cyclopentanedione, and 0.03 g of p-toluenesulfonic acid were dissolved in 30 ml of benzene and the solution was heated reflux in an apparatus fitted with a water separation tube for 3 hours, while azeotropically separating the water produced. After the reaction, the solution was cooled to room temperature, a yellow crystal was precipitated. The precipitated yellow crystal was collected by suction filtration, and the crystal was washed with diethyl ether, then dried to obtain the title compound 1.16 g (yield 80.4%) as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][CH:11]([OH:20])[CH2:12][CH:13]([OH:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=[O:20])[CH2:12][CH:13]([OH:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(O)CC(O)C=Cc1ccc(Cl)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(O)CC(=O)C=Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
Activated manganese dioxide (40 g) was added to a solution of methyl 7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate (6.8 g, 21.3 mmol) in chloroform (600 mL) and the black suspension was vigorously stirred at ambient temperature for 20 hours. After filtration and evaporation of the solvent the residual amber oil (4.5 g, 1 major spot on TLC with Rf 0.61 on Whatman MK6F silica using CHCl -MeOH; 19:1 as eluent) was chromatographed on a Still column to obtain the product (3.9 g, 58%) as a pale yellow oil which solidified on standing, m.p. 77°-79° C.; NMR (CDCl3) δ: 2.57 (2H, d, J=6Hz, --C2CO2 --), 2.93 (2H, d, J=6Hz, --CH2 --CO--), 3.70 (3H, s, --CO2CHp3), 4.4-4.8 (H, m, --CH(OH)--), 6.67 (H, d, J=16 Hz, =CH--CO), 7.1-7.7 (3H, m. ArH), 7.93 (H, d, J=16 Hz, =CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)[CH:9]=1)[C:5]#[N:6].CC(C)([O-])C.[Li+].Cl[CH2:28][C:29]1[C:37]2[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:35][CH:36]=2)[N:31]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:30]=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:28][C:29]2[C:37]3[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)=[CH:35][CH:36]=3)[N:31]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[N:30]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4ncc5c(Oc6cc(Cl)cc(C#N)c6)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-chloro-5-[(5-chloro-1H-indazol-4-yl)oxy]benzonitrile (0.677 g, 2.225 mmol) and lithium tert-butoxide (0.178 g, 2.225 mmol) were dissolved in DMF (5 μL) and allowed to stir for 5 minutes. To this mixture at 0° C. was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (Intermediate 2; 0.896 g, 2.119 mmol) as a solution in DMF (5 mL). The mixture was then allowed to warm to room temperature overnight, after which aqueous ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with water (5×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to automated silica gel chromatography eluting with a gradient of 0-10% ethyl acetate in dichloromethane to yield the title product. LRMS (M+1)=691.8
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:37]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccccc1F
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3F)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 42 mg (0.22 mmol, 1.1 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 59 mg (57% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:27])[N:9]([CH:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]=2[CH:14]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)[nH]c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.40 (5.34 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIc) were dissolved in 200 ml of a 2-percent strength trifluoroacetic acid solution in dichloromethane and stirred at room temperature overnight. The solvent and excess trifluoroacetic acid were removed in vacuo, and the residue was taken up in toluene, concentrated in vacuo and dried.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH3:27]>>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH2:27])[O:18][C:17]=2[CH:19]=1)(=[O:25])=[O:24]
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CN)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (1.1 g, 2.5 mmol), NH3 (4 ml, 7N in methanol) was heated under microwave radiation at 120° C. for 20 min. The product was evaporated to dryness and was purified by flash column chromatography (EtOAc/MeOH). Yield 0.31 g. MS m/z (rel. intensity, 70 eV) 243 (M+, 35), 214 (bp), 199 (35), 79 (25), 56 (22).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:30]I>CN(C)C=O>[C:1]([C:3]1[C:4]([CH:19]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH3:30])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc2ccccc2c1
Reactant: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(C)c1ccc2ccccc2c1
Temperature: -25 °C
Yield: 78.6 %

Procedure:
A 1 L flask was charged with a big egg-shape stirring bar and ethyl 4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylate (14.5 g, 35.7 mmol). To the flask was added N,N-dimethylformamide (240 mL) and the mixture was evacuated and purged with nitrogen (×3). To the flask was added tetrahydrofuran (60 mL), and the mixture was stirred until it became a clear yellow solution. The solution was cooled to ˜−25° C. in a dry ice-acetone bath (the temperature was actively controlled by slow addition of dry ice between −30˜−40° C.). 1 M of Potassium tert-butoxide in tetrahydrofuran (42.8 mL) was added dropwise over 3 min. The mixture turned deep purple immediately. After the addition the mixture was stirred for 10 min at this temperature. Methyl iodide (11.1 mL, 178 mmol) was added over 1 min. By the end of addition the mixture turned light red. After stirring the resulting mixture at 0° C. for 10 min, the reaction was quenched by addition of 10 mL of water. All volatiles were removed under reduced pressure and the resulting mixture was distributed between brine and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with 10% LiCl(aq) soln (×3), then brine, dried, and concentrated to provide a yellow syrup. Purification on a silica gel column (gradient elution 5-20% EtOAc/hexanes) provided Ethyl 4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylate as a white solid (11.8 g, 78.7% yield). LCMS: (AA) ES+ 421; 1H NMR (400 MHz, CDCl3) δ 7.90-7.82 (m, 2H), 7.82-7.70 (dd, J=15.4, 8.1 Hz, 2H), 7.50-7.37 (m, 3H), 5.82-5.67 (q, J=7.3 Hz, 1H), 4.40-4.25 (qd, J=6.1, 5.0, 3.1 Hz, 2H), 3.86-3.72 (t, J=4.8 Hz, 4H), 3.54-3.44 (t, J=4.8 Hz, 4H), 1.95-1.85 (d, J=7.3 Hz, 3H), 1.42-1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:28])([F:27])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH2:24]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:28])=[CH:21][CH:20]=2)=[O:26])[CH2:11][CH2:12]1
Reactant: O=C(CCl)Nc1ccc(OC(F)(F)F)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-trifluoromethoxyphenyl)-2-chloroacetamide (51 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced the residue was purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.35 (d, J=6 Hz, 2H), 7.55 (t, J=6 Hz, 1H), 7.76 (m, 2H), 8.12 (d, J=5 Hz, 1H), 9.98 (s, 1H); MS (ESI/APCI+) m/e 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:37][CH2:36][S:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCSCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCSCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 58 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.3 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-thiopyran-4-yl) piperazin-1-yl]benzonitrile (1.1 g), the title compound (1.1 g) was obtained, melting point: 281° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 10 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
84 g of diketene were added over 30 minutes to a mixture of 200 g of m-benzyloxy-aniline [Morton, J. Biol. Chem., (1949), p. 259] in 1 liter of benzene cooled to 10°C. and after stirring the mixture for 6 hours, the benzene was distilled off under reduced pressure. The residue was added to isopropyl ether and the mixture was vacuum filtered. The recovered precipitate was washed with isopropyl ether and dried to obtain 240 g of m-benzyloxy-acetylacetanilide melting at 80°C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[S:18])=[O:15]>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:17](=[S:18])[NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[CH3:11])=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCOCC
Product: Cc1ccccc1C(=O)NC(=S)Nc1ccccc1C(N)=O
Yield: 95.8 %

Procedure:
To a stirred mixture of 4.9 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 6.67 g of 2-methylbenzoyl isothiocyanate in 100 ml of ether over 15 minutes After a few hours, the solid was collected, giving 10.8 g of the desired product as grey crystals, mp 181°-185° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:25]#[N:26])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.BrC1N=C(/C=C(/C#N)\C(NC(C2C=CC(OC)=CC=2)CCC)=O)C=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[C:9]([C:25]#[N:26])[C:10]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OC)cc1
Agent: CCCC(NC(=O)/C(C#N)=C\c1cccc(Br)n1)c1ccc(OC)cc1
Product: CCCC(NC(=O)C(C#N)=Cc1cccc(Br)n1)c1ccc(OC)cc1

Procedure:
To a solution of 3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-hydroxyphenyl)butyl)acrylamide (21 mg, 0.05 mmol) in acetone was added MeI (32.6 μL, 0.52 mmol) and potassium carbonate powder (7.25 mg, 0.05 mmol). The resulting mixture was stirred at room temperature for 4 hours before the addition of ethyl acetate. The organic solution was then washed with water (1×), saturated brine (1×), dried over sodium sulfate and concentrated to give a yellow oil as the crude product. The crude material was purified with preparative TLC plate to afford (E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-methoxyphenyl)butyl)acrylamide (8) as a light yellow solid (9.2 mg, 42% yield) and (Z)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-methoxyphenyl)butyl)acrylamide (9) as a white solid (4.4 mg, 20% yield). Mass spec ES+, m/z=414.0 (m+H+). E-isomer (8): 1H NMR (500 MHz, CDCl3/CD3OD) δ 7.59 (t, J=7.7, 1H), 7.52 (d, J=8.0, 1H), 7.27 (d, J=8.7, 2H), 7.22 (d, J=7.4, 1H), 6.83 (d, J=8.9, 2H), 6.81 (s, 1H), 3.89-3.83 (m, 2H), 3.81 (s, 3H), 1.65 (dd, J=15.4, 7.9, 2H), 1.39 (dd, J=15.1, 7.5, 2H), 0.94 (t, J=7.4, 3H). Z-isomer (9): 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.79 (d, J=7.6, 1H), 7.61 (t, J=7.8, 1H), 7.52 (d, J=7.9, 1H), 7.15 (d, J=8.8, 2H), 6.93 (d, J=8.8, 2H), 3.84 (s, 3H), 3.84-3.79 (m, 2H), 1.57 (dd, J=14.8, 7.1, 5H), 1.37 (dq, J=15.0, 7.5, 2H), 0.94 (t, J=7.4, 3H).
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.[NH2:15][C@H:16]1[C@@H:20]([CH2:21][F:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH2:21][F:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Yield: 80.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 740 mg, 2.70 mmol), (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (Intermediate 10, 714 mg, 2.83 mmol) and DIPEA (0.989 mL, 5.66 mmol) in DMF (8 mL) was heated to 80° C. for 16 hrs. The reaction mixture was concentrated and purified on silica gel column with Hexanes/EtOAc (1/1) to give the title compound (1.06 g, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.94 (br. s., 1H), 7.42-7.27 (m, 5H), 7.15 (s, 1H), 5.16-4.94 (m, 3H), 4.70-4.54 (m, 2H), 3.90-3.41 (m, 4H), 3.02-2.84 (m, 1H), MS (ES+) m/z: 490.1, 492.1 (M+H); LC retention time: 3.261 min (analytical HPLC Method H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(=O)CC>[F:19][C:18]([F:21])([F:20])[S:16]([C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:22][C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=3)[N:4]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2coc(/C=C/c3ccc(S(=O)C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
A suspension of 250 mg (0.74 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole, 90 mg (0.74 mmol) 4-hydroxy-benzaldehyde, 147 mg (0.45 mmol) cesium carbonate and 123 mg (0.74 mmol) potassium iodide in 25 ml butanone was stirred at 60° C. over night. After evaporation, the residue was quenched with water and extracted with ethyl acetate. The extract was washed with sodium hydroxide solution and water, dried, concentrated and purified on silica. Elution with heptane/ethyl acetate 5:1 containing 1% acetic acid yielded 245 mg (78%) 4-{2-[(E)-2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzaldehyde as white crystals, melting at 144-147° C.