Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].N1C=CC=CC=1.[C:21](Cl)(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(C(C)=O)C>[C:21]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1)(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 75.1 %

Procedure:
39.6 g (0.2mol) of 3,5-dinitrobenzyl alcohol, 23.7 g (0.3 mol) of pyridine and 200 ml of methyl ethyl ketone were introduced into a reactor and dissolved by stirring under a nitrogen gas stream at about 70° C. 35.3 g (0.2 mol) of pelargonic acid chloride was dissolved in 100 ml of methyl ethyl ketone and the resultant solution was added dropwise into the reactor as described above. After the completion of the addition, the mixture was refluxed and stirred under nitrogen for about 2 hours. Then the reactor was cooled by allowing to stand and pyridine hydrochloride was removed by filtration. The filtrate was concentrated and purified by using a column to give 50.8 g of 3,5-dinitrobenzyl pelargonate. 33.8 g of 3,5-dinitrobenzyl pelargonate and 4 g of a catalyst (5% palladium carried on active carbon) were introduced into a hydrogenation apparatus and reduced with hydrogen. After filtration and concentration, 27.8 g (0.1 mol) of 3,5-diaminobenzyl pelargonate was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[CH:18]=[O:19].[CH2:20]=[N:21][CH:22](S(C1C=CC(C)=CC=1)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[C:23]1([C:22]2[N:21]=[CH:20][O:19][C:18]=2[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: C=NC(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ocnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
To a solution of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbaldehyde (52.8 mg, 0.197 mmol) in MeCN (0.4 mL) were added N-methylidene-1-[(4-methylphenyl)sulfonyl]-1-phenylmethanamine (53.8 mg, 0.197 mmol) and K2CO3 (35.4 mg, 0.256 mmol) at room temperature. The suspension was stirred at room temperature for 1 day. The suspension was diluted with water, extracted with AcOEt, washed with brine, dried over MgSO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=90/10 to 0/100) and crystallized with AcOEt/hexane to yield the title compound (18.6 mg, 25% yield) as a solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.75 (1H, d, J=8.5 Hz), 7.33-7.43 (3H, m), 7.64-7.70 (2H, m), 7.72-7.83 (2H, m), 7.92-8.01 (2H, m), 8.65 (1H, s), 9.02 (1H, d, J=7.7 Hz). Anal. Calcd for C20H12F3N3O2.0.2H2O: C, 62.08; H, 3.23; N, 10.86. Found: C, 62.08; H, 3.38; N, 10.67.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.[S:41]1C=CN=C1>>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:41][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[CH:16][N:15]=2)[CH2:4][O:3]1
Reactant: c1cscn1
Reactant: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Product: CCCCCCCCOc1ccc(-c2cnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F

Procedure:
The synthesis of 2,5-substituted thiazoles is described in Scheme 9. Reaction of the desired alcohol para-methoxybenzyl alcohol (PMB-OH) with substituted 4-fluoroacetophenone 1 afforded the acetophenone intermediate 2. Acetophenone intermediate 2 was then converted to the corresponding bromo-acetophenone using Bu4NBr3 which, upon reaction with NaN3, provided the azido-acetophenone intermediate. Hydrogenation of the azido-acetophenone intermediate afforded amine 3, followed by coupling with orthogonally protected amino acid 4 gave amide 5. Removal of PMB group under hydrogenation gave phenol 6. Mitsunobu reaction of the phenol 6 with the desired alcohol followed by thiazole formation under Lawesson's reagent conditions afforded intermediate 7 in good yield. Removal of the protecting group from intermediate 7 afforded the final amino-alcohol 8.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH2Cl2 (150 mL) was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followed by addition of Et3N (3.0 mL, 21.5 mmol). The resulting reaction mixture was stirred at −78° C. for 20 min, and then diluted with CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white crystalline solid (3.027 g, 95% yield). MS (ESI) m/z 235.1.
Reaction SMILES: C(O[C:4](=[O:26])[CH:5]([CH3:25])[CH2:6][C:7]1[C:8]([Cl:24])=[N:9][C:10]([CH3:23])=[N:11][C:12]=1[NH:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:7]2[CH2:6][CH:5]([CH3:25])[C:4](=[O:26])[N:13]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[C:12]=2[N:11]=[C:10]([CH3:23])[N:9]=1
Reactant: CCOC(=O)C(C)Cc1c(Cl)nc(C)nc1Nc1c(C)cc(C)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(N2C(=O)C(C)Cc3c(Cl)nc(C)nc32)c(C)c1
Yield: 62.6 %

Procedure:
A mixture of 3-[4-chloro-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-2-methyl-propionic acid ethyl ester (173 mg, 0.46 mmol) and p-TsOH (56 mg) in 10 ml of toluene was heated at reflux using Dean-stark trap apparatus for 9 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated to give 184 mg of the crude material. The crude material was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 95 mg of the title compound as white crystals, mp 136-139° C., after recrystallization from ethyl ether. 1H NMR (CDCl3) δ 6.95(s,1H), 6.94(s,1H), 3.25(dd,1H), 2.8-3.0(m,2H), 2.41(s,3H), 2.32(s,3H), 1.96(s,3H), 1.93(s,3H), 1.37(d,3H)ppm.
Reaction SMILES: I[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:34][CH:35]=2)O1>>[N:36]1([C:33]2[N:34]=[CH:35][C:30]([C:2]3[CH:21]=[N:20][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]5[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=5)[C:4]=4[CH:3]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: FC(F)(F)c1ccc(CN2CCNc3ncc(I)cc32)o1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: FC(F)(F)c1ccc(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)o1
Yield: 30 %

Procedure:
7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (60 mg) was reacted with 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholine as in General Procedure 4A to give the title compound as an orange foam (30% yield). M.p. (foam), LCMS: m/z=446.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.42-3.47 (m, 2H), 3.48-3.54 (m, 4H), 3.58-3.67 (m, 2H), 3.80-3.89 (m, 4H), 4.47 (s, 1H), 5.02 (bs, 1H), 6.30 (s, 1H), 6.67 (d, J=5.2 Hz, 1H), 6.72 (s, 1H), 6.85 (s, 1H), 7.55-7.62 (m, 2H), 8.31 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CC(N(C)C)=O.O>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 120 °C
Yield: 92.1 %

Procedure:
Tetrahydro-2H-pyran-4-amine (0.45 g, 4.5 mmol) was added to (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.48 g, 0.89 mmol) in DMA (4 mL) in a microwave vial. The mixture was heated at 120° C. for 1 hour in a microwave. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc was washed three times with dilute aqueous NaCl, water, twice with brine, dried over MgSO4, filtered, and evaporated to yield the desired (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.46 g, 0.82 mmol, 92% yield) as a film.
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=1[CH2:8][N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=2[C:11]([C:22]#[N:23])=[C:10]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1.C(=O)([O-])[O-:43].[K+].[K+].OO>O>[NH2:23][C:22]([C:11]1[C:12]2[N:13]([CH3:21])[C:14](=[O:20])[N:15]([CH3:19])[C:16](=[O:18])[C:17]=2[N:9]([CH2:8][C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[Cl:5])[C:10]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]1)=[O:43]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)c2c(c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)c2c(c(C(N)=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.3 %

Procedure:
To a mixed solution of dimethyl sulfoxide (250 ml) and water (25 ml) were added tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (17.9 g) and potassium carbonate (4.7 g). In a water bath, an aqueous hydrogen peroxide solution (a 30-35% aqueous solution, 17 ml) was added dropwise and the resulting mixture was stirred at 25° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed three times with water and then once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (15.6 g) as a light-yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C(O)(=[O:16])C>O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:7]([CH2:6][CH2:5][C:4]2=[O:16])=[CH:8][C:9]=1[O:12][CH3:13]
Reactant: CC(=O)O
Reactant: COc1cc2c(c(Cl)c1Cl)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CC2
Reaction time: 1 h

Procedure:
4,5-Dichloro-6-methoxy-2,3-dihydro-1H-indene (21 gm., 0.097 mole) is dissolved in acetic acid (280 ml.) and chromium trioxide (14 gm., 0.14 mole) in a mixture of water (15 ml.) and acetic acid (40 ml.) is added dropwise with stirring over a period of one hour. The mixture is poured, with stirring into cold water (1200 ml.) and the solid that separates is removed by filtration, washed with water and dried. The product, which consists of a mixture of the desired material and the isomer described in Step D, is subjected to column chromatographic separation using 225 gm. of silica gel and chloroform is used for elution. Evaporation of the solvent gives 6,7-dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one, 5.2 gm., m.p. 154°-156° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[N+:13]([O-:15])=[O:14])=O.[CH3:16][CH2:17][O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20]>ClCCl>[CH2:17]([O:18][C:19](/[CH:21]=[CH:1]/[C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[N+:13]([O-:15])=[O:14])=[O:20])[CH3:16]
Reactant: O=Cc1cnc2c([N+](=O)[O-])cccc2c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc2c([N+](=O)[O-])cccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
A mixture of 3-formyl-8-nitroquinoline (65 mg) and ethyl (triphenylphosphoranilidene)acetate (123 mg) in dichloromethane (3 ml) was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 3-((E)-2-ethoxycarbonylvinyl)-8-nitroquinoline (92 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (70 mg, 0.2 mmol) in an analogous manner to Example 936 to afford an off white foam (81 mg, 80%). Mp: 171-4° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.42 (s, 1H), 8.57 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.63 (m, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 6.88 (d, J=8 Hz, 1H), 3.74 (s, 7H), 3.23 (m, 1H), 2.89 (m, 2H), 2.77 (s, 6H), 2.70 (m, 2H), 2.60 (m, 2H), 2.41 (m, 2H), 2.12 (d. J=11 Hz, 2H), 1.77 (m, 1H), 1.36 (m, 1H).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[CH:23]([CH2:29]Br)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[C:8]1([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([C:7]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:29][CH:23]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Br)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a THF (200 mL) solution of t-BuOK (11.4 g, 102 mmol) at −30° C. was added slowly di-tert-butyl malonate (20 g, 92.6 mmol). The internal temperature was maintained between −30° C. and −10° C. After 30 min, ethyl 2,3-dibromopropanoate (29 g, 111.1 mmol) was added. The cooling bath was removed. After 1.5 h, the reaction mixture was cooled to −10° C. for addition of t-BuOK (11.4 g, 102 mmol). The cooling mixture was removed and the mixture was stirred overnight. The solution was evaporated and the residue was extracted with ethyl acetate (600 mL), dried and purified by CombiFlash (PE:EA=15:1) to afford 1,1-di-tert-butyl 2-ethyl cyclopropane-1,1,2-tricarboxylate (18 g, 62%). 1H NMR (300 MHz, CDCl3): δ 1.34-1.51 (t, J=7.2 Hz, 3H), 1.54-1.56 (d, J=4.4 Hz, 18H), 1.58-1.60 (m, 1H), 1.90-1.94 (m, 1H), 2.52-2.57 (m, 1H), 4.21-4.31 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]2[CH2:11][CH:6]([C:7](Br)(Br)[CH:8]=1)[CH2:5][CH2:4]2.C(#N)C.S(=O)(=O)(O)[OH:16].[OH-].[Na+]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:3]2[CH2:11][CH:6]([CH2:5][CH2:4]2)[C:7](=[O:16])[CH:8]=1
Reactant: BrC1=CC(Br)(Br)C2CCC1C2
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: Clc1ccccc1
Product: O=C1C=C(Br)C2CCC1C2
Reaction time: 0.83 h
Yield: 6.3 %

Procedure:
To a solution of 89.9 g (7.9% w/w, 100%=7.1 g, 20.6 mmol) of 2,4,4-tribromobicyclo[3.2.1]oct-2-ene in chlorobenzene there are added 100 ml of acetonitrile and 100 ml of 10% sulfuric acid and stirring is carried out for 50 minutes at ambient temperature. The pH is then adjusted to 7 using aqueous sodium hydroxide solution and the aqueous phase is separated off. The organic phase is washed with 50 ml of water and then dried using magnesium sulfate. After filtration and removal of the acetonitrile using a rotary evaporator, 57.8 g (88% of theory) of 4-bromo-bicyclo[3.2.1]oct-3-en-2-one are obtained as a 6.3% solution in chlorobenzene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[C:20](#[N:23])[CH:21]=[CH2:22]>>[C:20]([CH2:21][CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)#[N:23]
Reactant: c1ccc(N2CCOCC2)c(N=C2CCCCN2)c1
Reactant: C=CC#N
Product: N#CCCN1CCCCC1=Nc1ccccc1N1CCOCC1

Procedure:
The product of Example 1 (2.6 g) was reacted at room temperature with excess acrylonitrile (5 ml). The product was recrystallised from ethylacetate to give 4((2-[1-(2-cyanoethyl)-2-piperidinylideneamino]phenyl))morpholine. (m.p. 148° C.).
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=O.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7][CH2:8][CH:2]1[F:1]
Reactant: CON
Reactant: O=C1c2ccccc2CCCC1F
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1c2ccccc2CCCC1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred suspension of 6-fluoro-6,7,8,9-tetrahydrobenzocylohepten-5-one CAS: 127053-30-9 (1.06 g; 5.95 mmol) in methanol (12 ml) was added pyridine (1.53 ml; 19.04 mmol) followed by a portionwise addition of methoxyamine hydrochloride (1.59 g; 19.04 mmol). The reaction mixture was stirred at 20° C. for 16 h under nitrogen. The solvent was removed in vacuo to afford 1.28 g (100% of theory) of crude 6-fluoro-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture as a brown oil.
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:27](=[O:28])[CH2:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nc2cccc(OC3CCCCC3)n2n1
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)Nc2nc3cccc(OC4CCCCC4)n3n2)c1

Procedure:
The title compound was prepared following procedure and work up described for intermediate B1 but starting from 5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A11), 80 mg; 0.34 mmol; 1.0 eq.) and 3-methoxyphenylacetyl chloride (64 μl; 0.41 mmol; 1.2 eq.) as a white powder (11 mg, 8%). HPLC, Rt: 3.60 min. (purity 88.2%). LC/MS, M+(ESI): 381.1, M−(ESI): 379.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)P(=O)(N(C)C)N(C)C.[Cu]>[CH3:16][O:15][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[O:1][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)c(OC)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
6.67 g of ethyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate and 5.69 g of 3-bromopyridine were dissolved in 13.3 ml of hexamethyl phosphoric triamide. To the solution were added 4.15 g of potassium carbonate and 0.57 g of a copper powder. The mixture was stirred for 3 hours at 160° C. in a nitrogen atmosphere. The reaction mixture was mixed with 100 ml of ice water and 100 ml of ethyl acetate. The resulting insolubles were removed by filtration. An organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: benzene/ethyl acetate=10/1) to obtain 1.93 g of light yellow oily ethyl (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]acrylate.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][C:20](OCC)=[O:21]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([OH:21])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(-c3ccccc3F)cc2O)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(2-fluorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 3, part A. 1H NMR (300 MHz, DMSO-d6): δ 6.15-6.17 (1H, m), 7.13-7.41 (4H, m), 8.07-8.12 (1H, m), 8.34 (1H, s), 8.48-8.50 (1H, m), 11.64 (1H, s). [M+H] Calc'd for C15H9FN4O, 281; Found, 281.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=[C:2]2[NH:1][CH:27]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26]2)=[CH:7][CH:8]=1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CNc1nccc(-c2cc(NC3CCN(C(=O)OC(C)(C)C)C3)c3cc(OC)ccc3c2)n1

Procedure:
tert-butyl 3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)pyrrolidine-1-carboxylate 147 was synthesized according to General Procedure E utilizing compound 33 and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopyrrolidine-1-carboxylate. LCMS: 450 [M+H].