Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared analogously to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazOl-4-yl)morphOline in methanol with 1N sodium hydroxide solution. After neutralisation with 1N hydrochloric acid, the mixture is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 12 and 4-chlorobenzene sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a colorless crystalline powder.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([CH:7]1[CH2:11][CH:10]([OH:12])[CH2:9][N:8]1[C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([N:8]1[CH2:9][CH:10]([OH:12])[CH2:11][CH:7]1[CH2:5][OH:4])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CC(O)CN1C(=O)CCCCCNC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCCCC(=O)N1CC(O)CC1CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of lithium borohydride (1.34 g) in anhydrous tetrahydrofuran (50 mL) was added a solution of methyl ester 2a in THF (50 mL) over a period of 30 mins at 0° C. After the addition the reaction mixture was brought to room temperature and stirred further under argon. The completion of the reaction was ascertained by TLC after 4 h. (Rf=0.4 in 10% MeOH/CHCl3). The reaction mixture was evaporated to dryness and cooled to 0° C. To the residue 3N HCl (100 mL) was added slowly. After stirring for 30 mins the product was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Organic layer was filtered and evaporated to dryness. Compound 3a was purified by column chromatography first by eluting with ethyl acetate to remove impurities followed by dichloromethane/methanol (5%) gave 14.3 g (70%)
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:17])[CH3:18])[CH:12]=[CH:13][CH:14]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1cccc(OCCCN=C=S)c1

Procedure:
A solution of carbon disulphide (8.36 g) in acetone (16 ml) was added dropwise to a stirred solution of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (20.8 g) in acetone (60 ml) at -10° to 0° during 15 minutes. A solution of mercuric chloride (27.2 g) in acetone (40 ml) was added slowly at -15° and after the addition the suspension was warmed to 0° and triethylamine (23 g) added dropwise. The suspension was refluxed for 45 minutes then filtered and evaporated to give an oil which was chromatographed (alumina, grade 3/ether). The appropriate eluate was evaporated to a yellow oil consisting of the title compound (8.7 g).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])=[CH:16][C:15]=3[F:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH3:28]>CO>[C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:28])/[CH3:24])=[CH:16][C:15]=3[F:27])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: N
Reactant: CC(=O)CC(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-((2-(-adamantan-1-yl)ethyl)amino)-3-fluorophenyl)-3-oxobutanamide (0.31 g, 0.83 mmol), MeOH (10 mL) and ammonia (10 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1.F[C:31](F)(F)[C:32]([O-])=[O:33].C(Cl)(=O)C.O>N1C=CC=CC=1>[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1)(=[O:33])[CH3:31]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@H](N)C3)n3nccc3n2)cc1
Reactant: O=C([O-])C(F)(F)F
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N[C@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
As crude product mixture of (S)—N-(7-(3-aminopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 305, Example 319), trifluoroacetate salt (50 mg, 0.054 mmol) was dissolved in pyridine (2 ml). At 0° C. acetyl chloride (0.013 ml, 0.18 mmol) was added and the mixture was stirred for 2 hours at room temperature. Afterwards an additional amount of acetyl chloride (0.008 ml) was added to drive the reaction to completion. Water (2 ml) was then added to quench the reaction. The mixture was concentrated in vacuo, and the crude product was purified by preparatory HPLC (25-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled compound (50 mg, 33%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.91 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.03-7.95 (m, 3H), 7.64-7.57 (m, 2H), 7.38 (s, 1H), 6.36 (d, J=2.3 Hz, 1H), 4.13 (br. s., 2H), 3.87 (br. s., 1H), 3.22-3.13 (m, 1H), 3.08 (dd, J=9.5, 11.5 Hz, 1H), 2.00-1.86 (m, 2H), 1.82 (s, 2H), 1.76 (br. s., 1H), 1.52 (br. s., 1H), 1.46 (s, 5H); ESI-MS: m/z 437.5 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.O.[Pd]>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)OC1CCNCC1
Yield: 92 %

Procedure:
10% Pd/C (500 mg) was added to a solution of 1-benzylpiperidin-4-yl acetate [(11 g, 47 mmol), J. Org. Chem. 68(2), 613-616; 2003] in a mixture of ethanol and water (90:10, 110 mL), and the mixture was stirred at 60° C., under 60 psi of hydrogen gas for 18 hours. The reaction mixture was then filtered through Arbocel®, washing through with ethanol, and the filtrate was concentrated in vacuo to afford the title product in 92% yield, 7.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[CH2:12]1[NH:19][CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][N:19]2[CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]2)=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Br)cc(F)c1CBr
Reactant: O=S1(=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1(=O)CCN(Cc2c(F)cc(Br)cc2F)CC1

Procedure:
A solution of 3.8 g (11.3 mmol) 5-bromo-2-bromomethyl-1,3-difluoro-benzene, 1.83 g (13.6 mmol) thiomorpholine dioxide and 1.88 ml (13.6 mmol) triethylamine in 40 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is taken up in diethylether, vigorously stirred, and the title compound is obtained after filtration as a white crystalline solid.
Reaction SMILES: [NH4+:1].[Cl-].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1>>[CH:6]1[C:7]([C:8]#[N:1])=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: [Cl-]
Product: N#Cc1ccc(Cl)cc1
Temperature: 220 °C

Procedure:
A 2 L glass resin kettle was fitted with an overhead stirrer, glass thermocouple well, and a 15 cm (6 inch) 24/40 U-connector tube wrapped with an electrical heating tape and set at a 120° to 150° C. skin temperature. The U-connector tube was attached to a 1 L, 3-necked, round bottom flask fitted with an air condenser, which was used as a sublimate trap to a stop the easily sublimed product. To this was added either 1.1 eq. (first two runs) or 1.0 eq. (last three runs) NH4Cl, 7.50 g MgO (0.5 wt % based on the PCBTC) and 1500 g of 99 wt % PCBTC. The kettle was heated with a mantle to 220° C. The temperature was controlled using an Instruments for Research and Industry "Therm-O-Watch" model L11-1500 temperature controller with a K-type thermocouple. Samples were removed periodically and were analyzed by gas chromatograph (GC). Because p-chlorobenzoylchloride (PCBOC) has the same boiling point as PCBN but a slower reaction rate, the reaction was continued until all of the PCBOC had been consumed. In general, when less than 5 wt % of PCBTC remained (after 15 to 20 hours of reaction at 220° C.) the 1 L sublimate receiver was exchanged for a clean one and the product was up and over distilled. After cooling the reactor, it was recharged with the sublimate from the previous run, NH4Cl, and PCBTC, and the sequence was repeated. In this manner, 7 kg of PCBTC gave a 90.5 wt % isolated yield of PCBN with an average purity of 97 wt % by GC area%.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([O:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1)[CH3:12].CN1CCCN(C)C1=O.[CH3:30][O:31][C:32]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:33]=1[CH2:34][NH:35][C:36](=[O:39])[CH2:37]I>C1COCC1>[CH3:30][O:31][C:32]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:33]=1[CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH:17]1[CH2:18][CH2:19][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]1=[O:20]
Reactant: CCOC1=CC(=O)CCC1
Reactant: COc1ccc(CNC(=O)CI)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC1=CC(=O)C(CC(=O)NCc2ccc(OC)cc2OC)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 55.9 %

Procedure:
To a −78° C. solution of 1.0 M lithium hexamethyldisilazide in THF (0.90 mL) in 4.0 mL THF was added 3-ethoxy-2-cyclohexen-1-one (0.100 mL, 0.687 mmol). After stirring at −78° C. for 40 minutes, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.0 mL, 8.3 mmol) was added. After 5 minutes, N-(2,4-Dimethoxy-benzyl)-2-iodo-acetamide (0.342 g, 1.02 mmol) was added as a solution in 2.0 mL THF. The reaction was kept at −78° C. for one hour, and then quenched with water and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in dichloromethane) yielded 133.5 mg (56%) of N-(2,4-dimethoxy-benzyl)-2-(4-ethoxy-2-oxo-cyclohex-3-enyl)-acetamide. LCMS (Method E, ESI): RT=1.57 min, m+H=336.2; 1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J=8.1 Hz, 1H), 6.47-6.39 (m, 2H), 6.35 (s, 1H), 5.32 (s, 1H), 4.38-4.30 (m, 2H), 3.90 (dd, J=13.5, 6.5 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.77 (dd, J=14.3, 5.6 Hz, 1H), 2.68 (dt, J=10.6, 5.5 Hz, 1H), 2.59-2.48 (m, 1H), 2.37 (ddd, J=12.0, 6.3, 2.9 Hz, 1H), 2.17 (ddd, J=13.1, 11.2, 4.6 Hz, 2H), 1.72 (ddd, J=25.0, 12.6, 4.9 Hz, 1H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6]O)CCO.II.[C:10]1(=[O:16])O[C:13](=O)[CH:12]=[CH:11]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>C(O)COCCO>[N-:1]=[C:10]=[O:16].[N-:1]=[C:10]=[O:16].[C:17]1([CH2:27][C:6]2[CH:5]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCNCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: II
Solvent: OCCOCCO
Product: [N-]=C=O
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
The above amounts of diethanolamine and iodine were added to the above amount of soybean oil with stirring. The mixture was stirred for 23 hours at a temperature between about 210° F. and about 225° F. Then, the above amounts of maleic anhydride, diethylene glycol, and p-toluenesulfonic acid were added with stirring. The mixture was stirred under vacuum for 5 hours at a temperature between about 215° F. and about 235° F. to give a liquid soybean oil based polyol with a hydroxyl number of 54. A reaction mixture of about 10.00 grams of the polyol and the above indicated amount of diphenylmethane diisocyanate yielded a solid soybean oil based polyurethane material.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([OH:35])([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>C1COCC1.CO.CN(C=O)C>[OH:35][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]phenyl}piperidin-1-yl)-acetic acid ethyl ester (137 mg, 0.27 mmol) was dissolved in THF/MeOH/DMF (3:1:1, 5 mL) and to the solution was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was filtered and purified by reverse-phase preparative HPLC to give the title compound: 1H NMR (400 MHz, DMSO-d6) ppm 1.54 (qd, J=12.38, 4.29 Hz, 1 H) 1.42 (qd, J=12.51, 4.42 Hz, 1 H) 1.77 (td, J=14.08, 1.14 Hz, 2 H) 2.78 (m, 1 H) 2.98 (td, J=12.63, 2.27 Hz, 1 H) 3.29 (s, 2 H) 3.87 (dd, J=11.37, 2.27 Hz, 1 H) 4.39 (ddd, J=12.69, 1.83, 1.64 Hz, 1 H) 7.04 (d, J=8.59 Hz, 1 H) 7.32 (d, J=8.34 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.80 (d, J=8.84 Hz, 1 H) 7.99 (dd, J=8.72, 2.65 Hz, 1 H) 8.55-8.62 (m, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 8.92 (d, J=2.27 Hz, 1 H) 9.93 (s, 1 H); (M+H)+ 473.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>CO>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:10](=[O:11])[C:9]([F:16])([F:15])[F:8]
Reactant: CNCCCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: CN(CCCCO)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.1 %

Procedure:
To a 250 mL round bottom flask, charged with 10.0 g (96.9 mmol) of the amine (6) in 100 mL of dry methanol, was added 17.5 mL (147 mmol) of ethyl trifluoroacetate. The mixture was stirred at room temperature for 24 h and then concentrated to afford 18.55 g of the product (7) as a near colorless oil (96%): 1H-NMR (200 MHz, D2O); 3.63 and 3.50 (2t's, 4H), 3.20 and 3.05 (d and s, 3H), 1.82-1.47 (m, 4H) ppm.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[F:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:19]=1.C(N(CC)CC)C>CN(C)C=O>[F:17][C:18]1[C:23]([NH:24]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:19]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCN(c2ccc(N)c(F)n2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(F)n2)CC1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
(4E)-6-Iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.26 g, 0.80 mmol), 2-fluoro-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine (contaminated with triethylammonium trifluoroacetate, approximately 0.80 mmol) were coupled in N,N-dimethylformamide (10 mL) with triethylamine (0.66 mL). The mixture is heated in a 100° C. oil bath for one hour. The reaction mixture is purified by reverse phase HPLC and then flash silica gel chromatography (methanol/chloroform) to give (4Z)-4-({[2-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione (0.20 g, 49%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:17](=[O:26])[CH:16]3[CH2:27][CH2:28][CH:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[OH:30])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:40]12[CH2:47][CH2:46][N:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2>C1(C)C=CC=CC=1>[Br-:1].[F:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:17](=[O:26])[CH:16]([CH2:27][CH2:28][CH:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[OH:30])[CH:15]2[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N+:40]45[CH2:47][CH2:46][N:43]([CH2:44][CH2:45]4)[CH2:42][CH2:41]5)=[CH:39][CH:38]=3)=[CH:14][CH:13]=2)=[CH:24][CH:23]=1
Reactant: C1CN2CCN1CC2
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(CBr)cc3)cc2)N1c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(C[N+]45CCN(CC4)CC5)cc3)cc2)N1c1ccc(F)cc1
Product: [Br-]
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
180 mg of (12) and 300 mg of 1,4-diazabicyclo[2.2.2]octane (DABCO) were dissolved in 5 ml of toluene and stirred at 80° C. for 90 min. After the reaction ended, the mixture was allowed to cool and the colorless solid was filtered off with suction. This gave 195 mg of product (13) of molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[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.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCOCC1
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(CC(=O)C2COCCC2=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
Tetrahydro-4H-pyran-4-one (0.138 mL, 1.50 mmol) was dissolved in toluene (1 mL) and cooled to 0° C. LHMDS (1.573 mL, 1.57 mmol) was added. 3-Methoxyphenylacetyl chloride (0.117 mL, 0.75 mmol) was added after 2 minutes. After 5 minutes, acetic acid (0.129 mL, 2.25 mmol) and water was added. The organic phase was separated and the crude product was purified by flash column chromatography (EtOAc 0-40% in heptane) yielding 3-(2-(3-methoxyphenyl)acetyl)dihydro-2H-pyran-4(3H)-one (86 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.S(Cl)(Cl)=O.[Cl-:16].[Al+3].[Cl-].[Cl-].[CH:20]1[CH:25]=CC=CC=1>ClCCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[CH2:25][CH2:20][Cl:16])=[C:4]([F:11])[CH:3]=1
Reactant: [Cl-]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [Al+3]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=C(CCCl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a suspension of 4-bromo-2-fluoro-benzoic acid (10 g, 45.65 mmol) in benzene (50 ml) was added thionyl chloride (7.8 ml, 12.79 g, 91.32 mmol) and the resulting mixture was heated to reflux for 12 hours. Thionyl chloride was evaporated, the reaction mixture was diluted with 1,2-dichloroethane (50 ml) and added to a slurry of aluminum chloride (5.7 g, 42.53 mmol) in 1,2 dichloroethane (50 ml) at room temperature. Ethylene was bubbled through the reaction mixture for 5 hours and the reaction mixture was stirred for another 2 hours at room temperature. It was then quenched with 2N HCl (50 ml). The layers were separated. The aqueous phase was extracted twice with 100 ml dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution (50 ml) followed by water (50 ml). It was then dried over Na2SO4 and evaporated under reduced pressure to get the crude product, which was purified subsequently by column chromatography (silica gel, 0-5% ethyl acetate/hexane) to afford 8.6 g (71%) of the title compound as reddish solid.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH3:18]>C(O)C.CO>[NH2:18][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6]
Reactant: N
Reactant: COC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CO
Product: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
3-Methoxy-3-(4-nitrophenyl)-2-cyanoacrylonitrile (14.4 g, 0.063 mol) was suspended in ethanol (1 L) in a flask equipped with a magnetic stirrer. To the suspension was added 60 mL (ca. 0.20 mol) of a 10% (w/w) solution of ammonia in methanol. The mixture was stirred vigorously for 15 min, at which time HPLC analysis showed the absence of starting material. The now homogeneous mixture was concentrated in vacuo to ca. 80 mL. The solid that had formed was collected with the aid of a small amount of additional ethanol and was pressed well with rubber dam. The cake was washed with of ethanol (2×5 mL) and was left to dry in a hood draft. The dry solid weighed 8.8 g. The filtrate was concentrated and mixed with dichloromethane (10 mL). The resulting solid was collected, washed with dichloromethane (2×2 mL), dried, and combined with the 1st crop to yield 9.9 g (46% for 2 steps). HPLC analysis indicated a purity of 91%. NMR (60 MHz) (DMSO-d6) δ 8.8 (bs, 0.5H); 8.0 (AB, 4H); 3.2 (bs, 1H); 2.8 (bs, 0.5H). The IR spectrum showed nitrile stretches at 2221 and 2207 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:14]([CH2:16][CH3:17])[CH3:15])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>[OH-].[Na+].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:14]([CH2:16][CH3:17])[CH3:15])=[N:8][C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1N(C)CC
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1N(C)CC
Temperature: 135 °C
Yield: 41 %

Procedure:
A mixture of 4.0 g (15.6 mmol) 6-chloro-2-(ethyl(methyl)amino)-4-methyl-pyridine-3-carboxylic acid ethylester and 13.6 ml (155.8 mmol) morpholine was heated in the MW to 135° C. for 2 h. Then the mixture was diluted with a 1M aq. NaOH sol. and EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 2.0 g (6.4 mmol, 41%) 2-(ethyl(methyl)amino)-4-methyl-6-morpholino-pyridine-3-carboxylic acid ethylester.