Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:3]=1>C(O)C.[Pd]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:5][C:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[N:3][CH:2]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc(-c2cnc(-c3ccncc3)nc2-c2ccncc2)cc1
Reaction time: 28 h

Procedure:
A stirred mixture of 4-chloro-5-(4-fluorophenyl)-2,6-bis-(4-pyridyl)-pyrimidine (99 mg,, 0.27 mmol) and 10% palladium-on-carbon (70 mg) in ethanol (10 ml) was hydrogenated under an atmosphere of hydrogen for 28 h. Filtration and evaporation of the solvent was followed by flash chromatography (ethyl acetate) on a column of silica gel to provide the title compound. MS (m/z): 329.2 (M+H)+; C20H13FN4requir. 328.4. 1H-NMR (CDCl3) d 8.91 (s, 1H, H-6, Pyrim.), 8.83, 8.65, 8.40, 7.45 (4m, each 2H, Pyrid.), 7.30-7.06 (m, 4H, PhF).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[Cl:15]SCl>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:10]
Reactant: O=C(O)CCCOc1cccc(F)c1
Reactant: ClSCl
Product: O=C(Cl)CCCOc1cccc(F)c1
Temperature: 25 °C

Procedure:
A solution of 4-(3-fluorophenoxy)butanoic acid (3.00 g, 15.1 mmol) in dichlorosulfane (15 mL) under N2 was refluxed for 3 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:22])[C:10]([CH:18]2[CH2:21][CH2:20][CH2:19]2)([OH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:28][C:27]([CH3:29])=[CH:26][CH2:25][CH2:24][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:22])[C:10]([CH:18]2[CH2:19][CH2:20][CH2:21]2)([OH:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: CC(C)=CCCBr
Reactant: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
0.83 g of N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide hydrochloride, 0.42 g of 5-bromo-2-methyl-2-pentene, 42 mg of potassium iodide and 1.42 g of anhydrous potassium carbonate were suspended in 25 ml of anhydrous N,N-dimethylformamide, and this suspension was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, mixed with water, and then extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/4) to obtain 449 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14][C@:12]2([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[F:28])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14][C@:12]2([C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[F:28])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc([N+](=O)[O-])ccc2F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CO[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc(N)ccc2F)C1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A solution of tert-butyl[(4aR*,6S*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate (118 mg) and iron (133 mg) in ethanol (8 mL)-a saturated ammonium chloride solution (0.303 mL) was stirred at 87° C. for 30 minutes. The reaction solution was cooled to room temperature and then poured into water-ethyl acetate, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (83 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>O1CCCC1>[CH3:30][O:26][C:20]1([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C1(O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 1-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)cyclohexanol (108 mg; 0.278 mmol) in tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (22 mg; 0.55 mmol). The reaction was stirred at 0° C. for 30 minutes. Then iodomethane (50 uL; 0.80 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 16 hours. More iodomethane (20 uL; 0.32 mmol) was added and stirred for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified over a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethyl acetate in heptane) to give 63 mg (55%) the title compound as a colorless oil. MS-GC (El): Calc: 402.5, Found: 383 (M−F). 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (d, J=7.88 Hz, 1H), 7.46 (d, J=7.47 Hz, 1H), 7.35 (d, J=8.30 Hz, 1H), 5.05 (s, 2H), 2.94 (s, 3H), 2.16 (d, J=12.45 Hz, 2H), 1.8-1.56 (m, 8H), 0.98 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: OS([O-])(=O)=O.[K+].O[C:8]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1)([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:8](=[CH2:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23]2
Reactant: CCOC(=O)C(C)(O)c1ccc2cc(OC)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1ccc2cc(OC)ccc2c1
Yield: 15678.2 %

Procedure:
A mixture of freshly fused KHSO4 (2,50 g, 18 mmol), ethyl 2-hydroxy-2-(6-methoxynaphth-2-yl)propionate (0,60 g, 2,19 mmol), butylated hydroxytoluene (0,007 g) and toluene was refluxed for 22 hours. The mixture was filtered hot and the residue was washed with hot dichloromethane (3×30 ml). The solvent was removed and the crude oil was submitted to flash chromatography on silica gel, giving ethyl 2-(6-methoxynaphth-2-yl)acrylate (0,088 g, 16%) as a white solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5]1([CH:11]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][CH2:13][N:14]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:1]([N:31]1[CH2:32][CH2:33][CH:28]([N:14]([CH2:13][CH2:12][CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)=[O:16])[CH2:29][CH2:30]1)(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
117 mg (175 μmol, 3.5 eq.) of P-EDC resin is preswollen in 1.5 ml of anhydrous dichloromethane. Acetic acid (7.5 mg, 125 μmol, 2.5 eq.) is added and the mixture is agitated for 10 minutes. Then N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 50 μmol) is added in its turn and the mixture is agitated overnight. The resin is filtered and the filtrate is concentrated. The oil obtained is passed through a silica gel cartridge eluting with an equimolar mixture of heptane and ethyl acetate in order to obtain 16 mg (yield=62%) of a white foam after concentration.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1>O>[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)n1
Reactant: C[C@H]1CCCN1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 84.6 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (1.12 g, 10 mmol) and (S)-2-methylpyrrolidine (1.03 g, 12 mmol) in water (1 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=5:1) to give (S)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (1.5 g, 83%) as a colorless oil. LC-MS: [M+H]+, 178.2, tR=1.066 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([O:16][CH3:17])=[C:4]([O:18][CH3:19])[CH:3]=1.[C:20]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]1)#[N:21].O.C(OC(C)C)(=O)C>CS(C)=O.C(#N)C>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:18][CH3:19])=[C:5]([O:16][CH3:17])[C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:1]=[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]2)[N:21]=1
Reactant: CS(=O)(=O)Nc1cccc2c1CCN(C#N)C2
Reactant: COc1cc(N)c(C#N)c(-c2ccccn2)c1OC
Solvent: O
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: COc1cc2nc(N3CCc4c(cccc4NS(C)(=O)=O)C3)nc(N)c2c(-c2ccccn2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a stirred solution of 6-amino-3,4-dimethoxy-2-(2-pyridyl)benzonitrile (see Example 2 or 2A, 50 g, 196 mmol) and N-(2-cyano-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide (see Example 3 or 3A, 63 g, 251 mmol) in DMSO (300 ml) at room temperature, was added sodium-t-pentoxide (64.2 g, 582 mmol) portionwise over 120 minutes keeping the temperature below 30° C. The resulting slurry was then stirred for 2 hours. After this time, water (500 ml) was added over 5 minutes followed by isopropyl acetate (150 ml). The aqueous phase was collected and partitioned with ethyl acetate (500 ml) before reducing the pH of the biphasic mixture to a range of 7.0–8.0 with 12M aqueous HCl (22 ml). The aqueous phase was extracted with ethyl acetate (250 ml). The combined organics were reduced in volume and replaced with acetonitrile to give a final volume of 500 ml and stirred for 13 hours. After this time, the resulting slurry was filtered to yield 105 g of the crude product. This was then suspended in acetonitrile (525 ml), heated to reflux for one hour, cooled to room temperature and stirred for 13 hours. The resulting slurry was filtered to yield 87 g (87%) of the title compound.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>CCOCC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:12][CH:11]=1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2CCC2)cc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Cyclobutanecarbonyl chloride (5.5 g) was added to a solution of 2-(4-methoxyphenyl)ethylamine (7 g) and triethylamine (6.5 ml) in ether (300 ml) at ambient temperature. The mixture was stirred overnight, poured onto water and acidified with 2M hydrochloric acid, then the mixture was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried and the solvents removed in vacuo to give a residue. This was washed with petroleum ether and dried in vacuo to give N-[2-(4-methoxyphenyl)ethyl]cyclobutanecarboxamide as a solid (9.54 g), mp 118°-120° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.N(OCCC(C)C)=O>O1CCOCC1>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2nc(N)sc12
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Product: COc1ccc(F)c2ncsc12
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a solution of 4-fluoro-7-methoxy-1,3-benzothiazol-2-amine (C12) (15.40 g, 77.69 mmol) in 1,4-dioxane (700 mL) was added isoamyl nitrite (15.0 mL, 111.6 mmol). The reaction mixture was stirred at 85° C. for 18 hours and then cooled to room temperature. The solvent was removed in vacuo, and purification was carried out with silica gel chromatography (Eluant: 1:1 dichloromethane/hexanes) to afford the title compound as a yellow solid. Yield: 12.0 g, 65.5 mmol, 84%. 1H NMR (300 MHz, CDCl3) δ 3.98 (s, 3H), 6.77 (m, 1H), 7.16 (m, 1H), 8.98 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:18]([O-])(O)=[O:19].[Na+].C=O.[Na+].[Cl-]>CCO>[OH:19][CH2:18][CH:3]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])[C:2](=[O:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccccc1
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 173.4 %

Procedure:
tert-butyl 1-oxo-1-phenylethan-2-ylcarbamate (18) (2.4 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (41 mL, 200 proof). Next, a 0.5 M solution of NaHCO3 (420 mg, 5.0 mmol, 0.5 equiv.) was added followed by a 37% solution of formaldehyde (1.2 mL, 15.0 mmol, 1.5 equiv.). The solution was stirred at rt. for 6 days and transferred to a separatory funnel with a 1.0 M solution of NaCl (5.0 g, 85.5 mmol). The solution was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a crude light yellow oil. The residue was purified by flash column chromatography (30% EtOAc/hexanes) to give 2.3 g (88%) of 19 as a colorless oil which crystallized to a white solid. (Note: It is essential to use a 100 mL RBF for full vortex stirring over the entire reaction period) Rf=0.16 (30% EtOAc/Hexanes); mp=69-71° C.; IR (film) 3420, 2976, 2931, 1683, 1503, 1366, 1165, 1061 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.0 Hz, 2H, Ph-H), 7.60 (t, J=7.0 Hz, 1H, Ph-H), 7.48 (t, J=7.0 Hz, 2H, Ph-H), 5.96 (d, J=6.0 Hz, 1H, carbamate-NH), 5.36 (br s, 1H, Boc-NH—CH), 4.00 (m, 1H, CH—CH2), 3.86 (m, 1H, CH—CH2), 3.29 (br s, 1H, CH2—OH), 1.45 (s, 9H, t-butyl-CH3); 13C (125 MHz, CDCl3) δ 197.4, 156.3, 134.6, 134.1, 129.0, 128.9, 80.5, 64.7, 58.1, 28.4; LRMS (ESI-MS m/z): Mass calcd for C14H19NNaO4 [M+Na]+, 288.29. Found 288. Anal. calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.22; H, 7.25; N, 5.28.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][O:23][CH2:22]3)[CH2:17]2)=[CH:13][C:12]([C:25]#[N:26])=[CH:11][C:10]=1[NH:27][C:28]1[N:33]=[C:32]([N:34]([CH:44]2[CH2:46][CH2:45]2)CC2C=CC(OC)=CC=2)[C:31]2=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]2[N:29]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][O:23][CH2:24]3)[CH2:17]2)=[CH:13][C:12]([C:25]#[N:26])=[CH:11][C:10]=1[NH:27][C:28]1[N:33]=[C:32]([NH:34][CH:44]2[CH2:45][CH2:46]2)[C:31]2=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]2[N:29]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C5COC5)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC2CCN(C3COC3)C2)c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
TFA (25% in DCE, 2 ml, 26.0 mmol) was added to a solution of (+/−)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg, 0.062 mmol) and anisole (0.027 ml, 0.248 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 2 hours. Solvent was evaporated in vacuo and the residue was dried under vacuum overnight. The crude was trituated with hexane 3×1 ml, dissolved in acetonitrile and neutralized with 2N ammonia in methanol. Solvent was evaporated to give a solid which was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 1-4% 2 N ammonia in methanol/dichloromethane). (+/−)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (22 mg) was obtained as a white solid.
Reaction SMILES: [Br-].[F:2][CH:3]([F:34])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:9][C:8]2=[O:33].[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:44])[C:41]=1[CH:42]=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:44])[C:41]=1[CH:42]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH:3]([F:2])[F:34])=[CH:13][CH:12]=2)[C:8](=[O:33])[O:9]1
Reactant: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(OC(F)F)cc21
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC(=Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc21
Temperature: 4 °C
Reaction time: 3 h
Yield: 191.5 %

Procedure:
A solution of (5-difluoromethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)triphenyl-phosphonium bromide (11.4 g, 21 mmoles), prepared as described in example 96, in dry CH2Cl2 (110 ml), under N2, was added with 3,5-dichloro-4-formyl-pyridine (4.06 g, 23.1 mmoles). The mixture was cooled to 4° C. and added with triethylamine (3.8 ml, 27.3 mmoles) while keeping the temperature below 10° C. At the end of the addition the mixture was stirred at room temperature for 3 hours, then cooled and added with 5% HCl. The organic phase was washed with an aqueous NaCl solution, discoloured with charcoal, filtered over celite and dried to give 14.4 g of the title compound (stoichiometric yield; containing 1 equivalent of triphenylphosphine oxide).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](=[NH:42])[NH:40]O)=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O1CCOCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:11][C:10]=1[C:22]1[O:23][N:42]=[C:39]([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[N:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C2CCCC2)nc(C(=O)O)c(OCc2ccccc2)c1=O
Reactant: N=C(Cc1ccc(F)cc1)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(C2CCCC2)nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-cyclopentyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.33, 1 mmol) in CH2Cl2 (3 mL) was added a catalytic amount of DMF followed by 3 mL of a 2M solution of oxalyl chloride dissolved in CH2Cl2. The resulting yellow reaction mixture was stirred for 1 h and concentrated to give a yellow oil. The yellow oil was dissolved in 1,4-dioxane (9 mL) and added to a stirred solution of 2-(4-fluorophenyl)-N-hydroxyacetimidamide (0.18 g, 1.1 mmol) and DIEA (0.2 mL) in 1,4-dioxane (1 mL). After 4 h at room temperature, the reaction mixture was heated at 90° C. for 14 h. The mixture was cooled to room temperature and purified by flash column chromatography on a silica gel column using 7:1 hexanes/EtOAc as eluant to afford the title compound (0.29 g, 63% yield) as an off-white solid. 1HNMR (500 MHz, CDCl3) δ: 7.43-7.39 (2H, m), 7.33 (2H, dd, J=8.6, 5.2 Hz), 7.28-7.23 (3H, m), 7.00 (2H, t, J=8.6 Hz), 5.34 (2H, s), 4.14 (2H, s), 3.63 (3H, s), 3.21-3.14 (1H, m), 2.05-1.99 (4H, m), 1.88-1.80 (2H, m), 1.71-1.62 (2H, m). HRMS (M+H) calcd for C26H26N4O3F: 461.1989. found: 461.1979.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH2:26](I)[CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:26][CH3:27])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Product: CCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c(C#N)c1=O
Yield: 76.8 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 76.8%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)C1C=CC=CC=1.O>CCO.[Pd]>[CH:16]1([CH2:15][C:13]2[CH:12]=[CH:11][C:10]([N:21]3[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]3)=[C:9]([OH:8])[CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C1CN(c2ccc(CC3CCCC3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(CC3CCCC3)cc2O)S(=O)(=O)N1

Procedure:
A solution of 5-(2-benzyloxy-4-cyclopentylmethylphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one in EtOH (2 mL)/water (6 mL) is hydrogenated at 1 atm over 10% Pd/C for 18 h. The catalyst is filtered and the filtrate evaporated. The residue is purified by preparative HPLC to give the title compound: (M−1)−=309. HPLC retention time: 1.14 min. (Method A).