Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a mixture of ethyl 3-{[(6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-3-yl)carbonyl]amino}propanoate (366 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (287 mg, 83%) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1.I[CH2:18][CH:19]([CH3:24])[O:20][CH2:21][CH2:22]I>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1([C:6]2[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:24])[CH2:18]1)=[O:13])[CH3:16]
Reactant: CC(CI)OCCI
Reactant: CCOC(=O)Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cc(F)cc(F)c2)CCOC(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 9.17 g) was added portionwise to a solution of ethyl 3,5-difluorophenylacetate (17 S) in THF (400 ml) and the mixture was stirred at ambient temperature for 1 hour. A solution of 1,5-diiodo-2-methyl-3-oxapentane (30.3 g) in THF (20 ml) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 19:1 v/v mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained, as a mixture of diastereoisomers, 4-ethoxycarbonyl-4-(3,5-difluorophenyl)-2-methyltetrahydropyran (16.5 g). The mixture of diastereoisomers was separated by further chromatography using a 10:1 v/v mixture of petroleum ether (b.p 40°-60° C.) and ethyl acetate as eluent. There was thus obtained:
Reaction SMILES: [NH2:1][C:2]1C=CC(Cl)=C(C(F)(F)F)C=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.[C-]#N.[K+]>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[C:2]#[N:1])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [C-]#N
Agent: [K+]
Product: N#CC(c1ccc(Cl)c(C(F)(F)F)c1)N1CCOCC1

Procedure:
According to the method in "Organic Syntheses", 5-amino-2-chlorobenzotrifluoride is converted to 4-chloro-3-(trifluoromethyl)benzaldehyde. As in Example 35, the following reactions are carried out. 4-Chloro-3-(trifluoromethyl)benzaldehyde (13.9 g.), 14.27 g. of p-toluenesulfonic acid, 13.01 g. of morpholine and 4.88 g. of potassium cyanide is reacted to give α-[4-chloro-3-(trifluoromethyl)phenyl]-4-morpholineacetonitrile as white crystals, m.p. 73°-74° C. This compound (14.0g.) is reacted with ethyl acrylate to give ethyl γ-cyano-γ-[4-chloro-3-(trifluoromethyl)phenyl]-4-morpholinebutyrate as a yellow oil (16.5 g.). This compound (16.5 g.) is reacted with 2.11 g. of hydrazine in 100 ml. of ethanol to give 6-[4-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone (4.2 g.) as white crystals, m.p. 195°-198° C. This intermediate is heated with bromine in acetic acid to give 6-[4-chloro-3-(trifluoromethyl)phenyl]-3-(2 H)-pyridazinone as white crystlas, m.p. 249°-251° C. A mixture of this compound (5 g.) and 60 ml. of phosphoric oxychloride is refluxed 18 hours to give 3-chloro-6-[4-chloro--3-(trifluoromethyl)phenyl]pyridazine as cream colored crystals, m.p. 145°-147° C. A mixture of 2.2 g. of the preceding compound, 0.9 g. of formylhydrazine, and 50 ml. of n-butanol is refluxed for 48 hours to give 2.1 g. of product, m.p. 211°-214° C. Recrystallization from n-propanol gives cream colored crystals, m.p. 217°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])[C:5]([C:6]([NH:8][CH:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:17][C:15]([CH3:16])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=2)=[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:19]=1
Reactant: CCOC(=O)C(NC(=O)c1cnc(Cl)cc1NC(C)C)C(C)=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2cnc(Cl)cc2NC(C)C)oc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate (27a) (200 mg, 0.58 mmol) in DCM (10 mL), triphenyl phosphine (2 equiv.), iodine (2 equiv.) and triethyl amine (3 equiv.) were added and stirred at room temperature for 4 h. The reaction mixture was diluted using DCM and washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography using silica gel and EtOAc: Pet. Ether as eluent to obtain the title compound, ethyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.25 (d, J=6.40 Hz, 6H), 1.33 (t, J=7.20 Hz, 3H), 2.67 (s, 3H), 3.90-3.95 (m, 1H), 4.31 (q, J=7.20 Hz, 2H), 6.89 (s, 1H), 8.47 (d, J=7.60 Hz, 1H), 8.54 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:15]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CCN(Cc2ccc(I)cc2)Cc2nccn2CC(=O)O)cc1

Procedure:
A solution of tert-butyl 2-(2-(((4-iodobenzyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetate (24 mg, 0.0393 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 5 hrs. Solvent was removed under a stream of nitrogen to give a residue, which was purified by HPLC to give compound (20) containing 2 TFA as a white solid (30 mg, 100%). 1H NMR (400 MHz, DMSO-d6) 7.68-7.57 (m, 6H), 7.26 (d, J=8.0 Hz, 2H), 7.25 (s, 2H), 7.13 (d, J=8.4 Hz, 2H), 4.90 (s, 2H), 3.94 (s, 2H), 3.67 (s, 2H), 2.80 (t, J=7.8 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H); MS (ESI), 555.0 (M+H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:24](=[O:25])[O:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1oc2c(ccc3[nH]c(=O)oc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 7-amino-3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-chromen-4-one (0.0532 g, 0.16 mmol) in anhydrous methylene chloride (2 ml) is treated at room temperature with a 20% phosgene in toluene solution (0.08 ml). After 30 min, triethylamine (0.032 g, 0.045 ml, 0.32 mmol, 2 eq.) is added, and the reaction mixture is stirred at room temperature for 1 h, transferred to the head of an aminoalkylated silica gel column (Sepra NH2, 50 micrometer, Phenomenex) and purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 1% acetic acid in ethyl acetate) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[N:22]=[CH:23][CH:24]=[N:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1nccn1

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.15 g, 0.57 mmol) and 1,2,3-triazole (0.037 mL, 0.63 mmol) gives the title compound.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1>C(Cl)Cl.N1C=CC=CC=1.CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(c4cccnc4)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (100 mg, 0.21 mmol), 3-pyridineboronic acid (265 mg, 2.10 mmol), Cu(OAc)2 powder (190 mg, 1.05 mmol) in 5 mL DCM and 1 mL pyridine was stirred at RT for 2 days. It was diluted with methanol and filtered through celite. The filtrate was treated with TFA and concentrated in vacuo. The residue was subjected to reverse phase HPLC to isolate the title compound. MS found for C29H28F2N6O as (M+H)+ 515.5. UV: λ=268 nm. 1H NMR: (CD3OD) δ 8.41 (1H, m), 8.16 (1H, s), 8.09 (1H, s), 8.06 (1H, s), 7.81 (1H, m), 7.35 (2H, dt, J=8.4; 2.0 Hz), 7.24 (1H, m), 7.16 (1H, m), 7.12-7.07 (3H, m), 5.79 (1H, s), 4.55 (2H, s), 4.12 (2H, m), 3.13 (2H, m), 2.91 (1H, m), 2.04 (2H, m), 1.87 (2H, m) ppm.
Reaction SMILES: [CH2:1]1[CH2:9][N:8]2[C@@H:4]([C@H:5]([OH:11])[C@H:6]([OH:10])[CH2:7]2)[C@H:3]([OH:12])C1.C1(=O)O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](O)[C@@H]1[OH:15]>>[OH:12][C@H:3]1[CH:4]2[N:8]([CH2:7][C@@H:6]([OH:10])[C@H:5]2[OH:11])[CH2:9][C@H:1]1[OH:15]
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](O)[C@@H]1O
Reactant: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Product: O[C@@H]1CN2C[C@@H](O)[C@@H](O)C2[C@@H]1O

Procedure:
The tetrahydroxyprrolizidone (1) is an analogue of 1,8-diepiswainsonine. A similar analogue of swainsonine can be made by analogous methods starting with D-glycero-D-talo-heptono-1,4-lactone to produce the novel (1S, 2R, 6R, 7S)-1,2,6,7-tetrahydroxypyrrolizidine.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH2:13]([O:20][C:21]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:22]=1[NH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:23]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:22]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:21]=1[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: COC(=O)CNc1c(F)cccc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(c1c(F)cccc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Chlorosulfonylisocyanate (379 μL, 616 mg, 4.36 mmol) is dissolved in dichloromethane (5 mL) cooled in an ice bath. To this is added a solution of tert.-butanol (416 μL, 322 mg, 4.35 mmol) in dichloromethane (2 mL) dropwise then the mixture is stirred cold for 5 min then 15 min at RT. To the rechilled solution is added dropwise a solution of methyl 2-(2-benzyloxy-6-fluoroanilino)-acetate (840 mg, 2.90 mmol) and Hunig's base (859 μL, 637 mg, 4.93 mmol) in dichloromethane and the resulting solution allowed to warm to RT. After 4 h LC/MS showed the reaction to be complete. The solution is extracted with water, and the organic layer dried, filtered, and solvent removed under reduced pressure. The residual material is chromatographed on an Isco Companion (80 g silica gel, 20-50% gradient of hexane/ethyl acetate) to afford N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-6-fluorophenyl)glycine methyl ester as an oil. MS (M−1)−=467; NMR (CDCl3): δ 7.51 (br s, 1H), 7.40 (m, 5H), 7.24 (m, 2H), 6.78 (m, 2H), 5.16 (s, 2H), 4.60 (dd, J=101 and 18 Hz, 2H), 3.64 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: N1C=CN=CC=1C(N[C@H:10]([C:18]([NH:20][C@H:21]([C:29](O)=O)[CH2:22]C1C=CC=CC=1)=O)CC1C=CC=CC=1)=O.[CH:32]1[CH:33]=CC2N(O)N=NC=2[CH:37]=1.Cl.C(N=C=NCCCN(C)C)C>C1COCC1>[CH:32]([N:20]([CH2:18][CH3:10])[CH:21]([CH3:22])[CH3:29])([CH3:33])[CH3:37]
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Yield: 200 %

Procedure:
N-pyrazineformyl-L-phenylalanyl-L-phenylalanine (0.42 g, 1 mmol) of Preparation example 5 was dissolved in 7 ml of THF, HOBt (0.16 g, 1.2 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5 mmol) were added at −20° C., then reacted for 30 min followed by addition of LeuBdiol-NH2 (0.3 g, 1 mmol) obtained in Preparation example 42 and N,N-diisopropylethylamine (0.26 g, 2 mmol), the mixture was stirred overnight at −20° C. TLC monitored the reaction, the after the reaction was completed, insoluble substance was removed by filtration, and solvent was evaporated under reduced pressure, the residue was dissolved with 20 ml of ethyl acetate, washed with 10% citric acid solution, 5% sodium bicarbonate solution, saturated table salt solution (3×15 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give 0.54 g of compound 4a as a white solid with a yield of 82%. m.p.: 78-80° C.; 1H-NMR (CDCl3, 500 MHz): δ 9.31-9.26 (m, 1H), 8.82-8.77 (m, 1H), 8.58-8.54 (m, 1H), 8.23-8.19 (m, 1H), 7.32-6.99 (m, 10H), 6.48-6.42 (m, 1H), 5.72-5.67 (m, 1H), 4.80-4.77 (m, 1H), 4.59-4.55 (m, 1H), 4.36-4.33 (m, 1H), 3.19-3.09 (m, 4H), 2.90-2.88 (m, 1H), 2.36-2.22 (m, 2H), 2.08-2.03 (m, 1H), 1.94-1.86 (m, 2H), 1.47-1.39 (m, 3H), 1.30-1.28 (m, 3H), 1.29-1.21 (m, 3H), 0.90-0.83 (m, 9H); 13C-NMR (CDCl3, 125 MHz): 169.86, 169.77, 163.21, 147.63, 144.33, 143.52, 142.69, 136.25, 135.94, 129.22, 129.13, 128.81, 128.45, 127.28, 126.72, 84.72, 54.73, 54.27, 51.50, 39.41, 39.37, 38.37, 38.03, 37.84, 37.64, 35.68, 28.53, 28.44, 27.05, 26.36, 26.32, 25.58, 23.96, 22.36; MS (EI): m/z 665.6 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15](=[S:17])=[S:16].[OH-].[K+].Cl/[CH:21]=[CH:22]\Cl>CS(C)=O.O.CCCCCC>[S:16]1[CH:22]=[CH:21][S:17][C:15]1=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: S=C=S
Reactant: CC(C)OC(=O)Cc1ccc(F)cc1
Reactant: Cl/C=C\Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)OC(=O)C(=C1SC=CS1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of isopropyl 4-fluorophenylacetate (98.1 g) in dimethylsulphoxide (1.2 g) there are added carbon disulphide (38.0 g) and then, slowly, a solution of potassium hydroxide (84.9 g) in water (150 ml). The mixture is stirred for 2 hours at 40° and cooled to room temperature. cis-1,2-Dichloroethylene (50 g) is added very slowly and the mixture is stirred at 45° for 2 hours. Water (1.5 l) and hexane (1 l) are added, the two phases are separated and the aqueous solution is extracted with hexane (3×1 l). The combined organic phases are washed with water (2×1 l), dried over magnesium sulphate and evaporated. The residue is crystallised from hexane. The product is dried in vacuo to constant weight to yield isopropyl (1,3-dithiol-2-ylidene)-(4-fluorophenyl)-acetate, m.p. 86°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CS(O)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:11]=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2nnc[nH]2)cc1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Brc1ccc(-c2nncn2C2CCCCO2)cc1
Yield: 248.3 %

Procedure:
A solution of 3-(4-Bromophenyl)-4H-1,2,4-triazole (14.1 g, 62.9 mmol), 3,4-dihydro-2H-pyran (10.59 mmol) and methanesulfonic acid (1.19 g, 6.29 mmol) in tetrahydrofuran (150 mL) was heated at 75° C. for 2 h. The solution was condensed and partitioned between sodium bicarbonate solution and ethyl acetate (3×), the organics dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The solid was triturated with 10% ethyl acetate in hexanes to afford the title compound (8.1 g, 26.3 mmol, 70% yield). MS (ESI) m/z 308.4 [M]+, 310.5 [M+2]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12

Procedure:
5 cm3 of thionyl chloride are added to 0.3 g (0.84 mmol) of 3-carboxy-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.35 g of 3-chlorocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:15][C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][N:9]1[C:7]1[CH:8]=[C:3]([CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])=[CH:20][CH:21]=2)[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-phenyl-urea (388 mg) was dissolved in DCM (15 mL) and triethylamine (0.194 mL) and the solution was cooled to 0° C. Methanesulfonyl chloride (0.108 mL) was added and the reaction stirred for 90 mins at 0° C. The reaction mixture was concentrated in vacuo and partitioned between DCM (20 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to give the desired compound (273 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1I.[CH3:21][Si:22]([CH3:39])([CH3:38])/[CH:23]=[CH:24]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1/[CH:24]=[CH:23]/[Si:22]([CH3:39])([CH3:38])[CH3:21]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1/C=C/[Si](C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Methyl 6-amino-2-(4-chloro-2-fluorophenyl)-5-iodopyrimidine-4-carboxylate (400 mg, 0.981 mmol) and tetrakis(triphenylphosphine)palladium(0) (113 mg, 0.098 mmol) were added to a 20 mL Biotage microwave reaction vessel. The vessel was sealed and purged with nitrogen gas. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (497 mg, 1.276 mmol) in dioxane (4907 μl) was added and the reaction mixture was stirred overnight at 90° C. under nitrogen. The cooled reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto silica. Purification by flash chromatography (SiO2, 0-20% EtOAc:Hex gradient) provided the title compound as a tan solid (0.283 g, 76% yield): 1H NMR (400 MHz, DMSO-d6) d 0.16 (s, 9H), 3.78 (s, 3H), 6.14 (d, J=19.1 Hz, 1H), 6.80 (d, J=19.1 Hz, 1H), 7.21-7.68 (m, 4H), 7.92 (t, J=8.4 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −110.46; ESIMS m/z 380 ([M+H]+), 378 ([M−H]−).