Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[I:21]I.[Li]>CCOCC.O>[I:21][C:13]1[S:12][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=1
Reactant: c1ccc2sccc2c1
Reactant: II
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: Ic1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Butyllithium 1.6M in hexane (112.5 ml, 180 mmole) and absolute ether (70 ml) were placed in a 500 ml three-necked flask under an argon atmosphere and cooled in an ice bath to 0° C. Benzothiophene (20.1 g, 150 mmole) dissolved in absolute ether (40 ml) was then added dropwise within 30 minutes while cooling with ice and the mixture was stirred for 2.5 hours in an ice bath. The reaction mixture was left overnight in a cold cabinet. Iodine (75.0 g) and absolute ether (50 ml) were placed in a 500 ml capacity 3-necked flask under an argon atmosphere and the solution of the lithium compound was added dropwise while cooling with ice. The reaction mixture was slowly heated to room temperature, hydrolysed with water, washed with sodium thiosulfate solution and the organic phase was dried over sodium sulfate. The reaction solution was then concentrated by evaporation in vacuo and purified by means of flash chromatography with cyclohexane.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1Br.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH:19]=[O:20]
Reactant: Cc1c(F)ccc(Br)c1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C=O)c1F
Temperature: -78 °C

Procedure:
A cooled (−78° C.) solution of 2,4-difluoro-3-methylbromobenzene (2.000 g; 9.661 mmol) in anhydrous THF (36 ml) was treated dropwise (over 10 min.) with a solution of 1.6M n-BuLi in hexanes (6.04 ml; 9.661 mmol) while maintaining the temperature below −70° C. This mixture was further stirred at −78° C. for 2 min. before anhydrous DMF (1.49 ml; 19.326 mmol) was added dropwise (over 10 min.) while maintaining the temperature below −70° C. After completion of the addition, the resulting light brown solution was further stirred at −78° C. for 1 h30. The resulting mixture was then quenched at −78° C. with aq. sat. NH4Cl (10 ml), and was then allowed to warm-up to rt. Ether (50 ml) and water (20 ml) were added, and the organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure (caution: rotary evaporation bath at 30° C. because the aldehyde is volatile). The crude was purified by FC (DCM) to give the pure product 2,4-difluoro-3-methyl-benzaldehyde as a pale yellow oil (1.250 g; 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=O)O[C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[CH2:13][CH2:14][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC(c2ccc(Br)cc2)CC(=O)O1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 4.77 g (17.72 mmol) 3-(4-bromophenyl)glutaric anhydride (prepared as described in J. Org. Chem., 21, 704 (1956)), 1.90 g (17.72 mmol) benzylamine, and 80 mL toluene. The reaction was refluxed 1.5 hours cooled, and concentrated. The residue was taken up in 80 mL acetic anhydride, and heated at 100° C. for 16 hours then cooled and evaporated several times with toluene to remove excess acetic anhydride. The residue was dissolved in 80 mL dry tetrahydrofuran and treated with 40 mL (80 mmol) of a 2 N solution of borane methyl sulfide in tetrahydrofuran. The reaction was refluxed 18 hours cooled, and evaporated, then dissolved in 80 mL ethanol and treated with 3.5 g sodium carbonate and 3.5 g cesium fluoride. The reaction was refluxed 16 hours cooled, and concentrated. The residue was taken up in water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 2.94 g (50%) of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
Analogously, to example 1.4, (4-{tert-butoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was deprotected with TFA to give (4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester, MS: 451 (MH+), MP: 153-155° C., dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])[C:13]([F:26])=[CH:12][N:11]=1>>[F:26][C:13]1[C:14]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])=[N:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:11][CH:12]=1
Reactant: CC(Nc1nc(Cl)ncc1F)c1ccc(F)cc1
Reactant: Nc1cccc(O)c1
Product: CC(Nc1nc(Nc2cccc(O)c2)ncc1F)c1ccc(F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and (±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine were reacted to produce the desired (±)-5-fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=3.3 Hz), 7.38–7.34 (dd, 2H, J=5.2 and 8.5 Hz), 7.14 (t, 1H, J=4.5, Hz), 7.09 (d, 1H, J=8.5 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (br s, 1H), 6.84–6.78 (ddd, 1H, J=0.8, 2.0, and 8.2 Hz), 6.46–6.42 (ddd, 1H, J=0.8, 2.0 and 8.2 Hz), 5.26 (overlapped dq, 1H, J=7.1 and 7.9 Hz), 5.18 (d, 1H, J=7.1 Hz), 1.59 (d, 3H, J=7.1 Hz); LCMS: ret. time: 21.52 min.; purity: 92%; MS (m/e): 343 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>CC(N(C)C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: C[C@@H]1CNCCN1
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN[C@H](C)C1

Procedure:
Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc.) (2.0 g, 7.97 mmol), (R)-2-methyl-piperazine (3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound as a solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15]4=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]4[CH:17]=[CH:18][N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1nccnc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CN=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of 3-[4-(cyclohexyloxy)phenyl]pyrazin-2-amine (470 mg) in THF (dry) (25.00 mL) was added to a mixture of NaH (60%, 349 mg) and 2-chloroethanesulfonyl chloride (853 mg) in THF (dry) (25 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and THF was removed in vacuo. A precipitate was collected by filtration and washed with water-Et2O to give the title compound (522 mg) as a yellow solid. The solid was crystallized from CH3CN—IPE to give a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[F:26][C:27]1([F:42])[CH2:32][CH2:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:30]3[CH2:31][CH2:32][C:27]([F:42])([F:26])[CH2:28][CH:29]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccc(Oc2nccnc2C2=CCC(F)(F)CC2)cc1)c1nc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (0.5018 g, 1.431 mmol), 2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.698 g, 2.86 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.080 g, 0.114 mmol), and sodium carbonate (0.455 g, 4.29 mmol) in DME (3.58 mL) and water (1.192 mL) at 80° C. to stir overnight. Upon completion, solvent was removed. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 15 min to provide (1H-benzo[d]imidazol-2-yl)(4-(3-(4,4-difluorocyclohex-1-enyl)pyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[CH:14]=1)=[O:12].CC(O)=O>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[C:14]=1[Cl:1])=[O:12]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2c(Cl)c(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 32 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
N-Chlorosuccinimide (79 mg, 0.59 mmol) was added to a solution of Compound 132 (220 mg, 0.54 mmol) in CH2Cl2 (3 mL) with HOAc (1 mL) at r.t. The reaction was stirred for 18 h at 32° C. and was then concentrated in vacuo. Purification by prep-HPLC gave 88 mg (37%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.20 (br s, 1H), 8.23 (s, 1H), 8.11-8.19 (m, 2H), 8.00 (s, 1H), 7.87 (t, 1H, J=7.6 Hz), 7.74 (d, 1H, J=7.6 Hz), 7.28 (s, 1H), 4.01 (s, 3H), 3.23 (q, 2H, J=7.2 Hz), 2.37 (s, 3H), 1.34 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C22H19ClN2O4S, 443, 445; found 443, 445.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[CH3:14][NH2:15].O.CCCCCC>CCOC(C)=O>[Cl:13][C:6]1[C:3]([C:4]#[N:5])=[C:2]([NH:15][CH3:14])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CN
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of 2,6-dichloro-3-nitrobenzonitrile (98.7 g, 0.455 mol) in EtOAc (910 mL) was cooled to 5° C. 40% Aqueous methylamine (79.5 mL, 1.14 mol) was added with vigorous mechanical stirring, keeping the temperature at 10-15° C. After addition was complete, stirring was continued for 3 h at the same temperature. More methylamine (16 mL, 0.23 mol) was added, and the mixture stirred for a further 1.5 h at room temperature. Water (300 mL) was added, followed by hexane (450 mL). The mixture was stirred for 15 min, filtered, and the solid washed with water and MeOH, to give 6-chloro-2-methylamino-3-nitrobenzonitrile (80.3 g, 83%), mp 167-170° C.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[NH:6][C@@H:7]([CH3:10])[CH2:8][OH:9]>CN(C=O)C>[F:16][C:13]1[CH:12]=[CH:11][C:5]2[NH:6][C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:14]=1[F:15]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1COc2c(ccc(F)c2F)N1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To DMF (2 ml) was added sodium hydride (39 mg) and the mixture was heated to 60° C. in an oil bath. Next, a solution of the compound (100 mg) obtained in Example 51 in DMF was dropped there into and the obtained mixture was stirred for 1 hour. After treating in a conventional manner, the mixture was subjected to silica gel column chromatography to give 60 mg (66%) of the title compound. The optical purity determined by HPCL was >94% ee. Various spectral data was identical with those of a specimen synthesized separately.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[C:24]([N:28]1[C:32]([NH2:33])=[CH:31][C:30]([CH3:34])=[N:29]1)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[N:4]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:16][CH:15]=1)[N:3]=[C:2]2[NH:33][C:32]1[N:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:29]=[C:30]([CH3:34])[CH:31]=1
Reactant: CC(C)(C)c1ccc(-n2nc(Br)c3cc(Br)ccc3c2=O)cc1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(Br)cc23)n(C(C)(C)C)n1
Temperature: 100 °C
Reaction time: 20 h
Yield: 194.9 %

Procedure:
11 mg 4,6-Dibromo-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one (preparation see ZA-1) were reacted with 39.0 mg 1-tert.-butyl-3-methyl-1H-pyrazol-5-ylamine, 132 mg cesium carbonate, 7.0 mg tris-(dibenzylideneacetone)-dipalladium and 8.8 mg 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were stirred under argon at 100° C. for 20 hrs until HPLC indicated complete conversion. The solvent was removed under vacuum, the residue was taken up in dichloromethane and washed dilute HCl. Removal of the dichloromethane and chromatography on silica in first heptane and then heptan/ethyl acetate 8:2 yielded 25 mg of the title product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10]>>[C:8]([NH:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)Cl
Reactant: Nc1csc(Br)n1
Product: C=CC(=O)Nc1csc(Br)n1

Procedure:
4-Amino-2-bromothiazole is treated with acryloylchloride to give 4-acrylamido-2-bromothiazole which is refluxed with sodium in absolute methanol for sufficient time to produce the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1cc(F)cc(C2=CCOCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol (1.0 equiv.) was dissolved in DCM (0.2 M) and cooled to 0° C. TEA (2.8 equiv.) was added to the solution, followed by MsCl (1.3 equiv.). The reaction was stirred at rt for 2 hrs. The solution was cooled to 0° C. and DBU (3.0 equiv.) was added. The reaction was stirred at rt for 18 hrs. The solution was concentrated and the residue was purified by SiO2 chromatography (0-100% EtOAc in Heptanes) to afford 4-(3,5-difluorophenyl)-3,6-dihydro-2H-pyran in 38% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([O:30][CH3:31])(=[O:29])[CH:25]=[CH:26][CH:27]=[CH2:28]>O.CCOCC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]([O:30][CH3:31])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C=CC=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 48 %

Procedure:
A mixture of 3.0 g (10.5 mmol) of 1-(tert-butoxycarbonylaminomethyl)-2-bromobenzene, 4.5 ml (32.3 mmol) of triethylamine, 1.82 ml (15.7 mmol) of methyl 2,4-pentadienoate and 0.2 g (0.28 mmol) of bis (triphenylphosphine) palladium (II) chloride was sealed in a heavy-walled Pyrex, Teflon screw-capped flask and heated at 100° C. for 40 hours. After being cooled to 25° C. the reaction mixture was diluted with 150 ml of water and 50 ml of ether. The aqueous phase was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was chromatographed on a silica gel column that was eluted with a 5 to 10% gradient of ethyl acetate in hexane to give 1.6 g (53.3%) of colorless needles, mp 96°-97.5° C. after recrystallization from 1:3 ether:hexane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.C(N(CC)C(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[CH:5]=2)=[CH:12][CH:11]=1)=[O:32]
Reactant: Cn1nc(-c2ccco2)cc1-c1ccc(N)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccco2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of 71 (11 mg, 0.05 mmol) in CH2Cl2 (10 ml) was added N,N-diisopropylethylamine (DIEA, 26 mg, 36 μL, 0.2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 2,6-difluorobenzoyl chloride (15 mg, 0.08 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 72 (5 mg, 28%) as yellow solid. LC-MS: calcd. for C21H15F2N3O2: 380 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].[C:13]([Sn](CCCC)(CCCC)CCCC)([CH3:15])=[CH2:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]([CH3:15])=[CH2:14])=[CH:6][C:5]=1[Cl:11]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: C=C(C)c1ccc(C(=O)OC)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid methyl ester (500 mg, 2 mmol) in THF (15 mL) was added isopropenyltributylstannane (700 mg, 2.1 mmol) and PdCl2(dppf)-2-DCM (165 mg, 0.2 mmol). The solution was heated to 60° C. for 12 hours. The crude reaction mixture was then concentrated down and taken up in 20 mL EtOAc and 100 mL concentrated KF solution. The reaction stirred at room temperature for 3 hours, filtered through a pad of celite and concentrated down. The residual oil was subjected to flash chromatography (Isco Companion, 40 g SiO2 cartridge, solid loaded SiO2, neat heptanes to EtOAc gradient) to give 2-chloro-4-isopropenyl-benzoic acid methyl ester as a yellow oil. Amount obtained: 230.6 mg (55%). LCMS (M/Z): 211 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(Cl)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38860.4 %

Procedure:
Cyanuric chloride (11.0 g, 59.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -5° C. and gradually added dropwise with 50% aqueous dimethylamine solution (10.8 ml, 120 mmol). This reaction mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 11.0 g (yield: 95.4%) of 2,4-dichloro-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 122.5° C.-123° C. (2) The obtained 2,4-dichloro-6-dimethylamino-1,3,5-triazine (1.93 g, 10.0 mmol) was dissolved in DMF (8 ml), added with anhydrous potassium carbonate (1.40 g, 10.1 mmol) and cooled to -5° C.-0° C. This mixture was gradually added with imidazole (695 mg, 10.2 mmol). The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography, using ethyl acetate and methanol (95:5) as eluant, to obtain 873 g (yield: 38.8%) of 2-chloro-4-(1-imidazolyl)-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 88° C.-92° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:24]4[CH:32]=[CH:31][C:27]5[O:28][CH2:29][O:30][C:26]=5[CH:25]=4)[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:33][CH:34]([CH3:36])[CH3:35])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:24]4[CH:32]=[CH:31][C:27]5[O:28][CH2:29][O:30][C:26]=5[CH:25]=4)[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:33][CH:34]([CH3:36])[CH3:35])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2cc(OC(C)C)ccc2OC1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc2c(c1)C(c1ccc3c(c1)OCO3)=C(C(=O)O)C(c1ccc3c(c1)OCO3)O2

Procedure:
A mixture of compound (Ia-3) (57 mg, 0.117 mmol) and 1 M aqueous solution of sodium hydroxide (1.2 ml) in THF (2 ml) and methanol (2 ml) were refluxed for 1 h. The solvent was removed under reduced pressure, acidified with hydrochloric acid and extracted with ether three times. The ether layers were combined, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone-isopropylether to give compound (I-1) (37 mg, 66%) as yellow crystals.