Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]3[N:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cccnn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (37 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 213. MS m/z 404.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 11.11 (s, 1H), 9.22 (dd, 1H), 9.13 (dd, 1H), 8.55 (dd, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.83-7.78 (m, 1H), 7.71-7.65 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.35 (m, 3H), 3.90 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=1.[F:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[CH:19][N:18]=1>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[C:22]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: CCNc1ncccc1-c1sccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1sccc1-c1cccnc1F
Temperature: 75 °C
Yield: 31.2 %

Procedure:
A mixture of 3-bromo-2-(2-ethylaminopyridin-3-yl)thiophene (0.085 g), 2-fluoro-3-tributylstannylpyridine (0.26 g) and Pd(Ph3P)2Cl2 (0.014 g) in N-methylpyrrolidinone (2 mL) was heated at 75° C. under argon for 1 day. The mixture was diluted with ethyl acetate, washed, dried, filtered and evaporated. The residue was chromatographed to give 3-(2-fluoropyridin-3-yl)-2-(2-ethylaminopyridin-3-yl)thiophene (0.028 g). mp 86-89° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20](OC)=[O:21])[C:14]=2[CH:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1ccn2CCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=Cc1cccc2c1ccn2CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
3.6 g of Methyl 1-(2-benzyloxyethyl)-1H-indol-4-carboxylate was dissolved in 40 ml of diethyl ether, and 0.44 g of lithium aluminum hydride was added under ice-cooling. After stirring at room temperature for 10 minutes, the reaction solution was cooled with ice, and diethyl ether and water were added. When the insoluble substances adhered to and solidified on the wall of the flask, the reaction solution was dried over anhydrous magnesium sulfate, then the solvent was evaporated. The residue was dissolved in 40 ml of dichloromethane, 20 g of manganese dioxide was added, and the mixture was stirred at room temperature for 2 hours. After filtering off the manganese dioxide through Celite, and washing through with ethyl acetate, the solvent was evaporated, to give 1.5 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9](C)[CH2:10][CH2:11][C@H:12]1[C@H:20]([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClC(OCC)=O.Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:21][CH:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]1[CH2:11][CH2:10][NH:9][CH3:8]
Reactant: C[C@@H]1c2ccccc2N(c2ccccc2)[C@H]1CCN(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNCCC1C(C)c2ccccc2N1c1ccccc1

Procedure:
7.5 ml of triethylamine are added to a solution of 5.0 g of trans-2-(2-dimethylaminoethyl)-3-methyl-1-phenylindoline in 36 ml of toluene. 2.6 ml of ethyl chloroformate are added dropwise whilst refluxing the reaction mixture. After one and two hours 2.6 ml of ethyl chloroformate are again added. After a reaction time of 3 hours, cooling is effected and the reaction mixture is distributed between methylene chloride and dilute hydrochloric acid. After the mixture is washed with water and dried over sodium sulphate, the solvent is removed, whereupon the ethyl carbamate of the trans-3-methyl-2-(2-methylaminoethyl)-1-phenylindoline remains as a brown oil. 2. The latter is dissolved in 17 ml of n-butanol. 3.5 g of pulverized potassium hydroxide are added. The mixture is heated for 4 hours in an oil bath at 110°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:17].[CH:18]([Mg]Cl)=[CH2:19].CCOCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH:18]=[CH2:19])[OH:17]
Reactant: C=C[Mg]Cl
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (3.0 g, 9.66 mmol) at −78° C. in THF (48 mL) was added dropwise of vinylmagnesium chloride (17.51 mL, 28.0 mmol). After 30 min, the reaction was allowed to slowly warm to rt, then the reaction was quenched with 60 mL of saturated aqueious NH4Cl. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield 3.2 g of crude product as orange foam. This material was added ˜4 mL of Et2O and precipitate was formed and filtered through Bucher funnel to yield 7-bromo-3-chloro-5-vinyl-5H-chromeno[2,3-c]pyridin-5-ol (2.70 g, 7.97 mmol) as a yellow solid.
Reaction SMILES: IC1C=CC=CC=1N.FC1C=CC(B(O)O)=CC=1.[OH-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])=[CH:24][CH:23]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O1CCCC1.ClCCl.CN(C1C=CN=CC=1)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH:34][C:41](=[O:43])[CH3:42])=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1-c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The combined crops afforded the title compound as a homogeneous, colorless, crystalline, solid (24.0 g, 70%). m.p. 123-124° C.;
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Br:30].C(N(CC)CC)C.C[Si]([N:47]=[C:48]=[O:49])(C)C>C1COCC1>[Br:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:48]([NH2:47])=[O:49]
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: C[Si](C)(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2CNC(N)=O)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.13 g, 0.00023 mol) in THF (3.0 mL), was added triethyl amine (0.07 mL, 0.0005 mol) followed by the addition of trimethylsilylisocyanate (0.066 mL). The reaction mixture was stirred at room temperature for 1 h, and the desired product was isolated by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1>>[Cl:34][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][NH:12][CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][C:30]=1[OH:33]
Reactant: Clc1nccc(-c2cccc(CNCCc3cccnc3)c2)n1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNCCc4cccnc4)c3)n2)cc1Cl

Procedure:
Intermediate 172 from above was coupled with 4-(2-aminoethyl)2-chlorophenol following procedure F. LC-MS showed the product had the expected M+H+ of 460 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.50-8.43 (m, 2H) 8.29 (d, 1H) 8.21 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H) 7.63-7.55 (m, 2H), 7.42-7.38 (m, 1H), 7.19 (d, 1H) 7.09 (d, 1H), 6.99 (d, 1H), 6.8 (d, 1H), 4.2 (s, 2H), 3.6 (t, 2H), 3.3 (t, 2H), 3.0 (t, 2H), 2.8 (t, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[O-:10][N+:11]1[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][C:15]=2[N:14]=[C:13]([CH2:24][CH2:25][CH:26]=O)[N:12]=1)[CH2:21][CH2:20][CH2:19]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:26][CH2:25][CH2:24][C:13]1[N:12]=[N+:11]([O-:10])[C:16]2[CH:17]=[C:18]3[C:22]([CH2:21][CH2:20][CH2:19]3)=[CH:23][C:15]=2[N:14]=1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: COCCNCCOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCCN(CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3)CCOC
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Bis-(2-methoxyethyl)amine (3.0 g, 22.5 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 ml) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 80 (1.1 g, 50%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.19 (s, 1H, H-9), 7.83 (s, 1H, H-5), 3.61-3.68 (m, 4H, 2×CH2O), 3.31-3.38 (m, 4H, 2×CH2N), 3.26 (s, 6H, 2×OCH3), 3.20-3.14 (m, 4H, 2×CH2), 3.07-3.12 (m, 4H, H-6, H-8), 2.15-2.10 (m, 4H, H-7, CH2); 13C NMR δ 163.9, 154.7, 149.0, 146.7, 131.8, 122.2, 113.6, 58.0 (2), 57.4 (2), 52.4, 52.3, 32.5, 32.2, 25.3, 23.0 (2), 19.1; HRMS (FAB+) calcd for C19H29N4O3 (MH+) m/z 361.2240, found 361.2243.
Reaction SMILES: [Br-].[C:2]([CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4][CH2:5][CH3:6])=[O:3].CC(C)([O-])C.[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([C:44]2[C:48]([CH:49]=O)=[N:47][O:46][N:45]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[F:40]>C1(C)C=CC=CC=1.C1COCC1>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([C:44]2[C:48](/[CH:49]=[CH:7]/[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[N:47][O:46][N:45]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (carbethoxymethyl)triphenylphosphonium bromide (3.14 g, 7.32 mmol) in toluene (37 mL) was added sodium tert-butoxide (723 mg, 7.52 mmol) at rt under a nitrogen atmosphere. After stirring for 30 min, a solution of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide (811 mg, 3.01 mmol) in THF (10 mL) was cannulated into reaction flask. The resulting solution was heated at 80° C. for 3 h, then cooled to rt overnight. The reaction was quenched with a 1 N HCl solution, the aqueous solution was then extracted with ethyl acetate. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with flash chromatography (30% ethyl acetate/hexane) to give the desired product as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.92 (m, 2 H), 7.65 (m, 1 H), 7.26 (m, 1H), 7.01 (m, 1 H), 4.27 (m, 2 H), 1.33 (m, 3 H); LCMS for C14H12ClFN3O4(M+H)+: m/z=340.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C.C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol; Bionet Research, Cornwall, UK) in DMF (5 mL) was treated with potassium carbonate (400 μL, 6.63 mmol) and 4-methoxybenzyl chloride (600 μL, 4.42 mmol). The reaction was stirred at room temperature for 2 h, then diluted with DCM (200 mL) and washed with water (4×40 mL). The organic layer was then dried (MgSO4), filtered and concentrated in vacuo to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=2[CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C)c(-c2cc(Cl)ncn2)c1
Yield: 64 %

Procedure:
First, 4.97 g of 4,6-dichloropyrimidine, 5.02 g of 2,5-dimethylphenylboronic acid, 3.55 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put in a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was heated by being irradiated with microwaves (2.45 GHz, 100 W) for 30 minutes. Further, 1.25 g of 2,5-dimethylphenylboronic acid, 0.89 g of sodium carbonate, and 0.073 g of Pd(PPh3)2Cl2 were put in the flask, and the reaction container was heated again by being irradiated with microwaves (2.45 GHz, 100 W) for 30 minutes. Then, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate in a ratio of 5:1 as a developing solvent, so that the target pyrimidine derivative was obtained (pale yellow oily substance, yield of 64%). A synthetic scheme of Step 1 is shown in (d−1) below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[C:39]([B-](F)(F)F)([CH3:41])=[CH2:40].[K+].CCN(CC)CC>CC(O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:40]=[C:39]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:26][CH2:27]3)[CH:20]=[N:19][CH:18]=1)[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: C=C(C)[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (201.3 mg, 0.345 mmol), potassium isopropenyltrifluoroborate (Frontier Scientific, Inc., Logan, Utah; 61.1 mg, 0.413 mmol), PdCl2(dppf)-CH2Cl2 adduct (Acros Organics, Geel, Belgium; 14.28 mg, 17.48 μmol), and Et3N (0.048 mL, 0.350 mmol) in IPA (4.0 mL) was stirred under argon at 90° C. for 2 h. Additional potassium isopropenyltrifluoroborate (20.0 mg, 0.136 mmol) was added, and the resulting mixture was stirred at 90° C. for 1 h. The reaction was cooled to RT and diluted with EtOAc (150 mL). The resulting solution was sequentially washed with water (2×90 mL) and brine (60 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (ISCO, 12 g silica gel column, 0-30% EtOAc/hexanes, 15 min, 254 nm) provided (4R)-tert-butyl 4-(6-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (175.4 mg, 0.321 mmol, 93% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.05 (1 H, s), 8.45 (1 H, s), 8.19 (1 H, br. s.), 7.63-7.68 (1 H, m), 7.58-7.62 (1 H, m), 5.80 (1 H, d, J=8.6 Hz), 5.42 (1 H, s), 5.14 (1 H, s), 4.63 (1 H, br. s.), 4.47 (1 H, br. s.), 4.25 (1 H, d, J=8.4 Hz), 4.03 (1 H, d, J=11.2 Hz), 3.73-3.84 (1 H, m), 3.25 (1 H, d, J=13.7 Hz), 2.90-3.05 (1 H, m), 2.56-2.72 (1 H, m), 2.45 (1 H, br. s.), 2.24 (3 H, s), 2.21 (1 H, d, J=4.3 Hz), 2.12 (2 H, d, J=12.7 Hz), 1.75-1.87 (3 H, m), 1.11 (9 H, br. s.), 0.86 (2 H, br. s.), 0.72 (2 H, br. s.). MS (ESI, pos. ion) m/z: 546.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:35][CH:36]1[CH2:39][C:38]([F:41])([F:40])[CH2:37]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][C:38]1([F:41])[CH2:39][CH:36]([CH2:35][O:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:7]4[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:3][C:2]=4[F:1])[O:9][C:10]=3[CH:16]=2)[CH2:37]1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (770 mg), (3,3-difluorocyclobutyl)methyl methanesulfonate (459 mg), potassium carbonate (317 mg), and DMF (10 mL) was stirred at 60° C. for 2 hr. Then additional (3,3-difluorocyclobutyl)methyl methanesulfonate (459 mg) and potassium carbonate (317 mg) were added, and the mixture was stirred at 60° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (780 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][N:15](C)[CH2:16]CCN=C=NCC.ClCCl.CNC>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=Cc1ccc(Br)cc1C(=O)O
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
A 100 mL round-bottom flask was charged with 5-bromo-2-formylbenzoic acid (350 mg, 1.53 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (355 mg, 1.85 mmol, 1.20 equiv), 1-hydroxybenzotrizole (315 mg, 2.33 mmol, 1.50 equiv), dichloromethane (10 mL). The resulting solution was stirred for 15 min at room temperature. Dimethylamine (208 mg, 4.61 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (20 mL), extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (50/50) to provide 86.0 mg (22% yield) of 5-bromo-2-formyl-N,N-dimethylbenzamide as light yellow oil. LCMS (ESI, m/z): 256 [M+H]+.