Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Cl[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
A solution of [(3R,4S)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (50 mg, 0.10 mmol), 6-chloronicotinonitrile (21 mg, 0.15 mmol) in N-methylpyrrolidinone (0.5 mL) was treated with N,N-diisopropyl ethyl amine (52 μl, 0.30 mmol). The solution was stirred for 6 h at ambient temperature before it was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=80:20:0 to 0:90:10) afforded the title compound (52 mg, 86%) as an off-white foam. MS m/e: 596.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.O.NN.[O-]CC.[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: CC[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2ccc(Cl)cc2N1
Yield: 42.5 %

Procedure:
Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol, substantially according to C above, afforded 14.2 g of 6-chloro-2-oxindole, mp 196°-198° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[F:27][C:19]1[CH:18]=[C:17]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[CH:3][CH:4]=2)[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Br)cc2)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cscn3)cc2)cc1F
Yield: 87.5 %

Procedure:
To a stirred solution of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (0.361 g, 0.78 mmol) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol ), lithium chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.319 g, 87.6% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[CH:10][CH:9]=1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([Si:23]([O:18][C:15](=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)[CH:16]=[CH2:17])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(=O)Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(=Cc1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of 104 mL (104.0 mmol, 1.2 equiv.) of a 1.0M solution of potassium tert-butoxide in THF and 100 mL dry THF under nitrogen atmosphere at −78° C. was added a solution of 14.2 g (86.6 mmol, 1 equiv.) of 1-(4-fluorophenyl)but-3-en-2-one (step B) and 13.0 g (86.6 mmol) tert-butylchlorodimethylsilane in 100 mL dry THF. The reaction mixture was stirred at −78° C. for 6 hr and at RT for 6 hr then quenched by the addition of 50 mL water. The resulting mixture was warmed to RT, diluted with 150 mL hexanes, transferred to a separatory funnel and the organic layer separated. The organic layer was washed with 50 mL brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under vacuum to give 20.5 g of the crude title compounds which were used without further purification. 1H-NMR (CDCl3): δ: 7.52 (2H, m), 6.98 (2H, m), 6.33 (1H, dd, J1=13.2 Hz, J2=8.5 Hz), 5.97 (1H, s), 5.52 (1H, d, J=13.2 Hz), 5.17 (1H, d, J=8.5 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:30]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.20 (m, 4H), 5.40 (s, 2H), 3.79 (m, 4H), 3.37 (m, 2H), 3.28 (m, 2H), 2.49 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=401.1, found 401.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cccc2c(-c3ccc(N)cc3)nccc12
Yield: 88.9 %

Procedure:
Ethyl 1-(4-nitrophenyl)isoquinoline-5-acetate (4.2 g) was dissolved in 100 ml of ethanol, and 1.0 g of 10% palladium-carbon was added. The reaction was carried out in a stream of hydrogen. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether to afford 3.4 g of ethyl 1-(4-aminophenyl)isoquinoline-5-acetate having a melting point of 129.0° to 132.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[C:31]([NH:35][C:8]1[C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CC(C)(C)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 110 °C
Yield: 24.5 %

Procedure:
A mixture of 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (1000 mg, 1.917 mmol), tert-butylamine (565 μl, 5.75 mmol), brettphos palladacycle (77 mg, 0.096 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (44.7 mg, 0.096 mmol) and sodium tert-butoxide (553 mg, 5.75 mmol) were degassed. Toluene (9583 μl) was added to and reaction system was degassed and heated at 110° C. for 8 h. Solvent was evaporated in vacuo and partioned between water and EtOAc. Aqueous layer was extracted with EtOAc (2×) and combined organics were washed with water and saturated aqeous Brine, dried over Na2SO4 and concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with EtOAc/Hex (0-15%) affording N-(tert-butyl)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (219 mg, 0.469 mmol, 24.47% yield) as a white solid. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.52-7.13 (m, 15H), 6.30 (s, 1H), 5.76 (s, 1H), 1.24 (s, 9H). MS ESI calc'd. For C29H27ClN4[M+H]+ 467. found 467.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[C:5]([CH3:22])[CH:4]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:22])=[N:10]1)[CH:26]=[CH2:25]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2C)c2cccc(C(F)(F)F)c21
Yield: 53 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.090 g) as a white solid.
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[CH:27]=[C:28]([C:33]3([O:39][CH3:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:29]=[C:30]([F:32])[CH:31]=2)=[CH:21][CH:20]=1)[CH3:18]>>[F:32][C:30]1[CH:29]=[C:28]([C:33]2([O:39][CH3:40])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:27]=[C:26]([S:25][C:22]2[CH:21]=[CH:20][C:19]([CH:17]([O:15][N:14]=[C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH3:18])=[CH:24][CH:23]=2)[CH:31]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Reactant: ON=C(c1ccccc1)c1ccccc1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ON=C(c4ccccc4)c4ccccc4)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 38 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, benzophenone oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give benzophenone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl}-oxime as an oil in 38% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:30]=[C:17]4[C:18]([C:22]5[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=5)=[CH:19][CH:20]=[CH:21][N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[C:17]3[N:16]([N:15]=[C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([CH:4]5[CH2:5][CH2:6][N:1]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:2][CH2:3]5)=[CH:12][CH:11]=4)[N:30]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)cc1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5ccc(C#N)cc5)cccn4n3)cc2)CC1

Procedure:
2-(4-{4-[8-(4-Cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from 4-[2-(4-piperidin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridine-8-yl]benzonitrile (0.111 g, 0.281 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.043 mL, 0.422 mmol) in a manner analogous to Example 313 to give product (0.060 g, 44%). MP=245-246° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.71 (s, 1H), 8.87 (d, 1H), 8.40 (d, 2H), 8.00 (m, 3H), 7.62 (d, 2H), 7.15 (m, 3H), 3.12 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.80 (s, 3H), 2.40 (m, 1H), 2.12 (m, 2H), 1.65 (m, 4H). MS=480 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:44](OCCC(C)C)=O.C(=O)(O)[O-].[Na+].O.N>C(Cl)(Cl)Cl>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:13]=[N:44]1
Reactant: CCOC(=O)c1ccc(N)c(C)c1
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: N
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2[nH]ncc2c1
Reaction time: 1 h
Yield: 30.5 %

Procedure:
Ethyl 4-amino-3-methylbenzoate (12.6 g, 70.0 mmol) prepared in the Step 4-1-1 and potassium acetate (7.20 g, 73.5 mmol) were suspended in chloroform (70 ml). Acetic anhydride (14.3 g, 140 mmol) was added to the suspension, and the mixture was stirred for one hour. To the mixture, 18-crown-6 (3.70 g, 14.0 mmol) and isoamyl nitrite (18.9 g, 161 mmol) were added, and the resulting mixture was heated under reflux for 21 hours. After being allowed to cool, under an ice cooling the mixture was rendered faintly alkaline with a saturated sodium bicarbonate solution and a 25% ammonia water. The faintly alkalified mixture was subjected to extraction with chloroform, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (4.06 g, 31%) as a light-brown powder and ethyl 1-acetyl-1H-indazole-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>[Na+].[I-].CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][C:3]=1[F:9]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(Br)c(F)c1
Temperature: 56 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed 4-bromo-3-fluorophenol (50 g, 261.78 mmol, 1.00 equiv), acetone (500 mL), NaI (2.8 g, 0.07 equiv), potassium carbonate (54.2 g, 392.16 mmol, 1.50 equiv), and ethyl 4-bromobutanoate (61.3 g, 314.27 mmol, 1.20 equiv). The resulting solution was stirred at 56° C. overnight. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was dissolved in 1000 mL of EA and the resulting mixture was washed with 2×100 mL of sodium hydroxide (1 N) and 3×100 mL, of water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 80.6 g (crude) of ethyl 4-(4-bromo-3-fluorophenoxy)butanoate as a light yellow oil.
Reaction SMILES: [C-:1]#[N:2].[K+].CN([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]=2[Cl:17])[NH:10][CH:9]=1)C.CI.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[C:1]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:15]=2[Cl:17])[NH:10][CH:9]=1)#[N:2]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
Potassium cyanide (7.36 g, 113 retool) was added to a solution of 3-dimethylaminomethyl-4-chloro-5-benzyloxy-indole (9.30 g, 29.5 mmol) in sieve-dried DMF (150 ml). Methyl iodide (17.2 g, 121 mmol) was added dropwise, while stirring over 15 minutes, and stirring was continued for a further hour. The mixture was poured into 10% aqueous sodium sulphate and extracted with diethyl ether. The combined extracts were dried (Na2SO4) and evaporated to dryness leaving an oil which crystallised. Recrystallisation from methanol gave 3-cyanomethyl-4-chloro-5-benzyloxyindole (5.56 g), m.p. 130°-2° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:17])[O:13][CH2:14][CH:15]=[CH2:16]>O.C(Cl)Cl>[CH2:14]([O:13][C:12]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:17])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of trans-4-hydroxy-L-proline (35.9 g) and sodium hydroxide (23.9 g) in water (330 ml) was added dropwise a solution of allyl chlorocarbonate (36.3 g) in methylene chloride (250 ml) under ice-cooling, and stirring was continued for 2 hours. Aqueous layer was separated from the reaction mixture, washed twice each with methylene chloride (100 ml), and then acidified by adding concentrated sulfuric acid (25 g) dropwise at a temperature below 30° C. After adding table salt (120 g), the mixture was extracted twice each with ethyl acetate (220 ml). Extract was dried over magnesium sulfate. Distillation of the solvent gave crude crystalline trans-1-allyloxycarbonyl-4-hydroxy-L-proline (62 g). Purification of the crude crystals by repulping with toluene gave trans-1-allyloxycarbonyl-4-hydroxyl-L-proline (56.1 g) having m.p. 93-°94° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.[F:42][C:43]1[CH:55]=[C:54](B2OC(C)(C)C(C)(C)O2)[CH:53]=[CH:52][C:44]=1[CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>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].O>[F:42][C:43]1[CH:55]=[C:54]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]4[C:19]5=[N:20][C:21]([C:24]6[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=6)=[CH:22][N:23]=[C:18]5[N:17]=[N:16]4)[CH2:9]3)=[N:6][CH:7]=2)[CH:53]=[CH:52][C:44]=1[CH2:45][N:46]1[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(CN7CCOCC7)c(F)c6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.2 %

Procedure:
In a pressure tube reactor, (S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (40 mg, 0.08 mmol) was added, and then K2CO3 (36 mg, 0.26 mmol) was added. Pd(dppf)2Cl2 (4 mg, 0.004 mmol) was further added, and 1,4-dioxane (2 mL) and water (0.5 mL) were added. 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl)morpholine (42 mg, 0.13 mmol) was added, and then stirred at room temperature under nitrogen gas for 10 minutes, followed by stirring at 85° C. for 2 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Column chromatography using 50% ethyl acetate/hexane gave (S)-4-(5-(3-fluoro-4-(morpholinomethyl)phenyl)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (51 mg, 0.089 mmol) with a yield of 46%.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][C:38]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:10]=4)=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: Cn1ncc(Br)c1Nc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: (4-bromo-2-methyl-2H-pyrazol-3-yl)-(6-phenyl-pyridin-2-yl)-amine and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:23]([NH:22][C:20](=[O:21])[C@H:11]([CH2:10][C:9]([OH:27])=[O:8])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
5.09 g of Compound 6 obtained in Synthesis Example 5 was dissolved in 15 mL of ethyl acetate, 0.656 g of 5% palladium carbon (50% moisture content) was added thereto, and then the inside of the reaction system was substituted with hydrogen, and the reaction system was stirred at room temperature overnight and subjected to hydrogenolysis. The 5% palladium carbon was filtered off, and washed with ethyl acetate. Then, the organic layers were combined, distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 4.05 g of Compound 7.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1ccccc1C(=O)Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccccc3C)CC2)ccc1Cl
Yield: 63 %

Procedure:
The title compound (24 mg, 63%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2-methylbenzoyl chloride. MS:387.4 (MH+).