Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:28][C@@H:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH3:27])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(Cl)cc1
Temperature: 200 °C
Yield: 87.2 %

Procedure:
Two 20 mL microwave vials were charged with a half portion of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.50 g, 13.5 mmol), (R)-1-(4-chloro-phenyl)-ethylamine (4.20 g, 27.0 mmol), N,N-diisopropylethylamine (4.7 mL, 27 mmol) and acetonitrile (20 mL); and the mixture was heated in a microwave at 200° C. for 2.5 h. The mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL) and ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL), dried (Na2SO4), and concentrated. The residue was purified on silica gel column (0-5% MeOH/CH2Cl2) to give a pale yellow foam (4.46 g).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7](=O)[CH2:8]2)[CH2:3][CH2:2]1.Cl.[Br:12][C:13]1[CH:14]=[C:15]([NH:19]N)[CH:16]=[CH:17][CH:18]=1.C(O)C>Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:16]([C:6]3[CH2:5][N:4]4[CH:9]([CH2:1][CH2:2][CH2:3]4)[CH2:8][C:7]=3[NH:19]2)=[CH:17][CH:18]=1
Reactant: NNc1cccc(Br)c1
Reactant: O=C1CCN2CCCC2C1
Agent: Cl
Solvent: CCO
Product: Brc1ccc2c3c([nH]c2c1)CC1CCCN1C3
Yield: 26.6 %

Procedure:
Hexahydroindolizin-7(1H)-one (4.58 g, 32.9 mmol) and 3-bromophenylhydrazine hydrochloride (8.08 g, 36.2 mmol) were combined in concentrated hydrochloric acid (40 ml) and ethanol (15 ml) and heated at 105° C. for 48 h. Upon cooling, the solid was filtered off and partitioned between methylene chloride and 6 N NaOH solution. The organic layer was removed and concentrated to provide 8-bromo-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (2.55 g, 26%). The original filtrate was concentrated and partitioned between methylene chloride and 6 N NaOH solution. The organic layer was removed and concentrated, and the residue was purified by column chromatography (eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride) to provide the title compound (1.31 g, 14%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.44-7.43 (d, J=1.7 Hz, 1H), 7.31-7.29 (d, J=8.4 Hz, 1H), 7.06-7.03 (dd, J=Hz, 1H), 3.79-3.76 (m, 1H), 3.22-3.17 (m, 1H), 2.91-2.85 (m, 2H), 2.79-2.74 (m, 1H), 2.64-2.59 (m, 2H), 2.38-2.31 (m, 1H), 1.81-1.70 (m, 2H), 1.68-1.66 (m, 1H); ESI MS m/z 292 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:17])=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[N:11]2
Reactant: COc1cccc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)c1
Yield: 5.7 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[3-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 74) (55 mg, 0.16 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 5-methyl-N-[3-(methyloxy)phenyl]-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (3 mg) as a yellow solid. MS m/z 332 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([Cl:19])(=[O:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 25 °C

Procedure:
2-(N-benzyloxycarbonylamino)ethanesulfonic acid (0.6 g; 2.31 mmol) was suspended in dry toluene (6 mL) and PCl5 was added (0.65 g; 3.11 mmol). The mixture was refluxed for 2 h, until complete dissolution of the reagents. After cooling at room temperature, the solvent was evaporated off under vacuum to give the crude 2-(N-benzyloxycarbonylamino)-ethanesulfonyl chloride pure enough for the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:34]([NH:33][C:25]1[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:29][CH:28]=[CH:27][C:26]=1[CH:30]([CH3:32])[CH3:31])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCOc1ccc(NCc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)c1ccc(OCCCCO)cc1
Yield: 23.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl[4-(4-hydroxybutoxy)phenyl]amine (1.67 g) and 2,6-diisopropylphenyl isocyanate (1.37 g) as starting materials, 4-{4-[1-benzyl-3-(2,6-diisopropylphenyl)ureido]phenoxy}butanol (0.68 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:11].[H][H]>[OH-].[Pd+2].[OH-].C(O)C>[ClH:11].[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[F:1]
Reactant: [H][H]
Reactant: N#Cc1ccc(O)cc1F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc(O)cc1F

Procedure:
2-Fluoro-4-hydroxybenzonitrile (10 g, Allied Signal) was added to a 500 mL Parr flask, followed by palladium hydroxide (5 g). Anhydrous ethanol (200 mL) was then added under nitrogen atmosphere, followed by aq. concentrated hydrochloric acid (7.55 mL). The mixture was shaken under 50 psi of hydrogen for 1.5 h, then filtered through nylon. The filtrate was concentrated, washed with ethyl acetate, then dried in vacuo to yield the crude title compound (9.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred 0° C. solution of 1-t-Butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine (5.2 g, 18 mmol) from Step 1 was added NaH (800 mg of a 60% suspension in mineral oil, 20 mmol). After 30 min, ethyl bromoacetate (2.2 mL, 20 mmol) was added and the reaction was warmed to ambient temperature and stirred for 2 h. The reaction was quenched by the addition of acetic acid (1 mL), and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 20% EtOAc-hexanes as eluant. 1-t-Butyloxycarbonyl-4-((2-ethoxycarbonylmethoxyphenyl)amino)piperidine was obtained as an oil (90% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH2:34](N(CC)CC)C>CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:26][CH3:34])[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C(O)CCC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC1CCC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 841.4 %

Procedure:
To an ice cold solution of (2S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-6-hydroxypiperidine-1-carboxylate (2 g, 4.3 mmol) in methanol (20 mL) was added pyridinium p-toluenesulfonate (108 mg, 0.43 mmol). The reaction mixture was warmed to RT and stirred overnight. Triethylamine (87 mg, 0.86 mmol) was added, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluting with 0-15% EtOAc in petroleum ether), and combined with the product of three similar runs to provide the title intermediate (3.5 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:29]([O:36][C:37]([NH:39][C:40]1[C:41]([C:52](O)=[O:53])=[N:42][C:43]2[C:48]([CH:49]=1)=[CH:47][CH:46]=[C:45]([CH2:50][CH3:51])[CH:44]=2)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:52]([C:41]3[C:40]([NH:39][C:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:38])=[CH:49][C:48]4[C:43](=[CH:44][C:45]([CH2:50][CH3:51])=[CH:46][CH:47]=4)[N:42]=3)=[O:53])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.15 mg, 0.0158 mmol), 3-{[(benzyloxy)carbonyl]amino}-7-ethylquinoline-2-carboxylic acid (4.6 mg, 0.013 mmol), HATU (12.5 mg, 0.0328 mmol), DMF (0.0305 mL) and DIPEA (5.09 mg, 0.0394 mmol) was stirred at room temperature for 1 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative LC MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give pure sub-title compound as a colorless gum (4 mg, 40%). LCMS calc. for C40H47N6O7 (M+H)+: m/z=723.4. Found: 723.3.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]([OH:8])[CH3:7])=[O:5].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:8][C@@H:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)OS(C)(=O)=O
Temperature: 20 °C
Yield: 96.6 %

Procedure:
To a solution of (L)-ethyl lactate (124 g, 1.05 mol) and triethyl amine (126 g, 1.25 mol) in toluene at 10-15° C. was added methanesulfonyl chloride (124 g, 1.08 mol) dropwise for about 2 hours. The mixture was allowed to warm to about 20° C. and the solid was filtered off. The solution was washed with water and dried, concentrated to afford the product (S)-ethyl 2-(methylsulfonyloxy)propanoate (199 g, yield 96.7%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[Cl:35][C:36]1[N:41]=[C:40](O)[C:39]([NH:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[CH:38][N:37]=1>ClCCCl>[Cl:35][C:36]1[N:37]=[CH:38][C:39]2[N:43]=[C:44]([C:45]3[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=3)[O:51][C:40]=2[N:41]=1
Reactant: O=C(Nc1cnc(Cl)nc1O)c1ccncc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Clc1ncc2nc(-c3ccncc3)oc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
12.0 g (35.9 mmol) polymer bound triphenylphosphine and 5.03 mL (35.9 mmol) triethylamine are added to 4.77 g (20.0 mmol) hexachloroethane in 40 mL 1,2-dichloroethane. The mixture is stirred for 5 min at rt. 1.00 g (4.0 mmol) N-(2-chloro-4-hydroxy-pyrimidin-5-yl)-isonicotinamide in 20 mL 1,2-dichloroethane are added and the mixture is stirred for 12 h at rt. Subsequently the mixture is concentrated in vacuo, treated with diethyl ether, filtered, and concentrated again. The residue is purified by HPLC (reversed phase; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([SH:14])=[N:13][C:8]2=[CH:7][CH:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([S:14][CH:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:17]([OH:19])=[O:18])=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Sc1nc2ccc(Cl)nc2s1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Sc1nc2ccc(Cl)nc2s1)c1ccc(Cl)cc1
Yield: 68.2 %

Procedure:
A methylene chloride solution of 6.0 g (0.03 m) of 5-chloro-2-mercaptothiazolo[5,4-b]pyridine, 7.5 g (0.03 m) α-bromo-α-(p-chlorophenyl) acetic acid and 6.0 g (0.06 m) triethylamine is heated to gentle reflux overnight. The solution is extracted twice with a dilute hydrochloric acid solution and then once with water. After drying over anhydrous MgSO4, the solvent is removed and the residual solid is recrystallized from acetonitrile. 7.5 g (68% yield) of title compound, melting at 144°-6° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32](I)=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[C:63]([F:65])[CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cc3c(I)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 42.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 33) (150 mg, 0.21 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (91.69 mg, 0.24 mmol) in sodium carbonate (66.77 mg, 0.483 mmol), Pd(PPh3)2Cl2 (7.36 mg, 0.01 mmol), 1,2-dimethoxyethane/water (10/2 ml) to give 70 mg (41% yield) of titled compound. MS: m/z=778.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (640 mg, yield: 87%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[C:26]([C:23]1([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:3][CH:4]=3)[CH:10]=2)=[O:28])[CH2:24][CH2:25]1)#[N:27]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)nc4)c3)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (2.0 g, 5.4 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.13 g, 5.94 mmol) under ice-cooling, and the mixture was stirred with heating at 80° C. for 2 days. After the reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate and diisopropyl ether to give the title compound (2.61 g, 92%) as a colorless solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][O:37][CH2:38][CH2:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH2:39][CH2:38][O:37][CH3:36])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 55.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 99, 1 g, 2 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (1.2 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (140 mg, 0.2 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-{1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-1H-pyrrolo[2,3-b]pyridine (0.6 g, 57%) as a white solid: LC/MS m/e calcd for C27H27FN2O5S2 [M+H]+ 543.65, observed 543.0.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH:7]3[NH:14][C:15]3[C:20]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[CH:19][N:18]=[C:17]4[NH:31][CH:32]=[CH:33][C:16]=34)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2].[H][H]>[Pd].CO.O1CCOCC1>[C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH:7]3[NH:14][C:15]3[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[C:17]4[NH:31][CH:32]=[CH:33][C:16]=34)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2]
Reactant: NC(=O)C12CC3CC(C1)C(Nc1c(C(=O)OCc4ccccc4)cnc4[nH]ccc14)C(C3)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)C12CC3CC(C1)C(Nc1c(C(=O)O)cnc4[nH]ccc14)C(C3)C2
Yield: 80.2 %

Procedure:
10% Palladium on carbon (50% wet) (40 mg) was added to a solution of benzyl 4-[(5-carbamoyladamantan-2-yl)amino]-1H-pyrrolo-[2,3-b]pyridine-5-carboxylate (183 mg) in methanol (5 ml) and 1,4-dioxane (5 ml), and hydrogenated under hydrogen atmosphere for 5 hours. Resulting precipitates were dissolved by tetrahydrofuran and filtered out the catalysts. The filtrates were evaporated in vacuo to give 4-[(5-carbamoyladamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (117 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (10.2 g, 50 mmol) in anhydrous tetrahydrofuran (200 mL) was cooled to −78° C. A solution of 4-chlorophenyl-magnesium bromide (1M in diethyl ether, 60 mL, 60 mmol) was added via syringe over 8 minutes. Stirring was continued at low temperature for 5 minutes and the reaction was warmed up to room temperature and stirred for 1 hour at this temperature. The solution was cooled in an ice-water bath and quenched by addition of saturated aqueous ammonium chloride solution (40 mL). The organic phase was decanted and the aqueous residue was concentrated under reduced pressure to remove any remaining organic solvent. The aqueous phase was extracted with ethyl acetate (200 mL×2) and the extracts were combined with the decanted tetrahydrofuran solution. This solution was washed with brine (25 mL) and was dried (sodium sulfate), filtered and concentrated under reduced pressure, giving crude (5-bromo-2-fluorophenyl)-(4-chlorophenyl)-methanol (15.2 g, 96% yield) as a yellow solid.