Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][N:19]=[N+]=[N-])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>[Pd]>[F:22][C:2]([F:1])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1
Agent: [Pd]
Product: NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1
Yield: 83 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-(trifluoromethyl)phenylboronic acid (3.72 g, 17.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (77%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (4.3 g, 9.59 mmol) with sodium azide (2.5 g, 38.46 mmol) generally according to the procedure described for Intermediate 98 gave 2.88 g (94%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide with palladium on carbon (0.28 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.46 g (83%) of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 213-215° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.13; H, 4.65; N, 4.13.
Reaction SMILES: C1C(=O)N(Br)C(=[O:4])C1.CC([Si](C)(C)[O:14][C@@H:15]1[CH2:28][C@@H:27]2[C@H:18]([C@H:19]3[C@H:24]([CH2:25][CH2:26]2)[CH2:23][C@:22]2([CH3:34])[C:29](=[N:32][OH:33])[CH2:30][CH2:31][C@H:21]2[CH2:20]3)[CH2:17][CH2:16]1)(C)C.[BH4-].[Na+].Cl>O1CCOCC1>[CH3:34][C@@:22]12[C@@H:29]([N+:32]([O-:4])=[O:33])[CH2:30][CH2:31][C@H:21]1[CH2:20][C@@H:19]1[C@H:24]([CH2:25][CH2:26][C@H:27]3[C@H:18]1[CH2:17][CH2:16][C@H:15]([OH:14])[CH2:28]3)[CH2:23]2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@]4(C)C(=NO)CC[C@H]4C[C@H]32)C1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@]12C[C@H]3CC[C@@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CC[C@@H]2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of NBS (210 mg, 1.3 mmol) in dioxane (4 mL) was added aqueous KHCO3 (260 mg, 2.6 mmol, 4 mL) at room temperature. The mixture was stirred for 30 min at room temperature. Compound 5 (105 mg, 0.26 mmol) in dioxane (10 mL) was added. The reaction was stirred for 14 h at room temperature and then NaBH4 was added (200 mg in 5 portions). The reaction was stirred for 3 h at room temperature. 6 N HCl (10 mL) was added and stirring at room temperature continued for 1 h. The product was extracted into EtOAc (50 mL×2). The combined extracts were dried, filtered, and removed. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to afford compound 6 (62 mg, 56%): mp 157-159° C.; [α]D20 +32.4 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 4.40 (t, J=8.2 Hz, 1H), 4.05-4.10 (m, 1H), 2.56-2.51 (m, 1H), 0.73 (s, 3H); 13C NMR (CDCl3) δ 94.4, 66.3, 47.9, 47.2, 47.0, 45.8, 45.1, 40.4, 38.3, 36.1, 33.9, 33.8, 32.7, 28.4, 25.7, 24.6, 2.32, 12.1; IR νmax 3385, 2212, 1542 cm−1. Anal. Calcd for (C18H29NO3): C, 70.32; H, 9.51; N, 4.56. Found: C, 70.12; H, 9.32; N, 4.33.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C1COCC1.CN(C=O)C>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Sc1ncccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(CSc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
2-mercaptopyrimidine (5.0 g) was dissolved in THF/DMF (150 ml), and to the solution was added triethylamine (7.4 ml) and then 4-nitrobenzyl bromide (8.7 g). The reaction solution was stirred for 1 hour at room temperature, added to water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate (=8/1), to give 2-[(4-nitrobenzyl)sulfanyl]pyrimidine (8.0 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:18]1([C:25]([OH:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]1)#[N:17].[CH2:28]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)C1C=CN=CC=1)C>C(Cl)Cl>[C:16]([C:18]1([C:25]([O:27][C:43]2[CH:44]=[CH:45][C:40]([C:37]3[CH:36]=[CH:35][C:34]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=3)=[CH:41][CH:42]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]1)#[N:17]
Reactant: CC1CCCC(C#N)(C(=O)O)C1
Reactant: CCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ccc(OC(=O)C3(C#N)CCCC(C)C3)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 23 g of dicyclohexylcarbodiimide in 50 ml of CH2Cl2 is added at room temperature to a mixture of 16 g of 1-cyano-3-methyl-cyclohexanecarboxylic acid, 25 g of 4'-hexylbiphenyl-4-ol, 1.2 g of 4-diethylaminopyridine and 200 ml of methylene chloride, and the mixture is stirred for 2 hours. Customary working up and separation by column chromatography (silica gel/toluene) and recrystallization gives the pure product 4'-hexylbiphenyl-4-yl 1-cyano-3-methylcyclohex-anecarboxylate, m.p. 51°.
Reaction SMILES: COCN[C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1>O1CCCC1.[Cl-].[NH4+]>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:5]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])=[CH:16][CH:17]=3)[CH:11]=2)=[O:6])=[CH:31][CH:30]=1
Reactant: COCNC(=O)c1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)c3ccc(F)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid methoxymethylamide obtained in Example 23-(1) (0.25 g) in tetrahydrofuran (3 mL), a solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran (1.0 M, 4.0 mL) was added dropwise in an ice bath and stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane:ethyl acetate=5:1 to 4:1) and silica gel column chromatography (eluting solvent: chloroform:methanol=95:5) to give the titled compound (0.11 g) as a light-blue solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.[CH2:17](Br)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>>[CH2:17]([N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2nc3cccnc3[nH]2)CC1
Reactant: BrCC1CCCO1
Product: CN1CCC(c2nc3cccnc3n2CC2CCCO2)CC1

Procedure:
Operation is carried out similarly to the above description with the difference that 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine is reacted with tetrahydrofurfurylbromide to obtain 3-tetrahydrofurfuryl-2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine which is isolated as difumarate melting at 154°-156° C. (ethyl alcohol).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Li+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (3.0 g, 13 mmol) in CH2Cl2 (200 mL) was treated with nicotinic acid (3.2 g, 26 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (6.6 g, 26 mmol) and triethylamine (6.6 g, 65 mmol). The reaction was stirred at room temperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. The reaction was stirred for 1 hour, and then saturated aqueous Na2CO3 was added (200 mL). The aqueous phase was extracted with CH2Cl2 (1×200 mL), and the aqueous phase was filtered. The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (3.5 g, 80% yield). 1H NMR (400 MHz, (CD3)2SO) δ 9.09 (d, 1H), 8.72 (dd, 1H), 8.32 (d. 1H), 8.26 (d, 1H), 7.50 (dd, 1H); LCMS (APCI+) m/z 336.9 (M+H)+, Retention time=2.19 minutes (Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]([CH3:29])[CH2:26][C:27]#[CH:28].CO>C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:28]#[C:27][CH2:26][N:25]([CH3:29])[CH3:24])[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3cc(C#CCN(C)C)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (300 mg, 0.63 mmol), 1-dimethylamino-2-propyne (90 μL, 0.84 mmol), 7.5 mg of tetrakis(triphenylphosphine)palladium(0) and 3 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. The combined aqueous layers are brought to pH 8 by adding 2 N sodium hydroxide. The aqueous layer is extracted with chloroform, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 225 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(dimethylamino)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile as red crystals, mp 164-166° C.; 1H NMR (DMSO-d6) δ 2.21 (s, 6H), 3.53 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.77 (s, 1H); MS 429.3, 431.2 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:17]2[C:12](=[CH:13][N:14]=[C:15]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:16]3=2)[C:11](=[O:29])[CH:10]=[CH:9]1.C(N(CC)C(C)C)(C)C.[CH3:39][CH:40]([CH3:46])[CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH2:41]([S:42]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]4[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:16]4=3)[C:11](=[O:29])[CH:10]=[CH:9]2)[CH2:4]1)(=[O:44])=[O:43])[CH:40]([CH3:46])[CH3:39]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: C[C@@H]1CCNC[C@@H]1n1ccc(=O)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)CS(=O)(=O)N1CC[C@@H](C)[C@@H](n2ccc(=O)c3cnc4c(ccn4COCC[Si](C)(C)C)c32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (23 mg, 0.056 mmol) in dichloromethane (2 mL) was mixed with N,N-diisopropylethylamine (30 μL, 0.17 mmol) and 2-methylpropane-1-sulfonyl chloride (12 μL, 0.092 mmol) under cooling with ice and stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol=1/1/0→0/10/1 (v/v/v)) to give the title compound as a pale pink solid (18.3 mg, yield 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>C(O)(=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:23])=[CH:4][CH:3]=[C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)[CH:11]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(-n3cccc3)ccc2c1O
Temperature: 25 °C

Procedure:
A mixture of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide and 0.043 mL 2,5-dimethoxytetrahydrofuran in 1 mL of acetic acid is refluxed for four hours. (The mixture rapidly turned very dark.) It is cooled to 25° C. and the precipitate is collected by filtration. It is washed with three 1 mL portions of acetic acid and dried in a stream of air. After drying at 75° C. the product is obtained as 20 mg of a brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3)c2CC1
Reaction time: 0.08 h

Procedure:
1-(4-Amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99, 0.05 mmol) was dissolved in 1 mL of DMF and treated with 1 equivalent of triethylamine. After 5 min, 1.5 equivalents of methanesulfonyl chloride were added and the mixture was stirred overnight. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was purified by preparative TLC (50% EtOAc/hexanes) to provide 1-(4-dimethanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The intermediate was then dissolved in 2 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.006 g of the title compound as an off-white solid. MS (ESI): exact mass calculated for C22H26N4O4S2, 474.14. found, m/z 475.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.35 (m, 1H), 7.22-7.20 (m, 2H), 7.13-7.11 (m, 2H), 5.34 (s, 2H), 2.97-2.94 (m, 4H), 2.92 (s, 6H), 2.89-2.87 (m, 2H), 2.82-2.80 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCOc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCCOc1ccncc1
Yield: 77.3 %

Procedure:
To a solution of 7.0 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 0.77 ml (5.52 mmol) of triethylamine in 30 ml of methylene chloride, 0.57 ml (4.63 mmol) of pivaloyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 840 mg of the desired compound (yield: 77.3%, colorless crystals).
Reaction SMILES: [N+](C1C=CC=CC=1O)([O-])=O.ClC1C2C(=CC=CC=2)N=CC=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24][CH:23]=1.[N+:32]([C:35]1[CH:51]=[CH:50][CH:49]=[CH:48][C:36]=1[O:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1)([O-])=O>[OH-].[Pd+2].[OH-].[C].[C].[Pd].CN(C)C=O>[NH2:32][C:35]1[CH:51]=[CH:50][CH:49]=[CH:48][C:36]=1[O:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccnc2ccccc12
Agent: [Pd+2]
Agent: [Pd]
Agent: Clc1ccnc2ccccc12
Solvent: CN(C)C=O
Product: Nc1ccccc1Oc1ccnc2ccccc12

Procedure:
Next, a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative is produced by reacting nitrophenol with the 4-chloroquinoline derivative or corresponding quinazoline derivative in the presence or absence of a suitable solvent to synthesize a 4-(nitrophenoxy)quinoline derivative or a corresponding quinazoline derivative, then conducting stirring in a suitable solvent, for example, N,N-dimethyl formamide, in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon, under a hydrogen atmosphere. Alternatively, the 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative may also be produced by reacting amino phenol with a 4-chloroquinoline derivative or a corresponding quinazoline derivative in the presence of a base, for example, sodium hydride.
Reaction SMILES: [Cl:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:23][C@@H:22]([OH:24])[C@H:21]([OH:25])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:35]3[C:30]([CH3:29])=[N:31][CH:32]=[N:33][CH:34]=3)[C:15]([N:19]3[CH2:23][C@@H:22]([OH:24])[C@H:21]([OH:25])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@H](O)C2)c(I)c1
Reactant: Cc1ncncc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ncncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1C[C@@H](O)[C@H](O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N-(4-(chlorodifluoromethoxy)phenyl)-6-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-5-iodonicotinamide (Stage 282.1, 100 mg, 0.190 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Stage 297.1, 62.8 mg, 0.285 mmol), Pd(Ph3P)4 (21.98 mg, 0.019 mmol) and K2CO3 (79 mg, 0.571 mmol) were added to a vial and flushed with argon. DMF (2 mL) was added and the mixture was stirred at 100° C. for 2 h. The solvent was evaporated off under reduced pressure. The crude product was dissolved in MeOH, filtered through a PL-resin Si-Thiol cartridge, the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 14-25% to 55% MeCN in 20 min) and followed by preparative SFC (Column Diol, from 20% to 25% in 6 min). The purified product was lyophilized in water/min vol. MeCN to afford the title product as a white powder. UPLC-MS (Condition 3), tR=0.86 min, m/z=492.2/494.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]5([C:39]([O:41]CC)=[O:40])[C:38]6[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:44])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>CO>[C:39]([C:26]1([CH2:25][CH2:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([C:11]3[CH:10]=[C:9]4[C:14]([CH2:15][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]4=[O:44])=[CH:13][CH:12]=3)[CH2:17][CH2:18]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=2[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([OH:41])=[O:40]
Reactant: CCOC(=O)C1(CCCCN2CCN(c3ccc4c(c3)C(=O)N(C3CCCCC3)C4)CC2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2cc(N3CCN(CCCCC4(C(=O)O)c5ccccc5-c5ccccc54)CC3)ccc2CN1C1CCCCC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
The compound (50 mg) prepared in Example 129 was dissolved in a mixed solvent composed of THF (0.3 ml) and methanol (0.3 ml). 1 N NaOH (0.3 ml) was added to the solution, and the mixture was heated at 65° C. with stirring for 3 hr. The temperature of the reaction solution was returned to room temperature, and 1 N HCl was then added thereto, followed by extraction with chloroform. The extract was dried over anhydrous MgSO4. The solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (chloroform:methanol=5:1) to give the title compound (29 mg).