Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH2:11][CH2:10][CH2:9]1.C=O.[C:27]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:27])[CH2:11][CH2:10][CH2:9]1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1C)CCNC2C1(c2ccccc2Cl)CCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1C)CCN(C)C2C1(c2ccccc2Cl)CCC1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
A mixture of the oxalate salt of 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline (4.42 g prepared as described in Example RC12), methanol (87 ml) and 37-40% aqueous formaldehyde solution (5.1 ml) was cooled to 10° C. and sodium cyanoborohydride (2.64 g) was added. After 10 minutes the mixture was allowed to warm to ambient temperature and was stirred for 24 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and dilute aqueous sodium hydroxide solution. The organic phase was washed with aqueous ammonia solution, then dried and concentrated to yield 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline (3.3 g).
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[F:24])[CH:8]=1)C.Cl.O1CCOCC1>[Pd].C(Cl)Cl.CCO>[F:24][C:18]1[CH:19]=[C:20]([NH2:21])[CH:22]=[CH:23][C:17]=1[O:16][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][CH3:4])[S:15][C:14]=12
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.2 %

Procedure:
Obtained as a by-product during hydrogenation of the alkyne of 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (Example 6, Step B). A mixture of N-4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (Example 6, Step B; 106 mg, 0.287 mmol), 4N HCl in dioxane (72 μL, 0.29 mmol), palladium on carbon (61 mg, 0.029 mmol; Degussa type, 10 wt % Pd. 50% water), and 1:1 CH2Cl2/EtOH (10 mL) was purged with N2 (3×), and then shaken under H2 (50 psi) for 18 hours at room temperature on a Parr shaker. The mixture was filtered, rinsing the Pd/C with MeOH. The resulting filtrate was concentrated, and the residue was partitioned between EtOAc (20 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (25% MeOH in CH2Cl2). The product was obtained as a waxy solid (8 mg, 8%). 1H NMR (400 MHz, CDCl3) δ 8.41 (m, 1H), 7.23 (s, 1H, overlaps with chloroform), 7.03 (m, 1H), 6.52 (m, 3H), 3.81 (br s, 2H), 2.93 (m, 2H), 1.80 (m, 2H), 1.03 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])C)[CH:7]=1.[H-].[Na+].ClC1O[C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:19][N:20]=1>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9]2[O:11][C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH:7]=1
Reactant: CC(=O)Nc1cc(N)ccc1C
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of N-(5-Amino-2-methyl-phenyl)-acetamide (1.1 g, 6.7 mmol) in DMF (20 mL) was added to a suspension of NaH (402 mg, 10.05 mmol, 60% dispersion in mineral oil) in DMF (20 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 30 min. at room temperature and cooled to 0° C. A solution of 4-(2-Chloro-oxazol-5-yl)-benzonitrile (1.37 g, 6.7 mmol) in DMF (20 mL) was added dropwise to the mixture. After 30 min., at 0° C., the reaction was poured into ice water (200 mL). The solid was collected by filtration, washed with water, and dried under vacuum to afford the title compound (1.45 g, 75%). m.p.=228° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH:4]=[CH2:5].S(C[N+:20]#[C-:21])(C1C=CC(C)=CC=1)(=O)=O.O1CCC[CH2:23]1>O>[NH:20]1[CH:21]=[CH:23][C:4]([C:3]([O:7][CH3:8])=[O:6])=[CH:5]1
Reactant: C=CC(=O)OC
Reactant: C1CCOC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc[nH]c1

Procedure:
Sodium hydride (57% dispersion in oil, 10.5 g., 0.25 mole) was placed in a flame dried flask and washed twice with dry benzene. Dry tetrahydrofuran (400 ml.) was added to the flask and the resulting slurry stirred under nitrogen. A mixture of methyl acrylate (11.3 ml., 0.128 moles) and tosylmethyl isocyanide (25 g., 0.128 moles) in 120 ml. of tetrahydrofuran was then added dropwise over 30 minutes. The reaction was exothermic and the reaction mixture refluxed during this process. After stirring for an additional hour (without external heating), the reaction mixture was cooled in an ice-water bath and water (approx. 120 ml.) added dropwise until solution resulted. The solution was allowed to warm and then extracted three times with ether. The combined ether extracts were back-washed with water and then saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield methyl pyrrole-3-carboxylate (6.4 g., m.p. 78°-81° C., m/e 125).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](O)([CH3:11])C.O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][CH:11]=[CH2:14])[C:2]=1[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cccc(C(C)(C)O)c1C
Solvent: c1ccccc1
Solvent: O
Product: C=CCc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2-(2,3-Dimethylphenyl)propan-2-ol, compound of formula (XXIV), prepared according to either example 1 or example 2, (1.10 g, 6.70 mmol), was dissolved in benzene (20 mL), and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 3 h. Silica gel (200 mg) was added, and stirring was continued for ca. 16 hours, and then the reaction mixture was refluxed for 30 min. After cooling to room temperature, the mixture was filtered, washed with aqueous K2CO3 solution, conventionally dried, and concentrated under reduced pressure, to yield 0.90 g (92%) of the title compound. 1H NMR: 2.02 (m, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 4.82 (m, 1H), 5.17 (m, 1H), 6.97 (m, 1H), 7.05 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH2:12]O)[N:11]=1)=[O:5].O=S(Cl)[Cl:31].CCN(CC)CC.O>C(Cl)Cl>[Cl:31][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])[S:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1nc(CO)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1nc(CCl)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Into a solution of Compound 39 (123 mg, 0.3 mmol) in 5 mL of CH2Cl2 was added SOCl2 (0.4 mmol) and NEt3 (0.5 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. The solution was treated with 10 mL of water and extracted with CH2Cl2. The combined extracts were washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with 5-50% ethyl acetate in hexane) to give Compound 70 (114 mg, 88%) as a white solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:13][C:3]=1[C:4]=23.[OH:21][C:22]1C=CC=C[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:35]N>C(#N)C.C(Cl)Cl>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C@H:12]1[CH2:11][C:5]2=[CH:6][NH:7][C:8]3=[CH:9][CH:10]=[C:2]([C:22]([NH:23][NH2:35])=[O:21])[C:3](=[C:4]23)[CH2:13]1)[CH2:16][CH3:17]
Reactant: NN
Reactant: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(I)c(c23)C1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(C(=O)NN)c(c23)C1
Reaction time: 15 h

Procedure:
To a solution of 5.0 g (13.1 mmol) of (4S)-6-iodo-4-(di-n-propylamino)-1,3,4, 5-tetrahydrobenz [cd] indole in 250 ml of acetonitrile was added 3.5 g (37 mmol) of 2-hydroxypyridine, 16.9 g (122 mmol) of powdered potassium carbonate, and 0.30 g (0.26 mmol) of tetrakis (triphenylphosphine)palladium. The resultant mixture was heated at 65° C. under a carbon monoxide atmosphere for 14 hours. The cooled mixture was then treated with 2 ml of hydrazine hydrate and stirred for another 15 hours. After filtering, the mixture was concentrated in vacuo to provide a residue. This residue was taken up in methylene chloride and extracted with aqueous tartaric acid solution. The aqueous layer was basified with 1M sodium hydroxide solution and the product was extracted into methylene chloride. Evaporation of solvent in vacuo left an oily solid which, after thorough washing with a 1:2 mixture of toluene and hexane, afforded 0.60 g of (4R)-4-(di-n-propylamino) -1,3,4,5-tetrahydrobenz [cd]indole-6-carboxylic hydrazide.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([O:11][C:12]1[C:17]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[C:22](=[C:24]([CH2:32][CH3:33])[N:25]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:26]=3)[N:23]=2)=[CH:16][C:15](I)=[CH:14][N:13]=1)[CH2:8][CH2:9][CH3:10]>C(N(CC)CC)C.C(#N)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>[CH2:7]([O:11][C:12]1[C:17]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[C:22](=[C:24]([CH2:32][CH3:33])[N:25]([CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[N:26]=3)[N:23]=2)=[CH:16][C:15]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
Pd(PPh3)2Cl2 (11.2 mg, 0.016 mmol), trimethylsilylacetylene (179 μl, 1.29 mmol) and cuprous iodide (3 mg, 0.016 mmol) were added to a stirred slurry of 5-(2-butoxy-5-iodo-3-pyridinyl)-2-[2-(dimethylamino)ethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 44 in Annex 1, PCT Application, IB 00/01430) (330 mg, 0.647 mmol) in triethylamine (8 ml) and acetonitrile (2 ml) at room temperature under a nitrogen atmosphere. The mixture was heated at 60° C. for 3 h, cooled and extracted from brine with dichloromethane (2×100 ml). The organics were dried (MgSO4), filtered and concentrated to give a yellow solid. Purification by flash column chromatography (elution with DCM/MeOH, 95:5) gave the title compound as a pale brown oil (290 mg, 93%).
Reaction SMILES: [ClH:1].[CH2:2]([C:10]1[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].[N:16]([CH2:19][C:20]([CH3:28])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:17]=[N-:18]>>[ClH:1].[CH3:28][C:20](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)[N:18]=[N:17]1
Reactant: C#CCCCCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCCCc2c[nH]c(N)n2)nn1
Yield: 64.5 %

Procedure:
4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.098 g, 0.568 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.118 g, 0.681 mmol) following the general procedure for click reactions outlined above to produce 4-{6-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-hexyl}-1H-imidazol-2-ylamine hydrochloride (0.147 g, 85%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), δ 7.25-7.15 (m, 5H), δ 6.65 (s, 1H), δ 6.36 (s, 1H), δ 5.23 (s, 2H), δ 2.78 (t, 2H), δ 2.38 (t, 2H), δ 1.74 (s, 3H), δ 1.64 (m, 2H), δ 1.51 (m, 2H), δ 1.33 (m, 4H) ppm; 13C (75 MHz, CD3OD) δ 147.5, 136.3, 132.9, 132.8, 129.9, 128.9, 128.6, 128.5, 128.3, 127.7; HRMS (ESI) calcd for C21H29N6(M+) 365.2448, found 365.2448.
Reaction SMILES: CS([O:5][CH:6]([C:8]([F:11])([F:10])[F:9])[CH3:7])(=O)=O.[N+]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-])=O>>[F:9][C:8]([F:11])([F:10])[CH:6]([O:5][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:7]
Reactant: CC(OS(C)(=O)=O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CC(Oc1ccc(O)cc1)C(F)(F)F

Procedure:
Following the above procedures, 1-trifluoromethylethyl methanesulfonate is reacted with 4-nitrophenol to give 4-(1trifluoromethylethoxy)phenol, which is then reacted with ethyl N-(2-chloroethyl)carbamate to give ethyl N-{2-[4-(1-trifluoromethylethoxy)phenoxy]ethyl}carbamate (compound 29, Table A).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1COCC1.O.CCOC(C)=O>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of aniline (30.1 mL, 0.33 mol) in THF (300 mL) at −78° C. was added LiHMDS (408 mL, 1 M in THF, 0.41 mmol) at such a rate that T≦−65° C. The reaction mixture was stirred at −78° C. for 30 min and was then added to a solution of 2,4-difluoronitrobenzene (50 g, 0.31 mol) in THF (200 mL) at −78° C. at such a rate that T≦−65° C. The mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with water (300 mL) and EtOAc (300 mL) and the emulsion which formed filtered through Celite®. The layers were separated and the aqueous fraction extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was stirred with pentane (300 mL) for 16 h then filtered to give the title compound as a tan solid. (50 g, 68%). 1H NMR 400 MHz (CDCl3) δ: 9.64 (1H, br s), 8.26 (1H, dd, J=9.5, 6.0 Hz), 7.49-7.42 (2H, m), 7.32-7.25 (3H, m), 6.80 (1H, dd, J=11.3, 2.5 Hz), 6.51-6.45 (1H, m)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(F)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1cccc(F)c1

Procedure:
To a solution of 3-fluorobenzaldehyde (10 g, 80 mmol) in tetrahydrofuran (370 ml) was added tert-butyl 2-(triphenylphosphoranylidene)acetate (27.6 g, 73.3 mmol) in 1 g portions over 30 minutes. Upon final addition, the mixture was heated to reflux for 10 minutes. The solvent was removed under reduced pressure. The white waxy residue was triturated with pentane (x2). The pentane extracts were combined and evaporated under reduced pressure. The residue was purified by filtration through a plug of silica gel using an eluent of diethyl ether:hexane (1:2) to afford the title compound as a colorless oil, 16.2 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:22]=[C:21]3[C:13]([C:14]4[C:15](B5OC(C)(C)C(C)(C)O5)=[CH:16][CH:17]=[C:18]([C:23]([NH2:25])=[O:24])[C:19]=4[NH:20]3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH:38]=[CH:39][CH:40]=[C:41]2[NH2:46].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[NH2:46][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH:43]=[CH:44][CH:45]=[C:36]2[C:15]1[C:14]2[C:13]3[C:21](=[CH:22][C:10]([C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[O:9])=[CH:11][CH:12]=3)[NH:20][C:19]=2[C:18]([C:23]([NH2:25])=[O:24])=[CH:17][CH:16]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(B4OC(C)(C)C(C)(C)O4)c23)CC1
Reactant: Nc1cccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c(N)cccc45)c23)CC1
Temperature: 90 °C
Yield: 42 %

Procedure:
Step 2 A mixture of 7-(4-methylpiperazine-1-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (the crude product prepared according to Step 1, 40 mg, 0.065 mmol), 5-bromonaphthalen-1-amine (21.61 mg, 0.097 mmol), and potassium carbonate (13.45 mg, 0.097 mmol) in toluene (1.5 mL) and ethanol (0.75 mL) was treated with [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) DCM complex (5.3 mg, 0.007 mmol) and purged with argon for ca. 5 min. The mixture was heated at 90° C. for 19 h, then was cooled to rt and concentrated. The residue was purified by preparative HPLC, then was partitioned between EtOAc and NaHCO3 (aq), the aqueous phase was extracted again with EtOAc, and the combined organic phases were dried and concentrated to provide 4-(5-aminonaphthalen-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a light yellow solid (13.1 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H) 8.22-8.27 (m, 2H) 8.07 (d, J=7.7 Hz, 1H) 7.73 (s, 1H) 7.55 (br. s., 1H) 7.52 (dd, J=8.6, 6.8 Hz, 1H) 7.42 (dd, J=6.9, 1.0 Hz, 1H) 7.09 (d, J=7.7 Hz, 1H) 6.96 (dd, J=8.2, 7.6 Hz, 1H) 6.64-6.70 (m, 2H) 6.49 (d, J=8.3 Hz, 1H) 6.38 (d, J=8.1 Hz, 1H) 5.85 (s, 2H) 3.48-3.59 (m, 4H) 2.17-2.37 (m, 4H) 2.14 (s, 3H). Mass spec m/z 478.10 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].Cl[C:11]1[CH:31]=[CH:30][CH:29]=[C:28](C)[C:12]=1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=2)[C:16]([CH3:27])=[N:15]1>>[CH3:9][C:4]1[C:3]([CH2:2][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=3)[C:16]([CH3:27])=[N:15]2)=[C:7]([CH3:8])[O:6][N:5]=1.[CH2:13]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=2)[CH:16]=[CH:27]1)[C:12]1[CH:11]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Product: Cc1noc(C)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1

Procedure:
The titled compound (16.5 mg) as a white solid was prepared from the compound [102-4] obtained in the process (4) of Example 102 (21.0 mg) and 4-(chloromethyl)-3,5-dimethylisoxazole according to the method of the process (5) of Example 102.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].[Br:13]Br>CC(O)=O.C(OCC)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:13])[C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(Cl)cc1N
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a solution of 2-Amino-4-chloro-benzoic acid methyl ester (1.85 g, 10.0 mmole) in HOAc (20.0 ml) was injected bromine (0.512 ml, 10.0 mmole) dropwise. The reaction was stirred at room temperature for an hour. The mixture was diluted with ethyl ether (200 ml) and then the solvents were decanted. The residue was partitioned between ethyl acetate (200 ml) and 0.100N NaOH(aq) (200 ml). After separated the two layers, the organic layer was dried over Na2SO4, filtered and concentrated to provide the crude product (2.08 g, 78%), which was used directly for the next step without further purification. MS (ES+): 264, 266 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1.CCCCCC>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (7.15 g) [CAS No. 59942-88-0] in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and then a solution of n-butyllithium in hexane (1.6 M; 46 mL) was added dropwise and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise at −78° C., and stirring was continued for 1 hour. After increasing the temperature of the reaction mixture to room temperature and adding water, extraction was performed with ethyl acetate and the extract washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (7.1 g) was obtained from the n-hexane:ethyl acetate (50:1) fraction as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.C(Cl)Cl.CS(C)=O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccccc1)c1ccc2occc2c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc2occc2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanol (4.0 g, 18 mmol) and triethylamine (7.3 mL, 54 mmol) in 30 mL 1:1 DCM/DMSO under nitrogen at 0° C. was added a solution of SO3*py (8.5 g, 54 mmol) in 20 mL DMSO dropwise via addition funnel. The reaction was allowed to stir 5 h at 0° C. and was quenched by addition of water and 250 mL Et2O. The organic layer was washed with water, 1N HCl, 1N NaOH, brine, and was dried over sodium sulfate, filtered, and concentrated. The resulting solid benzofuran-5-yl(phenyl)methanone was used without further purification. MS (ESI) m/z: Calculated: 222.1; Observed: 223.0 (M++1).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[C:16]([OH:17])=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:17][C:16]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(-c2nc3ncccc3cc2O)cc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccc(C)cc3)c2cc1OC
Temperature: 130 °C
Reaction time: 14.5 h
Yield: 19.5 %

Procedure:
2-p-Toluyl-[1,8]naphthyridin-3-ol (2 mg), 4-chloro-6,7-dimethoxyquinoline (6 mg), and 4-dimethylaminopyridine (3 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 130° C. for 14.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (0.7 mg, yield 20%).