Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH2:26][OH:27])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO[Si](C)(C)C(C)(C)C)nc(N)n2)CC1
Agent: [H+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[7-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (150 mg, 0.27 mmol) in 1,4-dioxane (3 mL) was added 1.7 M of fluorosilicic acid in water (480 uL). The reaction mixture was stirred at r.t. for 2 h., and then concentrated to remove dioxane. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS(M+H)+: m/z=433.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(N(Cc2ccccc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-iodophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and benzyl bromide (0.039 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:ethyl acetate/hexane=1/15) to obtain N-benzyl-N-(4-iodophenyl)pyrimidin-2-amine (67 mg).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:31]=[CH:30][C:23]([CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Cc2nnn[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(Cc3nnn[nH]3)cc2)cc1
Temperature: 130 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 5-(4-bromobenzyl)-1H-tetrazole (53.2 mg, 0.223 mmol), Na2CO3 (79 mg, 0.742 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.313 mg, 1.855 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 130° C. for 120 min. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z=348.1 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.5 Hz, 0.4H), 1.46 (d, J=6.6 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.02-2.11 (m, 2H), 2.22-2.33 (m, 1H), 3.05-3.21 (m, 4H), 3.36-3.48 (m, 1H), 3.52-3.62 (m, 1H), 3.72-3.83 (m, 1H), 4.36 (s, 2H), 7.36-7.44 (m, 4H), 7.61-7.67 (m, 4H).
Reaction SMILES: C1(C)C=CC=CC=1.O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[CH2:29]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>N1C=CC=CC=1>[CH2:29]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:44][C:18]2([C:21]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[O:22])[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=3)=[CH:16][CH2:17]2)=[O:43])=[CH:45][CH:46]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCCCCCOc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCCCCCCOc1ccc(C(=O)OC2(C(=O)OCC(C)CC)C=CC(c3ccccc3)=CC2)cc1
Reaction time: 8 h
Yield: 45 %

Procedure:
A toluene solution containing 10 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate and 3 g of pyridine was added dropwise to the above-described toluene solution of the acid chloride compound. After conclusion of dropping, the temperature was raised, and reaction was carried out for 8 hours at 50° C. After conclusion of the reaction, the product was washed with water and dried over magnesium sulfate, and the dried product was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 8.2 g of the objective ester compound. (Yield: 45%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[N+:10](/[C:13](/[CH3:14])=[CH:5]/[C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: C/C(=C\c1cccc(O)c1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (20 g, 0.16 mol) in acetic acid (40 mL) was added nitro ethane (32 mL, 0.45 mol) and ammonium acetate (8 g, 0.1 mol). The resulting mixture was stirred at 80° C. for 6 hours. The reaction mixture was poured into a solution of 400 mL of water and the precipitate was collected by filtration to obtain the title compound as a solid (23.68 g, 81%). MS (M+): 180.
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:16]([O:20][C:21]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCC(=O)N1CCCCC1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a stirred, cooled (0° C.) solution of 14.3 grams (61.4 mmol) of tridecanoyl chloride in 50 mL of methylene chloride was added 7.49 grams (61.3 mmol) of N,N-dimethylaminopyridine. The resulting suspension was stirred for 10 minutes and then 11.0 grams (51.3 mmol) of 2-[N-(tert-butoxycarbonyl)aminomethyl]piperidine in 50 mL of methylene chloride was added. The mixture was allowed to warm to room temperature while stirring overnight and poured into water. The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with brine and dried over MgSO4. Solvent was removed at reduced pressure and the crude product was chromatographed on 250 grams of silica gel eluting with 25% ethyl acetate in hexane to provide 20.9 grams (99%) of N-(tert-butoxycarbonyl)-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)amine as a viscous orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[NH2:29][CH2:30][CH2:31][OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:29][CH2:30][CH2:31][OH:32])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NCCO
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NCCO)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-aminoethanol. 1H NMR (400 MHz, CDCl3) δ ppm 3.10 (s, 3H) 3.39 (s, 3H) 3.53-3.57 (m, 2H) 3.78-3.81 (m, 2H) 6.81 (t, J=8.0 Hz, 1H) 7.47-7.52 (m, 2H) [M+H] calc'd for C15H16FIN4O4, 463. found, 463.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][O:29][CH2:30][CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[CH3:37].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:15]([NH:14][C:11]1[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]4[CH2:34][CH2:33][N:32]([CH3:37])[CH:31]([CH2:30][O:29][CH3:28])[CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=1)[CH2:16][CH2:17]2
Reactant: COCC1CNCCN1C
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(NC2CCc4cccc(OC)c42)=N3)CCN1C
Yield: 33 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55, step A) (328 mg, 0.85 mmol), commercially available rac-2-methoxymethyl-1-methyl-piperazine (CAS no. 734507-92-7) (123 mg, 0.85 mmol) and diisopropylethyl amine (723 ul, 4.25 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (137 mg, 33%), MS (ISP) m/e=494.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:42])=[CH:44][CH:45]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1nccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-aminothiazole to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide was obtained (46%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, CDCl3) δ12.63 (s, 1H), 8.11-8.05 (m, 2H), 7.57-7.47 (m, 3H), 7.31-7.18 (m, 3H), 7.08-6.98 (m, 2H), 6.49 (s, 1H), 6.44 (s, 1H), 5.12-4.96 (m, 2H), 4.82 (ABq, 2H), 4.58-4.43 (m, 2H), 3.08-2.89 (m, 2H); MS (ES+) m/z 496.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:23]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1cccc(-c2ccccc2F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3F)c2)CC1

Procedure:
164 mg of the target compound (0.44 mmol, 87.1%) was obtained using 1-(2-methoxyphenyl)piperazine (192 mg, 1.00 mmol), 2′-fluorobiphenyl-3-carbaldehyde (100 mg, 0.50 mmol) and NaBH(OAc)3 (322 mg, 1.50 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH:17]=[CH2:18].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C=CCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of sodium hydride (14.8 g, 60% dispersion in mineral oil) in dimethylformamide (DMF, 150 ml) at 0° C. under nitrogen was added a solution of 3,4-dichlorophenylacetonitrile (68.9 g, 1 mol. equivalent) in DMF (300 ml) and the mixture was stirred for 3 hours. A solution of 4-bromobut-1-ene (50 g, 1 mol. eq.) in DMF (100 ml) was then added, and the mixture was stirred at room temperature for one hour, then heated to 60° C. for 5 hours. The reaction mixture was cooled and water (1 liter) was added. The mixture was then extracted with ethyl acetate (2×500 ml). The combined organic extracts were then washed with water (2×1 liter), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was then purified by column chromatography using silica gel, eluting with a solvent gradient of ethyl acetate:hexane (1:19 to 1:6, by volume) to give the title compound (51.5 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C>[CH:1]([NH:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccnc(N)n1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COC(=O)Cc1ccnc(NC=O)n1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of acetic anhydride (32.7 g.) and formic acid (16.2 g.) was stirred at 50° to 60° C. for 30 minutes. The solution was added to a suspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) in ethyl acetate (300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours. After removing the insoluble substance by filtration, water (300 ml.) was added to the filtrate, and then the mixture was adjusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal, and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103° to 107° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Br
Yield: 95 %

Procedure:
A solution of 4-Bromo-3-nitrophenol (1.0 g, 4.6 mmol) and benzyl bromide (0.82 mL, 7 mmol) in acetonitrile (30 mL) and acetone (15 mL) was treated with K2CO3 (970 mg, 7 mmol). The resulting mixture was heated at reflux under nitrogen for 17 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in 40 mL ethyl acetate. The solution was filtered under vacuum then the filtrate was washed successively with distilled water (30 mL ), 1M HCl solution (30 mL×3), brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 100 g of silica gel using 3:1 mixture respectively of hexanes and ethyl acetate to give the benzyl alcohol in 95% yield; 1H NMR(CDCl3) δ5.11(2H, s), 7.02(1 H, dd, J1=2.9, J2=8.9), 7.41(5H, m), 7.46(1 H, d, J=2.9), 7.60(1H, d, J=8.9); 13C NMR(CDCl3) δ71.4, 105.4, 112.4, 121.1, 128.1, 128.9, 129.1, 129.3, 129.5, 135.8, 136.0, 138.2, 158.7; HRMS calcd for C13H10NO3Br: 306.9844; found: 306.9846.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24][N:23]([C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CNCC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CNCC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 34 %

Procedure:
A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15.5 mg, 0.1 mmol), [4-(4-chlorophenyl)-piperidin-4-ylmethyl]-methylamine bis-hydrochloride (34 mg, 0.11 mmol) and triethylamine (150 μL, 0.7 mmol) in n-butanol (1 ml) was heated at 100° C. in a microwave reactor for 60 minutes. After cooling the reaction the solvents were concentrated. Purification on SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, followed by further purification by flash column chromatography on silica, eluting with 15% methanol in dichloromethane, gave [4-(4-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-methylamine (12.3 mg, 0.034 mmol, 34%). LC-MS (LCT2) m/z 356 [M+H+], Rt 2.64 min.
Reaction SMILES: [Cu][C:2]#[N:3].N1C=CC=CC=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:23]3=[O:29])[S:20][CH:21]=2)=[C:13]([F:30])[CH:12]=1>CC(N(C)C)=O.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>[CH3:27][C:26]1([CH3:28])[CH2:25][O:24][C:23](=[O:29])[N:22]1[C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:2]#[N:3])=[CH:12][C:13]=2[F:30])[N:18]=1
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2F)cs1
Yield: 116.6 %

Procedure:
Copper (I) cyanide (0.09 g, 1.0 mmol) and pyridine (0.17 mL, 1.6 mmol) were added under a nitrogen atmosphere to a solution of 3-[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]-4,4-dimethyl-1,3-oxazolidin-2-one (0.4 g, 1.0 mmol), prepared in step 7 of Example 78, and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) in dimethylacetamide. The reaction solution was sealed and placed in a microwave reactor (200° C./1 h). LC/MS indicated the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified on silica gel using a stepwise gradient of 1-3% methanol:methylene chloride to give the title compound (370 mg, 55%) as a yellow solid, mp 237° C. (dec.).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.C([O-])([O-])=O.[K+].[K+].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=1)=[O:26].O>CS(C)=O>[CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[N:8]3[C:30]1[CH:31]=[CH:32][C:27]([C:25](=[O:26])[CH3:24])=[CH:28][CH:29]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(-n2c3ccccc3c3ccc4ccccc4c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 11H-benzo[a]carbazole (2.00 g, 9.22 mmol) in DMSO (20 mL) is added K2CO3 (3.85 g, 27.9 mmol) at 180° C., and then the mixture is stirred for 1 hour. To the mixture is added 4-fluoroacetophenone (1.28 g, 9.228 mmol). After stirring for 8 hours, the reaction mixture is cooled to room temperature, and poured into water. The crude product is extracted with ethyl acetate, and it is washed with water and brine. The organic layer is dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (160 mg; 5%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 2.75 (s), 7.20 (d), 7.23 (t), 7.34-7.46 (m), 7.65 (d), 7.75 (d), 8.00 (d), 8.19 (d), 8.22 (d), 8.25 (d).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([OH:15])[C@@H:8]([CH2:16][O:17]C(=O)C)[O:7][C@H:6]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[C:23]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[CH:22]=1)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([CH2:16][OH:17])[O:7]2)=[CH:22][C:23]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC)c2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of acetate 74-5 (2.5 g, 4.12 mmol) in MeOH (40 mL) was added NaOMe (25 wt % in MeOH, 0.75 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was carried on to the next step without purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(OC(N1CCN(C2[C:50]3[C:45](=[CH:46][C:47](F)=[C:48](F)[CH:49]=3)[N:44]=CN=2)CC1)=O)(C)(C)C>>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[N:11]1[CH2:12][CH2:13][N:8]([C:6]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([O:24][C:21]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[CH:49][CH:50]=2)=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: COc1cc2nccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Product: COc1cc2nccc(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2cc1OC
Yield: 57 %

Procedure:
Substantially the same procedure as in Example 329 was repeated, except that 4-(6,7-dimethoxy-4-quinolyl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 17 was used in place of 4-(6,7-difluoro-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester, to give the desired compound.