Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])=[O:15])[CH:3]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: O=C(O)c1cc(Br)c2cccc(F)c2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2cccc(F)c2n1
Reaction time: 17 h

Procedure:
To a solution of 4-bromo-8-fluoroquinoline-2-carboxylic acid (C6) (1.34 g, 4.96 mmol) in dichloromethane (20 mL) was added (1S,2S)-2-aminocyclohexanol (0.857 g, 7.44 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.63 g, 5.95 mmol), and triethylamine (1.04 mL, 7.44 mmol). After 17 h, the mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate (1×) and brine (1×), dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-3% methanol in dichloromethane to provide 4-bromo-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (C7) that gave a mass ion (ES+) of 368.8 (81Br) for M+H+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:27][CH:28]=1)=[O:3])[CH3:6]
Reactant: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc(N)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C(=O)c2cccn2COCC[Si](C)(C)C)cc1
Reaction time: 1.75 h
Yield: 94.5 %

Procedure:
Ethyl chloroformate (0.21 g, 1.95 mM) was added dropwise to a stirred solution of 2-(4-aminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole (0.5 g. 1.58 mM) in pyridine (5 ml) at 5° C. After 5 minutes the cooling bath was removed and stirring continued for 1.75 hours. The mixture was treated with MeOH (2 ml) and evaporated and the residue partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was washed with water, aqueous citric acid, dried (MgSO4) and evaporated. to give 2-(4-ethoxycarbonylaminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole as an oil (0.58 g). MS: 389 (MH+). NMR: 0.0 (9H, s); 0.89 (2H, t); 1.38 (3H, t) 3.57 (2H, t); 4.28 (2H, q); 5.8 (2H, s); 6.34 (1H, m); 6.82 (1H, m); 7.50 (1H, m); 7.7 (2H, d); 7.83 (2H, d); 10.1 (1H, br s).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:32])[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(F)c1
Yield: 73 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.3 mL), 3-fluorocinnamic acid (2.7 g), WSC.HCl (3.2 g), and methylene chloride (100 mL), to give the captioned compound (4.2 g, 74%) as an oily product.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:16]=[N:17][C:5]=2[C:4](=[O:18])[O:3]1.[H-].[Na+].[Cl:21][C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH2:24]Cl>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH2:24][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:7]2[C:6]3[CH:2]([CH3:1])[O:3][C:4](=[O:18])[C:5]=3[N:17]=[CH:16][C:8]1=2
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: CC1OC(=O)c2ncc3[nH]c4ccccc4c3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1OC(=O)c2ncc3c(c21)c1ccccc1n3Cc1cc(Cl)ccc1Cl
Yield: 33.1 %

Procedure:
6-(2,5-Dichlorobenzyl)-1-methyl-1,6-dihydro-3H-furo[3′,4′:5,6]pyrido[3,4-b]indol-3-one was prepared using Method A from 1-methyl-1,6-dihydro-3H-furo[3′,4′:5,6]pyrido[3,4-b]indol-3-one (9 mg, 0.038 mmol), NaH (0.046 mmol, 2 mg of 60 wt. % suspension in mineral oil) and 2,5-dichlorobenzyl chloride (9 mg, 0.046 mmol) in DMF (1 mL). Purification of the crude product by preparative thin layer chromatography with hexane/ether (2:1) as eluent furnished the desired product (5 mg, 33% yield) as a yellow solid. 1H NMR (CDCl3) δ8.93 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.37-7.46 (m, 3H), 7.16 (d,J=2.2 Hz, 1H), 6.42 (d,J=2.2 Hz, 1H), 6.05 (q,J=6.6 Hz, 1H), 5.70 (s, 2H), 1.92 (d,J=6.6 Hz, 3H); MS (APCI; (M+H)+) m/z 397.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[N:32]1[C:41]2[C:36](=[CH:37][C:38](B(O)O)=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(=O)(O)[O-]>CN(C)C=O.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>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:32]=[CH:33][CH:34]=[CH:35]4)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4ncccc4c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and quinoline-6-boronic acid (91 mg, 0.527 mmol) in N,N-dimethylformamide (2.63 mL) was added saturated aqueous bicarbonate solution (880 μL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 16 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 571.1 [M+H]+.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:18][C:19]1[C:24](I)=[N:23][CH:22]=[CH:21][N:20]=1>CC(N(C)C)=O.[Zn].[Cu]I>[F:18][C:19]1[C:24]([CH:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: Fc1nccnc1I
Reactant: IC1CCCOCC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Fc1nccnc1C1CCCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of chlorotrimethylsilane (0.11 mL, 0.87 mmol) and 1,2 dibromoethane (0.075 mL, 0.87 mmol) was added slowly to a stirred mixture of zinc dust (0.71 g, 10.9 mmol) in DMA (2 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 15 min before a solution of 4-iodooxepane (1.97 g, 8.71 mmol) in DMA (5 mL) was added dropwise via syringe. The reaction mixture was stirred at room temperature for an additional 30 min before being warmed to 60° C. for 15 min. The reaction mixture was cooled to room temperature and added directly via syringe to a stirred mixture of 2-fluoro-3-iodopyrazine (1.39 g, 6.23 mmol), copper(i) iodide (0.12 g, 0.62 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(ii) (0.25 g, 0.31 mmol) in DMA (8 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with sat. ammonium chloride, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 2-fluoro-3-(oxepan-4-yl)pyrazine. [M+1]=197.1.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C@@:30]21[CH2:48][C:40]1=[N:41][CH:42]=[C:43]([C:45]([OH:47])=O)[CH:44]=[C:39]1[CH2:38]2.Cl.[NH2:50][C@H:51]1[CH2:56][C@@H:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:54]([CH3:63])[N:53]([CH2:64][C:65]([F:68])([F:67])[F:66])[C:52]1=[O:69].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:63][C@H:54]1[N:53]([CH2:64][C:65]([F:68])([F:66])[F:67])[C:52](=[O:69])[C@@H:51]([NH:50][C:45]([C:43]2[CH:44]=[C:39]3[CH2:38][C@@:30]4([C:31]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:37][C:29]4=[O:28])[CH2:48][C:40]3=[N:41][CH:42]=2)=[O:47])[CH2:56][C@H:55]1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 23 °C
Reaction time: 3 h

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.89 g, 4.28 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (1.10 g, 3.92 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 4) (1.15 g, 3.56 mmol), and N,N-diisopropylethylamine (3.11 mL, 17.8 mmol) in DMF (40 mL), and the resulting mixture was stirred at 23° C. for 3 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl actetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with hexanes initially, then grading to 100% EtOAc before stepping to 5% MeOH in EtOAc to afford the title compound as an amorphous solid, which was further purified by the following crystallization procedure. A solution of the amorphous product in a minimal amount of methanol required for dissolution was diluted with 10 volumes water, and the resulting slurry was seeded with crystalline product and stirred at 23° C. for 4 h. The solids were filtered, washed with water, and dried under a stream of nitrogen to give the title compound as a crystalline solid. HRMS: m/z=550.2068, calculated m/z=550.2061 for C29H27F3N5O3. 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.70 (s, 1H), 8.17 (dd, 1H, J=5.4, 1.5 Hz), 8.04 (s, 1H), 7.37 (m, 3H), 7.29 (t, 1H, J=7.3 Hz), 7.21 (d, 2H, J=7.3 Hz), 7.13 (dd, 1H, J=7.3, 1.2 Hz), 6.89 (dd, 1H, J=7.3, 5.4 Hz), 4.99-4.90 (m, 1H), 4.53 (dt, 1H, J=10.7, 6.6 Hz), 3.94 (p, 1H, J=5.9 Hz), 3.78 (d, 1H, J=17.1 Hz), 3.67 (d, 1H, J=16.4 Hz), 3.65 (m, 1H), 3.34-3.26 (m, 1H), 3.28 (d, 1H, J=17.1 Hz), 3.17 (d, 1H, J=16.6 Hz), 2.79 (m, 1H), 2.58 (q, 1H, J=12.7 Hz), 1.07 (d, 3H, J=6.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([S:25][C:26]1[C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=3[S:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CCCCCSc1ncccc1C(=O)Cl
Product: CCCCCSc1ncccc1C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-(n-pentylthio)pyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(pentylsulfanyl)nicotinamide as a tan powder, m.p. 158.0-161.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.47-8.41 (m, 2H), 8.21 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=7.6, 1.8 Hz, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 1H), 7.08 (dd, J=7.5, 4.8 Hz, 1H), 6.57 (broad s, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.27 (m, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.96 (m, 2H), 1.62-1.46 (m, 4H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.1 Hz, 3H); MS (EI) m/e 462.2196 (462.2202 calcd for C25H3oN6OS).
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C=O)C>[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)OC(C)Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)NC)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl ethyl carbonate (1.67 g, 11.0 mmol) was added dropwise at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-methylaminocarbonyl)-2,4,6-triiodobenzenecarboxylate (6.52 g, 10.0 mmol) and sodium iodide (150 Mg, 1.0 mmol) in dry DMF (50 ml). After stirring at 50° C. for 24 hours the solvent was removed at reduced pressure. The residue was dissolved in chloroform and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate and filtration, the solvent was removed at reduced pressure to give the title compound. Yield: (2.2 g, 38%). Purity by HPLC: 98%. 1H-NMR (DMSO-d6 ): delta=1.24 (t, J=7 Hz, CH3); 1.63 (d, J=6 Hz, CH3); 2.03 (s, CH3CO); 2.75 (d, J=3 Hz, NCH3); 4.21 (q, J=7 Hz, CH2): 6.93 (q, J=6 Hz, CH); 8.4-8.7 (m, NHMe); 10.03 ppm (s, NHAc).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:36])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)(=O)C.Br>[C:30]1([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[O:36])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Yield: 62 %

Procedure:
12.5 g (26 mmol) of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethyl-piperazinyl)ethanone and 2.8 g (26 mmol) of anisole were dissolved in a mixture of 37.5 ml of acetic acid and 12.5 ml of 47% hydrobromic acid. The resultant mixture was heated to reflux for 1 hour. After being cooled to room temperautre, the reaction mixture was washed with 200 ml of ether and then with 50 ml of ether to remove acetic acid. The resultant solution was neutralized with an aqueous 2N solution of sodium hydroxide. Separated organic substances were extracted with 120 ml of ethyl acetate and then washed with saturated saline. The ethyl acetate solution was dried over anhydrous sodium sulfate and then concentrated. The residue was taken up in 60 ml of isopropanol and allowed to stand at room temperature to give 6.28 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone (yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a mixture of 2-fluoro-5-methoxy-4-nitrobenzoic acid (53.8 g, 250 mmol), 1-methylpiperidin-4-amine (31.4 g, 275 mmol), DIEA (134 mL, 750 mmol) in 1 L of DCM at 0° C. was added HATU (114 g, 300 mmol) in four batches. The reaction mixture was stirred at room temp. for 16 h. After which, it was concentrated and diluted to IL of a mixture of MeOH in water (5%). The suspension was stirred vigorously for 2 h until seen a suspension of fine powder. The solid was filtered, washed with more water and dried to give 55 g of light yellow product. The filtrate was extracted with EtOAc, concentrated and re-suspended in water (5% of MeOH) and repeating the same procedure as above, after which another batch of solid was obtained (total 67 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (m, 2H) 1.81 (m, 2H) 2.04 (m, 2H) 2.19 (s, 3H) 2.77 (d, J=8 Hz, 2H) 3.73 (m, 1H) 3.94 (s, 3H) 7.42 (d, J=5.6 Hz, 1H) 7.98 (d, J=8.8 Hz, 1H) 8.51 (d, J=7.6 Hz, 1H). [M+H] calc'd for C14H18FN3O4, 312. found 312.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.Br[C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:1][C:20]4[CH:25]=[N:24][C:23]([O:26][CH3:27])=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[CH:21]=4)[N:3]=[CH:4][C:5]=3[CH2:6][C:7](=[O:18])[NH:8][C:9]=2[CH:16]=1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Reactant: COc1ncc(Br)cc1CCCN(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COc1ncc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1CCCN(C)C
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 2-amino-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.36 g, 1.38 mmol), 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropan-1-amine (0.38 g, 1.38 mmol), xphos (0.047 g, 0.099 mmol), and tris(dibenzyllideneacetone)dipalladium(0) (0.023 g, 0.026 mmol) in a sealed microwave tube was evacuated and purged with nitrogen three times. To the solids were added tert-butyl alcohol (3.6 mL) and t-BuOK (1M in t-BuOH, 2.63 mL) via syringe. The mixture was stirred well and then subjected to microwave irradiation (150 watts) while heating at 150° C. for 45 min. The reaction mixture was then poured into water (25 mL) with vigorous stirring. The precipitate that formed was filtered, washed with water, and air dried. The residue was purified by column chromatography to give 9-chloro-2-({5-[3-(dimethylamino)propyl]-6-methoxypyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.125 g, 18%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:15])=[C:7]([C:10]([CH3:14])=[CH:11][C:12]=1[CH3:13])[CH:8]=O.[CH3:16][C:17]([CH3:19])=[O:18]>O>[CH3:3][O:4][C:5]1[C:6]([CH3:15])=[C:7]([CH:8]=[CH:16][C:17](=[O:18])[CH3:19])[C:10]([CH3:14])=[CH:11][C:12]=1[CH3:13]
Reactant: COc1c(C)cc(C)c(C=O)c1C
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cc(C)c(C=CC(C)=O)c1C
Temperature: 65 °C
Reaction time: 4 h

Procedure:
An aqueous solution of 2% sodium hydroxide (16.5 ml) was added dropwise over a period of 5 minutes to a suspension of 3-methoxy-2,4,6-trimethylbenzaldehyde (23.5 g) in acetone (21.3 g) and water (13 ml). The mixture was stirred at a temperature of 65° C. for a period of 4 hours and then extracted with dichloromethane. The organic extract was washed several times with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The product, 1-(3-methoxy-2,4,6-trimethylphenyl)but-1-en-3-one, was obtained as a viscous oil (28.0 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.25 (6H, s); 2.36 (3H, s); 3.67 (3H, s); 6.27 (1H, d); 7.16 (1H, s); 7.61 (1H, d).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10](=O)[CH3:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br.[CH2:14]([S:20][C:21](=[NH:23])[NH2:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:14]([S:20][C:21]1[N:23]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:9]=[C:10]([CH3:11])[N:22]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)C#CCN1CCOCC1
Reactant: CCCCCCSC(=N)N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCSc1nc(C)cc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Morpholin-4-yl-pent-3-yn-2-one (1 g, 6 mmol) and 2-hexyl-isothiourea hydrobromide (1.06 g, 7 mmol) were dissolved under nitrogen in DMF (10 mL), then N,N-diisopropyl ethylamine (4.1 mL, 24 mmol) was added and stirring at the room temperature continued for 18 hours.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[O-:22][CH2:23][CH3:24].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1
Reactant: CC[O-]
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.31 g, 1.0 mmol) in ethanol (1.5 ml) was added sodium ethoxide (1M in ethanol, 1.5 ml) and the mixture was stirred at 60° for 1 hour. The resulting solution was allowed to cool, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 1 hour at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1), the solution was filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (6:1) to afford 2-amino-6-ethoxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (0.24 g, 85%), m.p. 150-152° C.; λmax (H2O) 213 (24,300), 249 (7,360), and 280 (9,270) nm; νmax (KBr) 3330, 3210, 2900, 1650, 1610, 1580 cm−1; δH [(CD3)2SO] 1.3-1.6 (4H, m, 3′-H and CH3), 1.73 (2H, q, J 7 Hz, 2′-H), 3.2-3.6 (4H, AB part of ABX, 2×4′-H), 4.04 (2H, t, J 7 Hz, 1′-H), 4.3-4.55 (4H, m, 2H D2O exchangeable, 2×OH; D2O exchange leaves 2H, q, J 7 Hz, 6-OCH2), 6.30 (2H, s, D2O exchangeable, 2-NH2), and 7.84 (1H, s, 8-H); (Found: C, 50.91; H, 7.00; N, 24.89%; C12H19N5O3 requires C, 51.23; H, 6.81; N, 24.90%).