Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(O)=O)CCCC(C(O)=O)C1.[C:13]([C:15]12[CH2:22][C:19]([NH:23][C:24]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)=[O:25])([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2)#[CH:14].Br[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1>C(#N)C.C(OCC)(=O)C.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>[CH3:39][C:35]1[N:34]=[C:33]([C:14]#[C:13][C:15]23[CH2:22][C:19]([NH:23][C:24]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)=[O:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)C1CCCC(C(=O)O)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cccc(C#CC23CCCC(NC(=O)c4cnccn4)(CC2)C3)n1
Temperature: 70 °C
Yield: 36.1 %

Procedure:
To a stirred mixture of intermediate 1, N-(5-ethynylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide (40 mg, 0.16 mmol) and 2-bromo-6-methylpyridine (30 mg, 0.18 mmol) in TEA (0.5 mL) and acetonitrile (2 mL) was added Pd(PPh3)4 (2 mg, 0.02 mmol), followed by an addition of CuI (4 mg, 0.02 mmol). After heated at 70° C. for three hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by Prep HPLC to afford 20 mg (36%) of the title compound, pyrazine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide, as a white solid. 1HNMR (500 MHz, CDCl3): δ 9.40 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 2.55-2.52 (m, 4H), 2.29-1.76 (m, 11H); ESI-MS m/z: 347 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:16])[CH:10]2[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pt]=O>[Cl:23][C:21]1[CH:22]=[C:17]([N:14]2[C:13](=[O:25])[CH:11]3[CH:10]([CH2:9][NH:8][CH2:12]3)[C:15]2=[O:16])[CH:18]=[C:19]([Cl:24])[CH:20]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1c1cc(Cl)cc(Cl)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C1C2CNCC2C(=O)N1c1cc(Cl)cc(Cl)c1
Yield: 100.5 %

Procedure:
A solution of 5-benzyl-2-(3,5-dichlorophenyl)-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (1.13 g, 3 mmol) in acetic acid (20 mL) was hydrogenated at atmospheric pressure over platinum oxide for 4 h. The catalyst was filtered off and the filtrate was poured into an ammonium hydroxide solution. The aqueous solution was extracted twice with methylene chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an oil (0.86 g) which was chromatographed over silica gel (CH2Cl2/MeOH/NH4OH: 90/9/1) to yield the above compound as a white solid (0.53 g). Mp=170° C. 1H NMR (DMSO-d6): 7.73 (1H, m), 7.47 (2H, m), 3.2-3.5 (4H, m), 2.8-2.9 (2H, m).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[O:24][C:25]4[C:30]3=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCN(C2CCCCC2)C1

Procedure:
Refluxing N-cyclohexyl-3-aminopyrrolidine with 9-acetoxyxanthene in dry toluene for 24 hours, then working up as in Example 1 gives N-(N-cyclohexyl-3-pyrrolidinyl)-9-xanthenylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:23]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([O:17][CH3:23])=[O:16])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1

Procedure:
3,5-Dinitro-4-hydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,5-dinitro-4-hydroxyphenyl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])=[CH:5][CH:4]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: COc1ccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(4-methoxy-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)[CH:7]=1.[CH2:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[CH2:35][CH2:36][CH3:37]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:41]3[CH:42]=[CH:43][C:38]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=3)=[CH:28][CH:27]=2)[CH:7]=1
Reactant: COC(=O)CNc1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1
Reactant: CCCCc1ccc(B(O)O)cc1
Product: CCCCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(NCC(=O)OC)c3)cc2)cc1

Procedure:
{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (55 mg, 0.1 mmol) was coupled with 4-n-butyl-phenylboronic acid (36 mg, 0.2 mmol) according to general procedure G to give {3-[2-(4′-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][OH:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][OH:47])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCCCCO)cc2)cc1

Procedure:
The product from Example 104A and 6-amino-1-hexanol processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-D) δ8.95 (s, 1 H), 7.73 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.87 (m, 4 H), 4.03 (d, 4 H), 3.35 (m, 2 H), 3.00 (dd, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.33 (t, 2 H), 1.37 (m, 4 H), 1.23 (m, 4 H); MS (APCI+) m/z 645 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:49]([N+:53]1[N:57]=[C:56]([CH3:58])[S:55][C:54]=1[CH3:59])[CH2:50][CH2:51][CH3:52]>>[CH2:49]([N:53]1[N:57]=[C:56]([CH3:58])[S:55]/[C:54]/1=[CH:59]\[C:4]([C:3]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=1[F:1])=[O:6])[CH2:50][CH2:51][CH3:52]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-fluoro-5-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.26-1.37 (m, 2 H) 1.72-1.79 (m, 2 H) 2.50 (s, 3 H) 4.19 (t, 2 H) 6.47 (s, 1 H) 7.50-7.58 (m, 1 H) 7.87-7.93 (m, 1 H) 8.09-8.12 (m, 1 H); MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:24](/[C@H:29]1[CH2:34][CH2:33][C@H:32]([CH:35]=O)[CH2:31][CH2:30]1)=[CH:25]\[CH2:26][CH2:27][CH3:28]>C(OCC)C>[CH3:2][O:3][CH:4]=[CH:35][C@H:32]1[CH2:31][CH2:30][C@H:29](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH3:28])[CH2:34][CH2:33]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC/C=C/[C@H]1CC[C@H](C=O)CC1
Agent: [Cl-]
Solvent: CCOCC
Product: CCC/C=C/[C@H]1CC[C@H](C=COC)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 21 g of anhydrous (methoxymethyl)triphenylphosphonium chloride in 100 ml of abs. diethyl ether is treated with 6.86 g of potassium tert.-butylate at 0° C. in a nitrogen atmosphere. The red suspension is stirred at 0° C. for 15 minutes and then treated dropwise at 5°-10° C. with a solution of 7.9 g of trans-4-(1E-pentenyl)cyclohexanecarboxaldehyde in 30 ml of diethyl ether. The mixture is stirred at room temperature for 4 hours, washed with 40 ml of ice-cold saturated sodium hydrogen carbonate solution and twice with 50 ml of water each time, dried over sodium sulphate, filtered and concentrated. The residue is dissolved in 100 ml of hexane and 40 ml of 80 percent aqueous methanol. The hexane phase is washed with 10 ml of 80 percent aqueous methanol and 20 ml of water, dried over sodium sulphate and concentrated. Distillation of the residue in a vacuum yields trans-1-(2-methoxy-vinyl)-4-(1E-pentenyl)cyclohexane as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=S)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([NH:23][NH2:24])=O.CS(C)=O>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[N:11]([CH:21]=[N:23][N:24]=2)[C:12]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=2[CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC=O
Reactant: CC(C)(C)OC(=O)N1CC(=S)Nc2cc(F)ccc2C1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of 8-fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (2.36 g, 7.97 mmol) in dry benzene (25 mL), was added formic acid hydrazide dissolved in 5 mL of dry DMSO (1.43 g, 23.91 mmol) at room temperature. The reaction mixture was heated at 80° C., using Dean-Stark apparatus for 18 h. After the completion of the reaction, as confirmed by TLC, distilled water (40 mL) was added and the crude compound was extracted with diethyl ether (3×40 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the crude compound which, was purified by column chromatography [silica gel, 1.5:8.5 Acetone:Pet. ether] to afford 9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester, (1.455 g, 60%) as a white solid.
Reaction SMILES: C(N1CCC(CCC(O)=O)CC1)(=N)N.NCC(N[C@H](C([NH:31][C@H:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)CC(=O)[O:23][C:24](C)([CH3:26])[CH3:25])=O.Cl.[NH+]1[CH:53]=[CH:52][CH:51]=CC=1>>[C:43]([O:42][C:40](=[O:41])[C@H:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:31])([CH3:46])([CH3:44])[CH3:45].[CH:24]([O:23][CH:52]([CH3:51])[CH3:53])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)CN)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: c1cc[nH+]cc1
Agent: Cl
Agent: N=C(N)N1CCC(CCC(=O)O)CC1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: CC(C)OC(C)C

Procedure:
Analogously to Example 1B)e), by coupling 1.6 g of 1-amidino-4-piperidinepropionic acid with 1.8 g of H-Gly-Asp(OtBu)-Phe-OtBu in the presence of 928 mg of pyridinium hydrochloride there are obtained 2.1 g of N-[N-[N-[3-(1-amidino-4-piperidinyl)propionyl]glycyl]-3-t-butoxycarbonyl)-L-alanyl]-3-phenyl-L-alanine t-butyl ester, m.p. 104°-106° C. (diisopropyl ether; decomposition).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[C:12](=O)(O)[O-].[Na+].COS(OC)(=O)=O>C(OCC)(=O)C>[CH3:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
1,2,3,4-Tetrahydroquinoline (6.66 g, 50 mmol) was added to 40 ml of water, 40 ml of ethyl acetate, and 5.04 g (60 mmol) of sodium bicarbonate to which was added 5.68 ml (60 mmol) of dimethylsulfate dropwise. The reaction was stirred at room temperature for 21/2 hours, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, then the organic layers were combined and evaporated to give 4.56 g (62% yield) of the title compound. NMR (CDCl3) δ 1.93 (quintet, 2, CH2), 2.74 (tr, 2, CH2), 2.81 (s, 3, NMe), 3.17 (tr, 2, CH2), 6.55 (m, 2, Ar), 6.97 (m, 2, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH:29]([NH:33][CH3:34])[CH2:30]2)=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:30]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2ccc(OC)cc2C1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(N(C)CCCN1CCc3cc(OC)c(OC)cc3CC1=O)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 7-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 189°-190° C. (decomp.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1>CN(C=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Compound 7 (215 mg, 0.81 mmol, 1 equiv) was dissolved in DMF (5 mL) and cooled to 0° C. under N2. Sodium hydride, 60% dispersion (36 mg, 0.89 mmol, 1.1 equiv), followed by 4-fluoro-2-(trifluoromethyl)benzaldehyde (312 mg, 1.63 mmol, 2 equiv) were added and the entire reaction mixture was heated to 70° C. for 3 days. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chomatography (10% EtOAc in hexanes) to provide 20 (308 mg, 87%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J=9.1 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.32-7.10 (m, 7H), 6.95 (dd, J=8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 2.20 (s, 3H). MS m/z 473.3 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[ClH:8].Cl.[CH3:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:19]1[CH2:23][CH2:22][CH2:21][N:20]=1>>[ClH:8].[CH3:10][C:11]1[C:16]([NH:17][C:5](=[O:7])[CH3:6])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:19]1[CH2:23][CH2:22][CH2:21][N:20]=1
Reactant: Cc1c(N)cccc1NC1=NCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1cccc(NC2=NCCC2)c1C

Procedure:
The title compound (2.5 g) was prepared by the method of Example 17 using acetic anhydride and 3.0 g of the product aniline of Example 45. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][C:25]([O:27][CH3:37])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(SCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylthio]acetic acid (88.8 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NCC)C.Br[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)/[CH:18]=[CH:19]\[C:20]([O:22][CH3:23])=[O:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]1(/[C:18](/[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19]\[C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:15][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)/C=C\c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: COC(=O)/C=C(/C#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.158 g of cuprous iodide and 0.424 g of phenylacetylene were added to 25 ml of a diethylamine solution containing 1.000 g of methyl (Z)-3-bromocinnamate and 0.029 g of bis(triphenylphosphine)dichloropalladium. The mixture was then stirred for 1 hour at room temperature, after which the solvent was distilled off under reduced pressure. Water was added to the residue, and the resulting mixture was extracted twice with benzene. The combined benzene extracts were washed with water, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel (70-230 Tyler mesh, 25 g). Those fractions eluted with a 39:1 by volume mixture of hexane and ethyl acetate were collected to afford 1.043 g of the title compound, melting at 73°-75° C. (after recrystallisation from hexane).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.CCN(CC)CC.[N+:15]1([O-])[C:16](=[CH:20][CH:21]=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])C(O)=O>C(Cl)(Cl)(Cl)Cl>[OH:3][C:16]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][N:15]=1
Reactant: O=C(O)c1ccc(C(=O)O)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(O)nc1
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
20.4 g of acetic acid anhydride (0.2 mole), 20.2 g of Et3N (0.2 mole) and 50 ml of CCl4 were put up in a flask. 18.3 g of isocinchomeronic acid-N-oxide (0.1 mole) was added by portions to this solution. The temperature rose to 50° C. After completion of the reaction the solvents were distilled off. About 100 ml of 20 percent KOH was added drop by drop to the viscous residue and the acetate was saponified over a 15 minute period at 80° C. After removal of the Et3N by extraction, the aqueous solution was acidified with concentrated HCl. The precipitate was sucked off, washed with water and dried under a vacuum. 11.0 g of 6-hydroxy nicotinic acid was obtained, which was pure according to NMR. The crude yield was about 79 percent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(C)cc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(C)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a mixture of 2-(3-bromo-5-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.1 g, 14.6 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.12 g, 42%) as a white solid: LC/MS m/e calcd for C21H24BrNO2 M+: 402.3, observed: 402.1, 404.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: O=C=Nc1ccccc1F
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccccc3F)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-fluoro-2-isocyanatobenzene (Aldrich, Cat. #159352) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=462.2.