Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].C([Cl:30])(=O)CCCCCCC/C=C\CCCCCCCC>ClCCl>[ClH:30].[ClH:30].[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: NCCNCCNCCN
Solvent: ClCCl
Product: Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1.12 g (7.5 mmol) of triethylenetetramine was added to 25 mL of dichloromethane and dissolved with stirring in an ice water bath at 5° C. for 30 minutes. To the solution, a solution of 2.00 g (6.0 mmol) of oleoyl chloride in 20 mL of dichloromethane in a separate reactor was added slowly dropwise while it was allowed to react at 5° C. for 3 hours. Due to hydrogen chloride produced during the reaction, unreacted triethylenetetramine HCl was precipitated. Before the end of the reaction, the upper layer solution was taken and analyzed by thin layer chromatography (TLC) with a mobile phase of ethanol:chloroform (2:1) to determine whether the reaction was completed.
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1(O)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30].[Cl-:32].[NH4+]>ClCCl>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1([Cl:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30]
Reactant: O=C1Nc2ccc(Cl)cc2C1(O)c1nc2ccccc2s1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C1(Cl)c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyridine (0.57 ml) and thionyl chloride (0.42 ml) were successively added to an ice-cooled solution of the intermediate from Step A (1.27 g, 4.0 mmol) in dichloromethane (40 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude intermediate was rapidly employed without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13](I)=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH:20]=[CH2:21])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cc(I)cc1Cl
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(Cl)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a solution of N-(2-bromopyridin-4-yl)-2,6-dichloro-4-iodobenzamide (3.0 g, 6.4 mmol) in THF (40 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.0 g, 12.8 mmol), 2M Na2CO3 (12 ml) and Pd2(PPh3)4 (222 mg, 0.19 mmol). The solution was degrassed with N2, and heated at 80° C. overnight. Then the reaction mixture was cooled to room temperature, poured into water (200 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (2×20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (Pet Ether/EtOAc=10:1 to 3:1) to give N-(2-bromopyridin-4-yl)-2,6-dichloro-4-vinylbenzamide (2.2 g, yield: 92%). 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.51 (d, J=3.5 Hz, 1H), 7.35 (s, 2H), 6.61 (m, 1H), 5.86 (d, J=17.5 Hz, 1H), 5.48 (d, J=11.0 Hz, 1H). LCMS (ESI) m/z: 371.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:14][CH:15]=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][CH2:14][CH:15]=[O:16]
Reactant: O=CCCl
Reactant: Cc1ccc(C(F)(F)F)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C(F)(F)F)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-trifluoromethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:26](Cl)(=[O:28])[CH3:27].C([Li])CCC.[O:35]1CC[CH2:37][CH2:36]1>>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:23]([C:36](=[O:35])[CH3:37])[C:26](=[O:28])[CH3:27])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1)C(C)=O

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.2 mmol, Example I) with acetyl chloride (2.1 mmol), n-butyl lithium (0.2 mmol) in tetrahydrofuran at a temperature 0-25° C. for 3 hours followed by silica gel column chromatographic purification in % yield.
Reaction SMILES: Br.[NH2:2][O:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][C:9]([O:12][C:13]([NH:15][C@H:16]([C:24](ON1C(=O)CCC1=O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.C(O)C>[C:9]([O:12][C:13]([NH:15][C@H:16]([C:24]([NH:2][O:3][CH2:4][C:5]([OH:7])=[O:6])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])([CH3:10])([CH3:11])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NOCC(=O)O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NOCC(=O)O

Procedure:
6.97 g (40.5 mmoles) of aminooxy-acetic acid hydrobromide are reacted with 14.68 g (40.5 mmoles) of BOC--Phe--OSu in 100 ml of DMF in the presence of 6.3 ml (45 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the oily residue is dissolved in 100 ml of chloroform, and the chloroform solution is washed thrice with 1 n hydrochloric acid. The organic solution is dried, evaporated in vacuo, and the oily residue is solidified with diisopropyl ether. The crude product is purified by precipitation from an ethyl acetate-diisopropyl ether solvent system. 9.70 g (74%) of BOC--Phe--OGly--OH are obtained; m.p.: 136°-137° C., Rf5 : 0.4, [α]D : -17.8° (c: 1.0, in ethanol).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].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.C(OCC)(=O)C.C(O)CC>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccccc4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A solution containing 27 mg of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine, 22 mg phenyl boronic acid, 42 mg potasium carbonate, 0.7 mg Pd(PPh3)4, 1.5 mL of H2O and 1.5 mL n-propanol was refluxed under nitrogen for 2 hours. The solution was cooled to room temperature, added to 100 mL of ethyl acetate and washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by MPLC eluting with methanol in methylene chloride to give 8.7 mg of the title compound. RF: 0.55 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, 3:1 CD3OD/CDCl3): δ 1.62 (d, J=6.9 Hz, 3H), 5.17 (q, J=7.0 Hz, 1H), 1H), 7.05 (d, J=5.8 Hz, 1H), 7.2-7.65 (m, 12H), 7.89 (br s, 1H), 8.36 (br s, J=5.6 Hz, 1H), 8.8-8.95 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 392.3 (M+1).
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.C[N+](C)=C[Cl:13].[Cl-].O[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])[C:18]([OH:20])=[O:19]>ClCCl>[Cl:13][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a magnetically stirred N,N-dimethylformamide (20 ml, 258.5 mmol) cooled in ice was added slowly dropwise thionyl chloride (30 ml, 411.2 mmol). To the resulting cold Vilsmeier reagent was added dichloromethane (100 ml), α-hydroxy-2-nitrobenzenepropanoic acid (20.0 g, 94.7 mmol) and a further 50 mL of dichloromethane as a rinse. The mixture, protected from extraneous moisture, was stirred at room temperature until solution was achieved and the solution was left at room temperature (25° C.) overnight. The solution was poured onto stirred ice and the mixture stirred for 1 hour during which time it warmed to room temperature. The dichloromethane layer was separated, washed thrice with water, dried (MgSO4) and evaporated to a syrup. The syrup was concentrated further at 40° C. under oil pump vacuum to remove traces of N,N-dimethylformamide. The resulting syrup was stirred magnetically with water while while cooling in ice. The resulting solid was ground in a mortar and collected on a filter. The solid was then stirred magnetically with water, collected on a filter and washed with water. Drying under vacuum over phosphorus pentoxide at room temperature provided 19.60 g (90%) of titled product, mp 107°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[C:6]2[CH:15]=O.[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[C:6]2/[CH:15]=[CH:18]/[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(=O)c1ccncc1
Reactant: CCCc1[nH]c2ccc(OC)cc2c1C=O
Solvent: C1CCNCC1
Solvent: CO
Product: CCCc1[nH]c2ccc(OC)cc2c1/C=C/C(=O)c1ccncc1
Temperature: 40 °C
Yield: 85.8 %

Procedure:
5-Methoxy-2-propylindole-3-carboxaldehyde (200 mg, 0.92 mmol) was dissolved in anhydrous methanol (7.5 mL) under an atmosphere of Argon (g). 4-Acetylpyridine (167.17 mg, 1.38 mmol) and piperidine (117.5 mg, 1.38 mmol) were added to the reaction mixture and the solution was refluxed for 24 hours. A precipitate slowly formed which was collected, washed with cold MeOH (30 mL) and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator heated to 40° C. to yield a bright yellow powder (253 mg, 85%): TLC Rf 0.43 in 4:1 ethyl acetate/hexanes. Melting point=221-224° C. 1H NMR (600 MHz, d6-DMSO) δ 11.87 (s, 1H), 8.82-8.82 (m, 2H), 8.10-8.07 (d, 1H, J=15.24 Hz), 7.94-7.93 (m, 2H), 7.46-7.45 (d, 1H, J=2.34), 7.40-7.37 (d, 1H, J=15.24 Hz), 7.34-7.32 (d, 1H, J=8.7 Hz), 6.87-6.86 (dd, 1H, J1=2.4 Hz, J2=8.7 Hz), 3.87 (s, 3H), 2.92-2.89 (t, 2H, J=7.44 Hz) 1.74-1.70 (m, 2H) 0.95-0.92 (t, 3H, J=14.7 Hz); 13C NMR (150 MHz, d6-DMSO) δ 188.0, 155.1, 150.5, 149.7, 145.0, 139.4, 131.1, 126.2, 121.3, 112.8, 112.3, 111.0, 109.0, 103.7, 55.5, 27.6, 22.8, 13.5. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.05; H, 6.32; N, 8.70.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([F:26])[C:18]=1[F:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)=[C:19]([F:26])[C:18]=1[F:27])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1F
Reactant: Brc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Fc1c(OCc2ccccc2)ccc(-c2ncc(Br)cn2)c1F
Yield: 26.5 %

Procedure:
A reaction of 14 mmol of 2,5-dibromopyrimidine, 17 mmol of 4-benzyloxy-2,3-difluorophenylboronic acid, 34 mmol of sodium carbonate and 0.14 mmol of tetrakis(triphenylphosphine)palladium(0) in 100 ml of toluene, 50 ml of ethanol and 50 ml of water is carried out analogously to the procedure indicated for precursor 3. Purification by recrystallization from 2-propanol gives 1.4 g (26%) of a colorless solid, m.p. 138° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH:31][CH:32]([CH3:34])[CH3:33])([CH3:30])[CH3:29]>CN(C=O)C>[OH:26][C@@H:25]([CH2:27][N:31]([CH:32]([CH3:34])[CH3:33])[CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(C)NC(C)C
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 19 h
Yield: 33.1 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), and diisopropylamine (0.45 ml, 3.2 mmol) in DMF (5 ml) was stirred at 70° C. for 19 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel, using gradient elution with dichloromethane/methanol (100/0 to 95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10) to give (2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (43 mg, 33%).
Reaction SMILES: Cl.C(=[N:9][N:10]([CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11])C1C=CC=CC=1>C(O)C>[NH2:20][C:19]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:10]([CH3:11])[N:9]=1
Reactant: CCOC(=O)C(C#N)=CN(C)N=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cn(C)nc1N
Yield: 103 %

Procedure:
At room temperature, 100 ml of concentrated hydrochloric acid were added dropwise over a period of 20 min to a suspension of 220 g (0.855 mol) of ethyl 3-(N′-benzylidene-N-methylhydrazino)-2-cyanoacrylate (XVI-1) in 1000 ml of ethanol. The mixture was then heated at the boil for 1 hour. After removal of the solvent, the oily residue was triturated with gentle heating with 200 ml of diethyl ether, resulting in the precipitation of a solid. Filtration with suction gave 149 g (95% of theory) of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate [logP (pH 2.3)=0.72].
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].ClC1C=CC=C(C(OO)=[O:20])C=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]>CCCCCC>[C:10]([CH2:9][CH2:8][CH:1]1[O:20][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH2:6]1)#[N:11].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CCCC1CCCCC1=O
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCCCCC
Product: N#CCCC1CCCCC(=O)O1
Temperature: 55 °C

Procedure:
A reactor is loaded with 151 g of 3-(2-cyclohexanonyl)propionitrile in 500 ml of n-hexane and 260 g of m-chloroperbenzoic acid (70% titer) dissolved at 50° C. in 2000 ml of n-hexane in 30 minutes. The solution is heated to 55° C. for 15 hours. Cooling of the solution separates, in crystalline form, part of the m-chlorobenzoic acid which is scarcely soluble in the system, together with a heavy liquid phase which is formed by 7-cyanoethyl-2-oxepanone and by m-chlorobenzoic acid. 71.5 g of 7-cyanoethyl-2-oxepanone, impure with m-chlorobenzoic acid, are recovered from the lower phase. 24 g of 7-cyanoethyl-2-oxepanone are recovered from the upper phase by concentration and several crystallizations. Conversion over the initial ketone is 85%. Yield on the converted amount is 57%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Reactant: O=C(Cl)CCCCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 6-Bromohexanoyl chloride (195.8 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 μL, 0.61 mmol, 1 equiv.). The beige suspension was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×10 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting brown foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 6-bromo-hexanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (166 mg, 55%) as a yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]3[N:20]=[CH:21][CH:22]=[N:23]C=3C=CC=2)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-:28].[K+].[OH2:30]>CCO>[N:23]1[C:22]2[C:21](=[CH:4][CH:6]=[CH:7][CH:8]=2)[N:20]=[CH:19][C:18]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:30])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3nccnc23)Cc2ccccc2C1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
The mixture of 2-[(quinoxaline-5-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (56) (480 mg, 1.33 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (13 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (40 mL) and acidified with conc. HCl dropwise until no more precipitate formed. The precipitate is filtered to give a pure product (54) as a brown solid (444 mg, 100%).
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:45][C:41](=[O:44])[CH:42]=[CH:43][C:2]1[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:28][C:29]=1[Cl:30])[CH3:47]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 95 °C

Procedure:
To a degassed solution of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (500 mg, 0.96 mmol, 1.0 equiv; Example 163) in propionitrile (10 mL) under Ar was added N-ethyldiisopropylamine (373 mg, 491 μL, 2.89 mmol, 3.0 equiv; [CAS RN 7087-68-5]), ethyl acrylate (0.58 g, 0.63 mL, 5.78 mmol, 6.0 equiv; [CAS RN 140-88-5]), palladium(II) acetate (22 mg, 0.10 mmol, 0.1 equiv; [CAS RN 3375-31-3]) and tri-o-tolyl-phosphane (59 mg, 0.19 mmol, 0.2 equiv; [CAS RN 6163-58-2]). The reaction mixture was heated to 95° C. over night. The crude reaction was filtered over Celite®, a sat. solution of NaCl (50 mL) added and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 320 mg (62%) of the title compound as a yellow foam. MS (ISN): 538.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.N>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COc1c(C)ccc(C)c1C
Yield: 92.1 %

Procedure:
A mixture of 50 g (0.367 mol) of 2,3,6-trimethylphenol, 55 g (0.4 mol) of potassium carbonate and 36 ml (0.38 mol) of dimethylsulphate in 500 ml of acetonitrile was heated under reflux overnight. 35 ml of conc. aqueous ammonia was then added, and the mixture refluxed for 1 hour. After filtration and evaporation, the residue was taken up in ether and washed twice with NaOH-solution and twice with NaHCO3 -solution. Drying (MgSO4) and evaporation gave 50.8 g (92%) of the product.
Reaction SMILES: NC1SC2C3C(CC=2C=1[C:14]([NH2:16])=[O:15])=CC=CC=3.[NH2:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3>>[NH:17]([C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(N)sc2c1CCc1ccccc1-2
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Product: NC(=O)Nc1sc2c(c1C(N)=O)CCc1ccccc1-2

Procedure:
The title compound was prepared by the same procedure as Example 2 except 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide to give the above title compound as brown solid. ESMS m/z: 288 [M+H]+.