Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Product: Nc1c(F)c(N2CC3=C(CNC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
The solution of 0.4 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide, and 0.6 ml of 1,8-diazabicyclo[5.4.0]undex-7-ene (DBU) in 40 ml of acetonitrile was refluxed at the reaction temperature of 100° C. for 7 hours. This reaction mixture was kept overnight at the room temperature, and the produced precipitate was filtered and then the residue was washed with ethanol to obtain 0.3 g of the title compound (yield 57%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([P:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>CC(C)=O>[CH2:17]([P:12]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:13][CH2:14][CH2:15][CH3:16])=[C:2]1[CH2:3][C:4](=[O:5])[O:6][C:1]1=[O:7])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Product: CCCCP(CCCC)(CCCC)=C1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Maleic anhydride (9.81 g; 0.1 mole) in 25 ml acetone and tri-n-butylphosphine (20.23 g; 0.1 mole) in acetone were blended at 0°-5° C under a blanket of dry nitrogen. The resulting red solution was stirred for 1 hour at room temperature and then placed under vacuum to remove the bulk of the acetone solvent. The resulting red viscous liquid gave 15 g of yellow-brown crystalline product. This solid was separated by filtration and washed with cold acetone giving a yellow crystalline product which melts at 70° C, resolidifies and melts again at 85° C with gassing. The infrared (IR) and nuclear magnetic resonance (NMR) spectra and elemental analysis of the product were consistent with a compound represented by the structure ##STR8##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>>[N:27]1[CH:28]=[CH:29][N:30]=[CH:31][C:26]=1[NH:25][CH2:20][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[N:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: Nc1cnccn1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNc4cnccn4)c3)n2)cc1

Procedure:
Intermediate 28 was coupled with 2-aminopyrazine following procedure B. LC-MS showed the product had the expected M+H+ of 399. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 2H), 8.1 (m, 1H), 8.0 (m, 3H), 7.7 (m, 2H), 7.5 (m, 3H), 7.1 (m, 2H), 6.7 (m, 2H), 4.6 (m, 2H), 3.6 (m, 2H), 2.8 (m, 2H).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6].[NH3:20]>CO>[NH2:20]/[C:12](/[CH2:11][S:10][CH2:9][CH2:8][NH:7][CH:5]=[O:6])=[CH:13]\[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: N
Reactant: CCOC(=O)CC(=O)CSCCNC=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)/C=C(\N)CSCCNC=O
Temperature: 0 °C

Procedure:
Acetic acid is added to a solution of ethyl 4-(2-formylamino-ethylthio)-3-oxo-butanoate (12.5 g) in MeOH (ml 120), previously saturated with ammonia at 0° C. and cooled at 0° C., up to pH 4-45. The mixture is refluxed for 2 hours and the excess solvent is evaporated in vacuum, to give a syrup from which a solid material is separated by treatment with AcOEt. After filtration, the organic phase is washed with water (8×10 ml), and with a saturated aqueous solution of NaHCO3 (3×10 ml), dried (Na2SO4) and concentrated in vacuum to give 11,5 g of ethyl 3-amino-4-(2-formylaminoethylthio)crotonate as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: OB(O)c1cccnc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1cncc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-pyridinylboronic acid to give (1H-pyrazol-3-yl)-(1-pyridin-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 288(MH+).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13]>>[C:2]([NH:6][N:7]=[C:9]([CH2:10][CH2:11][C:12](=[N:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])[CH3:13])[CH3:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Product: CC(CCC(C)=NNC(C)(C)C)=NNC(C)(C)C
Yield: 60 %

Procedure:
The procedure of Example (a) is followed using about 67.6 g (0.54 mole) of t-butyl hydrazine hydrochloride and about 28.5 g (0.25 mole) of 2,5-hexane-di-one. The title compound is isolated as a fraction distilled at about 106° C.-114° C. under 1.0 mm Hg pressure. The yield is about 60 percent based upon the initial amount of hexane-di-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]2[C:11]([F:18])=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=2[F:16])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]2[C:11]([F:18])=[C:12]([CH:13]=[CH:14][C:15]=2[F:16])[O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 3-[(5-bromo-2-fluoro-phenyl)methylamino]-2,4-difluoro-phenol (5.26 g, 15.8 mmol, 1.0 eq) in DMF (50 mL) was added Na2CO3 (2.35 g, 22.2 mmol, 1.4 eq). The reaction was stirred at room temperature for 30 min then ethyl bromoacetate (2.91 g, 17.4 mmol, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 40:1 to 30:1) to give the title compound as a colorless oil (5 g, 75%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][NH:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C[Si]([N:33]=[C:34]=[O:35])(C)C>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:26][N:27]([OH:28])[C:34]([NH2:33])=[O:35])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: ONCC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCCC1
Reactant: C[Si](C)(C)N=C=O
Product: NC(=O)N(O)CC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCCC1

Procedure:
In analogy to the procedure of Example 2, the title compound is prepared from 2.3 g (6.11 mmol) of the compound from Example XV and 0.77 g (6.68 mol) of trimethylsilyl isocyanate.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a solution of (R)-pyrrolidin-2-ylmethanol (0.7 g, 6.93 mmol) in CH2Cl2 (5 mL) was added (Boc)2O (1.66 g, 7.62 mmol) and triethylamine (1.40 g, 13.86 mmol) at 0° C. After stirring at 0° C. for about 10 minutes, the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was quenched with aqueous acetic acid, then diluted with CH2Cl2 (20 mL), extracted with H2O (2×20 mL). The organics were dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl (hydroxymethyl)pyrrolidine-1-carboxylate (1.26 g, 91%) as a solid. A solution of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.26 g, 6.26 mmol) in CH2Cl2 (25 mL) was treated with CBr4 (3.13 g, 9.45 mmol) and PPh3 (2.48 g, 9.45 mmol) at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 16 h. Silica gel was added to the mixture, and then the mixture was concentrated to dryness. Purification by flash column chromatography (silica gel, Hexane/EtOAc, 100:0 to 3:1) gave the title compound (0.99 g, 60%) as a solid: 1H NMR (500 MHz, DMSO-d6) δ 4.08-3.98 (m, 1H), 3.69-3.50 (m, 1H), 3.48-3.21 (m, 3H), 2.10-1.75 (m, 4H), 1.47 (s, 9H); ESI MS m/z 164 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:22]([CH3:23])[CH2:21][O:20][CH3:19])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.1 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 2-methoxy-1-methyl-ethylamine (0.12 g, 1.32 mmol) and Hunig's base (0.037 g, 0.29 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature and extracted with EtOAc/H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to yield 0.20 g (87%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 356.2 [(M+H)+, 86].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:42])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:41])[CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:25]=3)=[CH:15][CH:14]=2)[N:7]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][C:31]([NH:30][C:26]1[CH:25]=[C:24]([O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:42])=[CH:14][CH:15]=2)[CH:29]=[CH:28][N:27]=1)=[O:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)CNC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)CN)c3)c3ccccc23)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of tert-butyl 2-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-ylamino)-2-oxoethylcarbamate (187 mg, 92% pure, 0.259 mmol) in dry DCM (6 mL) 0° C. under nitrogen was added TFA (2.0 mL) and the reaction mixture maintained at 0° C. for 20 min and then warmed to RT for 3 hr. The resulting mixture was evaporated in vacuo and the residue was purified by SCX capture and release to afford the title compound, Intermediate G1, as a brown solid (130 mg, 87%); Rt 1.82 min (Method 2); m/z 564 (M+H)+ (ES+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:11]=1.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C(=S)=S>[CH3:17][CH:16]1[CH2:18][C:10]2[C:11](=[C:6]([CH3:5])[CH:7]=[CH:8][C:9]=2[CH:12]([CH3:14])[CH3:13])[C:15]1=[O:19]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1ccc(C(C)C)c2c1C(=O)C(C)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 1-liter three-necked flask equipped with a 200 ml dropping funnel were charged 87.61 g (0.66 mol) of anhydrous aluminum chloride and 150 ml of carbon disulfide, to which were added at room temperature through a dropping funnel p-cymene (47.0 ml, 0.301 mol) and methacryloyl chloride (33.0 ml, 0.338 mol) diluted with 30 ml of carbon disulfide. After stirring at room temperature for 5 hours, the reaction mixture was slowly poured on 1 kg of ice. After extraction of the reaction mixture with diethyl ether, the resulting organic layer was washed with an aqueous saturated solution of sodium hydrogen carbonate and with saline, and dried over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH3:12].S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH3:12]
Reactant: CSc1ccccc1OCCO
Reactant: O=S(Cl)Cl
Product: CSc1ccccc1OCCCl

Procedure:
o-(β-Hydroxyethoxy)-thioanisole (0.1 mole) is refluxed in excess thionyl chloride and evaporated to dryness to yield o-(β-chloroethoxy)-thioanisole.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cccc2c1c(Cc1ccc(Br)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 23-(1) and 4-bromobenzoyl chloride were treated in a manner similar to Example 27 to give the titled compound as a colorless powder. APCI-Mass m/Z 462/464 (M−H). 1H-NMR (DMSO-d6) δ 2.38 (s, 3H), 3.24 (m, 1H), 3.30-3.47 (m, 4H), 3.68 (m, 1H), 4.18 (s, 2H), 4.52 (t, J=5.5 Hz, 1H), 5.08 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.17 (d, J=5.8 Hz, 1H), 5.34 (d, J=9.2 Hz, 1H), 6.71 (d, J=7.1 Hz, 1H), 6.98 (t, J=7.7 Hz, 1H), 7.13 (d, J=8.3 Hz, 2H), 7.15 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>>[C:13]([O:17][C:18](=[O:21])[C:19](=[CH2:20])[CH:9]([OH:10])[C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
4-(Methoxycarbonyl)benzaldehyde (3.3 g, 20 mM), t-butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were mixed and stirred in a vessel at room temperature for 5 days. The resulting mixture was extracted with diethyl ether. The organic layer was separated, washed with 2N hydrochloric acid, water, and sodium bicarbonate in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography, to obtain 4.2 g of the title compound as a white solid (yield 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:9])([CH3:8])[C:6](=[O:10])[C:5]([CH3:12])([CH3:11])[C:4](=[O:13])[C:3]=1[C:14]([C:16]1[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=1)=[O:15].[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:26][C:17]1[C:16]([C:14]([C:3]2[C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[C:6](=[O:10])[C:7]([CH3:9])([CH3:8])[C:2]=2[Cl:1])=[O:15])=[CH:21][CH:20]=[C:19]([C:22]([F:23])([F:24])[F:25])[N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C(C)(C)C(=O)C(C)(C)C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2CBr)=C(Cl)C(C)(C)C1=O

Procedure:
0.39 g (1 mmol) of 5-chloro-2,2,6,6-tetramethyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-4-ene-1,3-dione and 0.20 g (1.1 mmol) of N-bromsuccinimide are refluxed in the presence of a catalytic amount of dibenzoyl peroxide in 10 ml of carbon tetrachloride. After the reaction has subsided, the resulting succinimide is removed by filtration and the crude product is purified by column chromatography (mobile phase: ethyl acetatelhexane 1:4). This gives pure 4-(2-bromomethyl-6-trifluoromethylpyridine-3-carbonyl)-5-chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione of melting point 94.5-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][CH2:29][OH:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:36]([Si:40](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:28][CH2:29][O:30][Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In N,N-dimethylformamide (15 ml) was dissolved 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxyethyl)piperazine (739 mg) and imidazole (226 mg). Under ice cooling, tert-butylchlorodiphenylsilane (0.70 ml) was added to the resulting solution, followed by stirring at room temperature for 23 hours. The reaction mixture was distilled off under reduced pressure. The residue was extracted with methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic layer thus obtained was washed with dilute hydrochloric acid and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography (hexane:ethyl acetate=2:1˜:2) using as a carrier silica gel, whereby the title compound (804 mg) was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1)(=[O:37])[CH3:36]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(N)CC3)nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(NC(C)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-aminopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (100 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of triethylamine (7 mL) and acetic anhydride (1 mL) at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under vacuum. This resulted in 0.1 g (90%) of methyl 3-(4-acetamidopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as light yellow oil.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[N:12]=[CH:11][N:10]2[N:13]=[CH:14][N:15]=[C:9]2[C:8]=1[CH2:16][CH2:17][CH3:18])[CH:2]([CH3:4])[CH3:3].[F:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:5]([CH2:6][C:7]1[N:12]=[CH:11][N:10]2[N:13]=[CH:14][N:15]=[C:9]2[C:8]=1[CH2:16][CH2:17][CH3:18])[C:26]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[N:25]=1)=[O:27])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCc1c(CNCC(C)C)ncn2ncnc12
Reactant: O=C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1c(CN(CC(C)C)C(=O)c2cccc(F)n2)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of isobutyl-(8-propyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-ylmethyl)-amine (2.8 mmol) and 6-fluoro-pyridine-2-carboxylic acid (0.47g, 3.34 mmol) in DCM (10 ml) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (Na2SO4) and solvent evaporated. Preparative TLC purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. H1 NMR δ (CDCl3) (mixture of rotamers) 9.25 (s, 0.51), 9.18 (s, 0.5H), 8.39 (s, 0.5H), 8.36 (s, 0.5H), 7.78-7.93 (m, 1H), 7.68 (d, 0.5H), 7.57 (d, 0.5H), 6.99 (d, 0.5H), 6.92 (d, 0.5H), 5.03 (s, 1H), 4.89 (s, 1H), 3.52 (d, 1H), 3.35 (d, 1H), 3.12 (t, 1H), 2.83 (t, 1H), 1.95-2.20 (m, 1H), 1.59-1.85 (m, 2H), 0.88-1.10 (m, 6H), 0.82 (t, 3H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Reactant: BrCC1CCCCC1
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3CC2CCCCC2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 49 step D from methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and (bromomethyl)cyclohexane, and was isolated as white solid after reverse phase chromatography (45%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.35-7.28 (m, 0.4H), 6.99 (d, J=8.4 Hz, 0.6H), 6.90 (t, J=2.5 Hz, 1H), 6.78-6.67 (m, 1H), 5.73 (d, J=2.7 Hz, 0.4H), 5.67 (d, J=2.7 Hz, 0.6H), 5.40 (s, 0.4H), 5.15 (d, J=2.1 Hz, 0.6H), 4.48-4.34 (m, 1H), 4.34-4.23 (m, 1H), 4.23-4.12 (m, 2H), 3.73-3.61 (m, 3H), 2.79-2.57 (m, 2H), 2.16-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.75-1.55 (m, 5H), 1.40-0.91 (m, 14H); LCMS (m/z) ES+=521 (M+1).