Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (63.2% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.98, 7.75, 7.64, 7.57, 7.37, 7.00, 4.06, 3.89, 3.82-3.64, 3.49, 3.36, 1.70, 1.50, 0.95.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:8][S:9][CH3:10]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)CCC(=O)O
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
Compound 2 (0.25 g, 1 eq.) was suspended in CH2Cl2 (12.5 ml, C=0.1M). Triethylamine (0.26 ml, 1.5 eq.) was added to the solution which was then stirred for 10 minutes. After stirring 4-dimethylamino pyridine (0.015 g, 0.1 eq.) and succinic anhydride (0.125 g, 1 eq.) were added and the reaction left to stir for 16 hours at room temperature. The reaction mixture was then shaken with 3×20 ml portions of hydrochloric acid (2M), the aqueous washings were subsequently extracted with 3×20 ml portions of diethyl ether. The DCM portion was discarded and the ether layers were combined and dried over anhydrous MgSO4, filtered and evaporated to yield a white solid 3 (0.199 g, 60% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([F:12])[F:11].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[CH2:19]([NH:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([F:12])([F:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(COCCCCCCBr)c1ccccc1
Solvent: CCOCC
Product: FC(F)(COCCCCCCNCc1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
A solution of Intermediate 7 (5.0 g, 15.6 mmol) and benzyl amine (3.4 mL, 31.1 mmol) was heated at 120° C. for two hours. The crude reaction was treated with ethyl ether and the resulting solid was filtered. The solvent was concentrated and the resulting oil was purified by column chromatography with silica gel and methylene chloride/methanol (from 99:1 to 95:5) as eluent, to yield N-benzyl-6-(2,2-difluoro-2-phenylethoxy)hexan-1-amine (3.2 g, 59%) as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].[C:16]([OH:24])(=[O:23])[C:17]([CH2:19][C:20](O)=[O:21])=[CH2:18]>>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[N:1]1[C:20](=[O:21])[CH2:19][CH:17]([C:16]([OH:24])=[O:23])[CH2:18]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(O)C1CC(=O)N(c2ccc(-n3ccccc3=O)cc2F)C1

Procedure:
Prepared analogously to Example 1d from 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one by melting with itaconic acid. The crude product is purified by reversed-phase chromatography.
Reaction SMILES: [Cl:1]Cl.[N+]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)([O-])=O>>[Cl:1][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1
Reactant: ClCl
Product: FC(F)(F)Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
Chlorine and p-nitrotrifluoromethoxybenzene (10.7 parts) were fed simultaneously at a molar ratio of 3:1, Cl2 : organic reactant, into a vapor phase reactor maintained at 300° to 320° C. over a 30 minute period to yield 8.2 parts of p-chlorotrifluoromethoxybenzene (83% yield). The structure of the product was confirmed by gas chromatographic-mass spectrum and F19 nuclear magnetic resonance analysis.
Reaction SMILES: CC1(C)OC(=O)[CH:5]([CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:15][CH:14]=2)[C:10]#[C:11][CH3:12])[C:4](=[O:28])[O:3]1.N1C=CC=CC=1.Cl>O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([C:10]#[C:11][CH3:12])[CH2:5][C:4]([OH:28])=[O:3])=[CH:14][CH:15]=1
Reactant: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(SCc2ccccc2C)cc1
Yield: 111 %

Procedure:
A solution of 28.3 (20 mg, 0.05 mmol) in 5:1 pyridine:water (6 mL) was heated to 80° C. for 72 hours. The reaction was poured into 500 mL of water and the solution was acidified with 1N HCl(aq) (65 mL). The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (Na2SO4) and concentrated in vacuo. The resultant residue was then purified via radial chromatography (30% ethyl acetate in hexanes) to yield 18 mg (quantitative) 3-[4-(2-Methyl-benzylsulfanyl)-phenyl]-hex-4-ynoic acid (28). LC/MSD m/e: 323.1 (M−H).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][C:9]=1[C:21](OC)=[O:22]>CN(C=O)C>[NH2:6][C:5]([NH2:7])=[N:4][C:21]([C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:19][C:20]=2[CH:8]=1)=[O:22]
Reactant: N=C(N)N
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(N)=NC(=O)c1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 192 mg portion of sodium hydride (60%) was added to 6.5 ml DMF solution of 573 mg guanidine hydrochloride and stirred at room temperature for 1 hour. A 6.5 ml DMF solution of 270 mg methyl 9H-carbazole-2-carboxylate was added to this solution, followed by stirring at 70° C. for 2.5 hours. After spontaneous cooling to room temperature and subsequent evaporation of the solvent, water was added thereto and the thus precipitated solid was purified by Chromatorex (methanol/chloroform) to obtain 236 mg of N-(diaminomethylene)-9H-carbazole-2-carboxamide as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[S:9][CH3:10])[CH3:3].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][CH:2]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[S:9][CH3:10])[CH3:3]
Reactant: COCCOCCl
Reactant: CSc1ccsc1C(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOC(C)c1sccc1SC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)3-methylthiothiophene (13.5 g, 0.077 mol) in dry methylene chloride (100 ml) was added methoxyethoxymethyl chloride (11.5 g, 0.092 mol) followed by N,N-diisopropylethylamine (12.1 g, 0.092 mol) with cooling. The solution was stirred at room temperature for 18 hours. Some starting material remained upon work up at this point. The material was recycled as above using 1/2 the above quantities of methoxyethoxymethyl chloride and N,N-diisopropylethyl amine. After 5 hours at room temperature the reaction was completed. The solution was washed with water, dilute HCl, saturated NaHCO3 solution and again with water. Then it was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Pure product was obtained as a yellow oil (17.6 g, 87%). TLC confirmed the purity and NMR and mass spectrometry (M/Z=262) supported the structure.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34]Cl)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CCl)N2C[C@H]1Cc1c[nH]c2ccccc12
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CN3CCOCC3)N2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 120 °C

Procedure:
To a solution of (3,5-bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6-chloromethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.06 g) in dimethylformamide (15 mL) was added morpholine (5 mL). The resulting mixture was heated at 120° C. for 6 hours. After cooling to room temperature, ethyl acetate and 5% aqueous sodiumbicarbonate were added and the layers were separated. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, MTBE/MeOH/NH4OH 95:4.5:0.5) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)-3-(1H-indol-3-ylmethyl)-6-(morpholin-4-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (407 mg). Rf 0.46 (MTBE/MeOH/NH4OH 95:4.5:0.5) (compound 2).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (370 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (113 mg, 0.009 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (235 mg, 52%) as a brown solid.
Reaction SMILES: [Na].O.C1(C)C=CC([S:9](O)(=O)=O)=CC=1.[O:14]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1.C(=O)(O)[O-].[Na+]>CO>[OH:14][C:16]1([CH2:15][SH:9])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium sufide nonahydrate (60 g, 0.25 mol) was dissolved in MeOH (1.25 L), and the resulting solution was degassed by applying vacuumn and filling nitrogen three times. The solution was then cooled to 0° C. with an ice-water bath. To the above solution was added p-toluenesulfonic acid hydrate (76 g, 0.4 mol) and the resulting mixture was stirred at 0° C. for 10 min A yellowish colored solution was formed. The tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21.2 g, 0.1 mol) was added to the reaction mixture and stirred at 0° C. for 1 h and then at room temperature for 1.5 h. Saturated sodium bicarbonate solution (200 mL) was added to the reaction, and the methanol was evaporated under reduced pressure. To the residue was added water (500 mL) and extracted with EtOAc (1×400 mL and 2×250 mL), the combined organic layer was washed with brine (250 mL) and dried over sodium sulfate. After concentration, the crude product (26.2 g) was obtained as an oil. The crude product was purified by flash column chromatography (SiO2, 5% to 40% EtOAc in hexanes) to afford the product as a white solid. (19.2 g, 78%). M.p.=54-55° C.; 400 MHz 1H NMR (CDCl3) δ: 3.97-3.80 (m, 2H), 3.19-3.08 (m, 2H), 2.61 (d, J=4.4 Hz, 2H), 2.22 (s, 1H), 1.68-1.60 (m, 2H), 1.50-1.40 (m, 11H); LCMS: 248 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:21].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2′,4′-dimethoxy-2-methylbiphenyl-4-carboxylate obtained in step 2 (2 g; 6.99 mmol) in EtOH (60 mL) at RT was treated with sodium hydroxide (4.19 mL; 5 M; 20.96 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give a brown solid that was taken up in water (40 mL) and the aqueous phase was washed twice with EtOAc and then acidified with HCl to pH 2. Then it was concentrated until precipitation (⅕ of the volume). The suspension was filtered off and dried under vacuum affording the title compound as an orange solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.59 (br s, 1H), 7.58-7.51 (m, 2H), 6.97-6.95 (d, J=8.03 Hz, 1H), 6.81-6.79 (d, J=8.39 Hz, 1H), 6.44-6.37 (m, 2H), 3.59 (s, 3H), 3.49 (s, 3H), 1.88 (s, 3H). LC/MS (Method A): 272.9 (M+H)+; 270.9 (M−H)−. HPLC (Method A) Rt 3.87 min (Purity: 99.7%).
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[C:3](=[O:23])[NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:24][C:2]([C:3]([NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1)=[O:23])([CH3:1])[NH2:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of 1,1-dimethylethyl (1,1-dimethyl-2-oxo-2-{[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]amino}ethyl)carbamate (Reference Intermediate 219, 50 mg) in dry dichloromethane (4 mL) at 0° C. TFA (1 ml, 12.98 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was diluted with dichloromethane (10 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated affording the title compound (35 mg) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reactant: CC(C)N=C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (2.24 g, 8.91 mmol) in CH2Cl2 (30 mL) was treated with isopropyl isocyanate (1.1 mL, 11 mmol). The reaction mixture was diluted with water, the CH2Cl2 was removed under reduced pressure, and the aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to the title compound as a white solid (2.6 g, 87%). MS (ES+) m/z 337 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27](B1OC(C)(C)C(C)(C)O1)=[CH:26][CH:25]=2.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:21])=[CH:30]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (850 mg, 2.90 mmol) in DME (20 ml) was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.4 g, 5.44 mmol), potassium carbonate (751 mg, 5.43 mmol), Pd(PPh3)4 (157 mg, 0.14 mmol) and water (5 ml) under an inert atmosphere of nitrogen. The resulting solution was stirred for 1 h at 90° C. and then diluted with water (300 ml), extracted with ethyl acetate (3×100 ml), and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by a silica gel column (1%-5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a yellow solid (660 mg, 58%).
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:13]=[CH:12][N:11]([C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([O-])=[O:17])[N:10]=2)[CH2:4][CH2:3]1.[Na+].[NH2:25][CH:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]([OH:31])[C:28]([NH2:30])=[O:29]>CN(C)C=O>[NH2:30][C:28](=[O:29])[CH:27]([OH:31])[CH:26]([NH:25][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[N:22][C:14]=1[N:11]1[CH:12]=[CH:13][C:9]([CH2:8][N:5]2[CH2:4][CH2:3][C:2]([F:23])([F:1])[CH2:7][CH2:6]2)=[N:10]1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C([O-])c1cccnc1-n1ccc(CN2CCC(F)(F)CC2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(F)(F)CC2)n1
Yield: 100.1 %

Procedure:
Coupling of sodium 2-(3-((4,4-difluoropiperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinate (310 mg, 0.900 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (227 mg, 1.171 mmol) in N,N-dimethylformamide (20 mL) according to example 1.3 and work-up gave 449 mg of the title compound; ESI-MS [M+H]+: 499.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH:17]([CH3:21])[NH:16][C:15](=[O:22])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:21][CH:17]1[NH:16][C:15](=[O:22])[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18]1
Reactant: CC1Cc2[nH]c(-c3cccc4ccc(Cl)nc34)cc2C(=O)N1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2[nH]c(-c3cccc4ccc(Nc5ccccc5)nc34)cc2C(=O)N1
Reaction time: 3 h
Yield: 31.3 %

Procedure:
2-(2-Chloroquinolin-8-yl)-6-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 31; 0.050 g, 0.160 mmol) and aniline (0.073 ml, 0.802 mmol) were treated with LHMDS (1.0 M solution in THF; 1.203 ml, 1.203 mmol). The dark red reaction was stirred for 3 h, at which point it was concentrated then treated with DMSO and TFA (0.185 ml, 2.406 mmol). This material was purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.018 g, 0.050 mmol, 31% yield, Example 237) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br. s), 9.52 (1H, s), 8.11 (1H, d, J=9.0 Hz), 7.93 (1H, dt, J=7.4, 0.9 Hz), 7.65 (2H, d, J=7.6 Hz), 7.58 (1H, dt, J=7.7, 1.0 Hz), 7.40 (2H, t, J=7.9 Hz), 7.28 (1H, t, J=7.7 Hz), 7.02-7.15 (2H, m), 6.82-6.97 (2H, m), 3.75 (1H, dt, J=11.3, 5.8 Hz), 2.65 (1H, dd, J=15.6, 5.3 Hz), 2.36-2.47 (1H, m), 1.23 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 369.2 (M+H)+. A portion of this material was resolved by chiral SFC (Chiralcel IC-H (150×21 mm, 5 μm); additive in supercritical fluid CO2 was 40% EtOH with 40 mM NH3; 70 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers 6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 33, first eluting enantiomer) and 6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 34, second eluting enantiomer).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].C([O-])(=O)C.[NH4+]>CC(O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
4-Cyanobenzaldehyde (2.62 g) was condensed with 2,4-pentanedione (3.0 g) in 2-propanol (10 ml) in the presence of ammonium acetate. Mp 86°-88° C., yield 0.55 g (13 %).