Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[S:22][C:10]2[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[C:8]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]>ClCCl>[Cl:3][CH2:6][C:7]1[S:22][C:10]2[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[C:8]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CCCC3)c(CO)sc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CCCC3)c(CCl)sc21
Reaction time: 1 h

Procedure:
Thionyl chloride (0.046 ml) was added to a solution of 1-{[1,2,3,4-tetrahydro-6-(hydroxymethyl)-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl }pyrrolidine (0.1 15 g) in anhydrous dichloromethane (5 ml) under nitrogen. After 1 hour, the mixture was evaporated. The residue was redissolved in ethyl acetate (25 ml), washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give the subtitle compound (0.11 g) as an oil.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([O:8][CH2:9][CH3:10])=[CH2:7].P([O-])([O-])([O-])=O.C(OCC)(=O)C>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:6]([O:8][CH:9]([S:1][CH2:2][C:3]([OH:5])=[O:4])[CH3:10])[CH3:7]
Reactant: C=COCC
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(C)SCC(=O)O
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
S-(1-ethoxyethyl)mercaptoacetic acid 16 was prepared according to the following procedure: A solution of mercaptoacetic acid (17.4 mL, 250 mmol) in 125 mL of dichloromethane containing p-toluenesulfonic acid monohydrate (0.24 g, 1.26 mmol) was cooled to -18° to -25° C. with stirring. Ethyl vinyl ether (23.9 mL, 250 mmol) in 125 mL of dichloromethane was added dropwise to the cold solution over a period of 90 minutes. The stirring was continued for an additional 30 minutes, with the temperature maintained in the -18° to -25° C. range. Then 200 mL of pH 7 phosphate buffer was added, and the reaction mixture was allowed to warm with stirring for 10 to 15 minutes. The mixture was then poured into a flask containing 900 mL of ethyl acetate and 200 mL of water. Layers were separated, and the aqueous portion extracted twice with ethyl acetate. The organic layers were combined, washed with brine, and dried (MgSO4). Removal of the solvent left 31.4 g of S-(1-ethoxyethyl)mercaptoacetic acid 16 as a colorless oil (77% yield): 1H NMR (CDCl3) 1.15(t,J=7.0 Hz,3H), 1.52(d,J=6.4 Hz,3H), 3.36(s,2H), 3.60(m,2H), 4.84(q,J=6.4 Hz, 1H), 11.65(s, 1H). The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].P(=O)(O)(O)[OH:31]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][C:10](=[CH2:26])[C:9]([OH:27])=[O:31])=[CH:15][CH:16]=1
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reactant: O=P(O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C

Procedure:
(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (27.7 g) is dissolved in THF (270 ml) at room temperature. Tetrabutylammonium bromide (0.24 g) is added followed with water (10 ml). The mixture is then cooled to 10° C. A solution of lithium hydroxide (7.3 g) in water (92 ml) is added over 2 h. Phosphoric acid (37 g, 85%) is added until pH 3. Phases are then separated. The organic phase is diluted with toluene (100 ml) and washed with brine. Phases are separated. The organic phase is then concentrated in vacuo. The residue is dissolved in acetonitrile (350 ml) at 80° C. and azeotropically distilled. Further acetonitrile is added (150 ml) and the mixture cooled to 0° C. The solid is collected by filtration and dried, to afford (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) (25.7 g). δH (400 MHz, DMSO) 1.30 (9H), 2.29 (1H), 2.50 (1H), 2.75 (2H), 3.91 (8H), 5.62 (1H), 6.09 (1H), 6.66 (1H), 7.28 (2H), 7.33 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=O)[CH:2]=1.[NH3:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)=[NH:20])=[CH:14][CH:15]=1
Reactant: N
Reactant: O=C(c1ccc(F)cc1)c1cnc2cccnc2c1
Agent: [Ti+4]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N=C(c1ccc(F)cc1)c1cnc2cccnc2c1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
4-fluorophenyl 1,5-naphtyridin-3-yl ketone (108 mg) was dissolved in anhydrous toluene (5 mL), and the solution was cooled at −30° C. Titanium chloride (0.08 mL) was dropwise added to the solution under nitrogen, and ammonia gas was passed through the mixture for about 20 minutes. Then the mixture was warmed up to room temperature and stirred overnight. Saturated potassium carbonate aqueous solution (1 mL) was added to the reaction mixture, and the mixture was stirred for an additional 1 hour. The organic layer was separated, washed with water and saturated saline once respectively and dried over anhydrous sodium sulfate. Then the solvent was evaporated in vacuo to give crude product of (4-fluorophenyl)(1,5-naphtyridin-3-yl)-methanimine (103 mg). The crude product was dissolved in anhydrous toluene (2 mL), and trimethylsilylcyanide (0.21 mL) and 1M tetrabutylammonium fluoride—tetrahydrofuran solution (0.01 mL) were added to the solution. The mixture was stirred at room temperature for 6 days. The reaction mixture was washed with saturated sodium hydrogen carbonate aqueous solution and saturated saline once respectively and then dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give crude product of 2-amino-2-(4-fluorophenyl)-2-(1,5-naphtyridin-3-yl) -acetonitrile. The crude product was dissolved in anhydrous toluene (2 mL). 1M Diisobutylalumium hydride—toluene solution (1.85 mL) was dropwise added to the solution at −78° C., and mixture was warmed up to 0° C. for 30 minutes. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred for one hour. Moreover, anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was stirred for one hour. Then insolubles were removed by filtration. The filtrate was concentrated in vacuo, and then the obtained residue was purified by silica gel column chromatography (C-300; chloroform: methanol=20:1→10:1→2:1) to give the title compound (17 mg).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5](=[O:35])[N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>C1COCC1.CO.CN(C=O)C>[O:35]=[C:5]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-acetic acid ethyl ester (229 mg, 0.46 mmol) was dissolved in THF/MeOH/DMF (3:1:1, 5 mL) and to the solution was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was filtered and purified by reverse-phase preparative HPLC to give the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (m, 1 H) 1.52 (m, 1 H) 1.76 (td, J=13.89, 1.52 Hz, 2 H) 2.72-2.81 (m, 1 H) 2.96 (td, J=12.63, 2.27 Hz, 1 H) 3.16 (d, J=5.31 Hz, 1 H) 3.85 (dd, J=11.37, 2.27 Hz, 1 H) 4.37 (ddd, J=12.69, 1.83; 1.64 Hz, 1 H) 7.03 (d, J=8.59 Hz, 1 H) 7.31 (d, J=8.34 Hz, 2 H) 7.60 (d, J=8.34 Hz, 2 H) 7.78 (d, J=8.84 Hz, 1 H) 7.98 (dd, J=8.72, 2.65 Hz, 1 H) 8.55 (d, J=2.53 Hz, 1 H) 8.58 (dd, J=8.59, 2.02 Hz, 1 H) 8.90 (d, J=2.27 Hz, 1 H) 9.91 (s, 1 H); MS (M+H)+ 471.2.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32].O>CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:31](=[O:32])[C:30]([F:37])([F:36])[F:29])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Nc3ccccc3[C@H]12
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Nc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-amine (Structure 35 of scheme IX where X=N(H), R1=H, R2=H, R3=Cl, R4=H, R5=H, R10=H) (350 mg, 1.17 mmol) in methanol (22 mL) and triethylamine (0.7 mL) was added ethyl trifluoroacetate (1.5 mL). The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ethyl acetate (3×). The organic layers were washed with brine, dried (Na2SO4) and evaporated. After purification on silica with heptane/ethyl acetate 6:4 the title compound (90 mg, 19%) was obtained. Data: 1H-NMR (400 MHz, CDCl3) 1.69 (m, 1H), 1.86-1.94 (m, 2H), 2.11 (m, 1H), 2.99-3.09 (m, 2H), 4.47 (d, 1H), 4.86 (m, 1H), 5.79 (s, 1H, NH), 6.62 (d, J=8.2, 1H), 6.75 (dd, J=7.8, 1H), 6.89 (t, J=7.8, 1H), 6.91 (dd, J=8.2, J=2.7, 1H), 7.10 (d, J=2.7, 1H), 7.18 (t, J=7.8, 1H), 7.24 (d, J=7.8, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccsc2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 61 h
Yield: 48.8 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methylbenzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol), 3-thiopheneboronic acid (347 mg, 2.71 mmol) and tripotassium phosphate (288 mg, 1.36 mmol) were suspended in 1,4-dioxane (8 ml), and at room temperature, tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) was added. The mixture liquid was stirred under nitrogen atmosphere at 95° C. for 61 hours, then cooled to room temperature. The insoluble matter was separated by filtration with washing with ethyl acetate, and the filtrate was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=19:1, v/v) to obtain the entitled compound (99 mg, 49%) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+]>C(#N)C.CCN(CC)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:23]=[CH:22][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (300 mg, 0.84 mmol) in acetonitrile (10 mL) and NEt3 (1 mL) was added 4-vinylpyridine(0.15 mL, 1.34 mmol), palladium acetate (28 mg, 0.13 mmol) and tri-o-tolylphosphine (141 mg). The reaction mixture was heated in a sealed tube at 100° C. for 16 h. After cooling to room temperature, saturated NaHCO3 solution was added. The mixture was extracted with EtOAc (2X). The combined organic solvent was dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc, 2:1 to 1:2) to afford an oil (255 mg, 80%): 1H NMR (CDCl3, 300 Hz) δ1.50 (s, 9H), 1.90 (m, 1H), 2.00-2.10 (m, 2H), 3.30-3.50 (m, 2H), 4.00 (m, 1H), 4.14-4.24 (m, 2H), 4.28 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.36-7.40 (m, 3H), 8.26 (s, 1H), 8.30 (s, 1H), 8.60 (d, 2H, J=6.5 Hz); MS (CI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[H-].[Na+].Cl[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([C:23]3[N:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1cc2ccn(-c3nc(C)cc(C)n3)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (10 mg, 0.04 mmol) in DMF (0.5 mL) is added NaH (95%, 3 mg). The reaction mixture is stirred at room temperature for 30 minutes, and then 2-chloro-4,6-dimethyl-pyrimidine (17 mg, 0.12 mmol)) is added. The mixture is heated at 60° C. overnight and cooled. Water (1 mL) and EtOAc (2 mL) are added to the mixture. The organic layer is separated, washed with water once and concentrated under reduced pressure. The residue is purified by PTLC (Hexane/EtOAc 4:1) to give the titled compound. 1H NMR: (CDCl3) 10.21 (s, 1H), 8.48 (d, 1H), 7.47 (s, 1H), 7.28 (t, 1H), 7.15 (d, 2H), 6.87 (s, 1H), 6.68 (d, 1H), 2.55 (s, 6H), 2.36 (m, 4H), 1.03 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 93 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H), 3.20-3.28 (m, 4H), 3.76-3.96 (m, 4H), 4.14 (s, 3H), 7.02-7.13 (m, 3H), 7.28 (s, 1H), 7.49-7.63 (m, 4H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1.O>[CH:33]([O:32][C:30](=[O:31])[NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)([CH3:35])[CH3:34]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 28.8 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.07 g, 0.25 mmol), triethylamine (0.052 mL, 0.38 mmol) and isopropyl chloroformate (1M solution in toluene) (0.281 mL, 0.28 mmol) were dissolved in toluene (3 mL) and stirred at 60° C. for 10 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL). The combined organic phases was dried over sodium sulfate, filtered and the filtrate evaporated. The residue was subjected to column chromatography (silica gel, heptane/ethyl acetate, 9:1, 4:1, 3:1) to yield the title compound (0.026 g, 41%) as a white foam; MS: m/e=361.7 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1cccs1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccs3)CC12
Reaction time: 1 h
Yield: 74 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(2-thienyl)acetic acid (0.71 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 2 hours at +5° C. and for 16 hours at 20° C. and is then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (10 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-thienyl)acetyl]-4-perhydroisoindolone (1.5 g) melting at 206° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CCCCCCCC.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].Cl>[Fe](Cl)(Cl)Cl.O.C(OC(=O)C)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([C:4]1[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])=[O:26]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(OC)c1OC
Temperature: 105 °C

Procedure:
A mixture of 3,4,5-trimethoxytoluene (9.11 g; 50 mmol), octane (25 ml) and iron(III)chloride (50 mg) is stirred at 105° C., and percolating nitrogene 2,6-dichlorobenzoylchloride (12.04 g; 57.5 mmol) is added dropwise within 15 minutes. The mixture is kept at 105° C. and stirred for another 15 minutes. After cooling to 50° C. ethylacetate (50 ml) is added, the mixture shaken twice with 2N hydrochloric acid, once with water and dried. The ethylacetate is evaporated (70° C.) and the liquid cooled with stirring. At 50° C. petrolether (50 ml) is added. The white crystals formed are sucked off, washed with petrolether and dried. Yield 12.55 g (70.7%), mp. 92° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1.ClC1C([Li])=CC=CN=1.[CH:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>CCCCCC.CCOCC.O>[Cl:13][C:8]1[C:7]([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[OH:31])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Clc1ncccc1Br
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Agent: [Li]c1cccnc1Cl
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COc1cccc(C(O)c2cccnc2Cl)c1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
71.5 ml of a 2.1N solution of n-butyllithium in hexane are added to 19.2 g 3-bromo-2-chloropyridine (obtained according to J. D. Cook et. al. J. Chem. Soc., Section C, 1969 1973-8) in 300 ml anhydrous ether at -60° C. and under a static nitrogen atmosphere. To this freshly prepared solution of 2-chloro-3-pyridyllithium, a solution of m-anisaldehyde (13.6 g) in 100 ml anhydrous ether is added dropwise. The reaction mixture is stirred for 1 hr. at -60° C. and then is added to ice:water. The organic phase is separated and the aqueous phase is extracted with ether. The combined organic solutions are washed with water, dried (MgSO4) and solvent evaporated. The crude oil is chromatographed over SiO2 and eluted with chloroform, obtaining 14.9 g of title product as an oil which spontaneously crystallises. Recrystallisation from methanol:water affords pure product, m.p. 114°-5° C.; Cl 14.65 (14.20).
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[NH2:7][CH2:8][C:9]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][C:16]2[C:21]([N:22]=1)=[C:20]([C:23]1[NH:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[CH:24]=1)[CH:19]=[CH:18][CH:17]=2)([CH3:11])[CH3:10]>C1COCC1.CC(O)C>[CH3:33][C:14]1[C:13]([NH:12][C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]2[NH:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[CH:24]=2)[N:15]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CNCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
A solution of methyl vinyl sulfone (0.016 mL, 0.178 mmol) (Sigma-Aldrich) in THF (1.0 mL) was added to a mixture of 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (341) (65 mg, 0.18 mmol) in 2-Propanol (2.00 mL); the reaction mixture was stirred at RT for 16 h when only a small amount of product was observed via lcms. More methyl vinyl sulfone (0.16 mL, 1.78 mmol) was added to the reaction mixture before it was heated in the microwave at 110° C. for 75 min when mostly product was observed via lcms. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-6% of 2 M NH3 in MeOH/DCM to give 2-(2-methyl-3-((2-methyl-1-((2-(methylsulfonyl)ethyl)amino)propan-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (342, 58 mg, 0.12 mmol, 69% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 6H) 2.57 (s, 3H) 2.91 (s, 2H) 2.92 (s, 3H) 2.97 (t, J=6.94 Hz, 2H) 3.18-3.25 (m, 2H) 3.25-3.31 (m, 2H) 3.65 (td, J=6.85, 2.35 Hz, 2H) 5.52 (br. s., 1H) 5.92 (s, 1H) 7.09 (d, J=1.76 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.64 (dd, J=8.12, 1.08 Hz, 1H) 7.91 (dd, J=7.63, 0.98 Hz, 1H) 12.49 (br. s., 1H). MS (ESI, pos. ion) m/z: 471.4 (M+1).