Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:3]=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CSc1ncnc2c(N3CCCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: CSc1ncnc2c(N3CCCC3)nc(N3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 g (0.01 mol) of 2-chloro-8-methylthio-4-pyrrolidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 300 ml of dimethylsulphoxide and then a solution of 4.3 g (0.05 mol) of piperazine is added. After being stirred for 1 hour at ambient temperature the solution is poured into 1.5 liters of water. The precipitate obtained is suction filtered, washed with water and dried.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>CS(C)=O.O>[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCc1cccc(I)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CNCc1cccc(I)c1
Reaction time: 2 h

Procedure:
3-Iodobenzylamine hydrochloride (1.0 g) and diisopropylethylamine (1.29 ml) were taken up in dry dimethylsulfoxide (60 ml) and treated with ethyl bromoacetate and stirred under nitrogen for 2 h. 2M HCl (1.85 ml) and water (250 ml) were added. This was extracted with EtOAc, the aqueous phase was taken to pH 8 and extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (Biotage, 40 g) eluting with EtOAc-cyclohexane-diisopropylethylamine (10:89:1 then 20:79:1) to give the title compound (0.571 g) LCMS RT 2.02 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:23][CH:25]3[O:27][CH2:26]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1cc(OCc2ccccc2)c2ccc(OCC3CO3)cc2o1

Procedure:
4-Benzyloxy-7-hydroxycoumarin (10.7 g, 0.041 mole) was dissolved in ethanol (200 ml) and a solution of potassium hydroxide (2.5 g) in water (10 ml) was added. Epichlorhydrin (40 ml) was added and the stirred mixture heated to reflux for 21/2 hr. After cooling, the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. Evaporation of the dried (MgSO4) organic phase gave the product as a white crystalline solid. Recrystallization from ethanol gave 11.1 g (83%) of material of m.p. 128°-129° C.; (Found; C, 70.48; H, 4.92; C19H16O5 requires; C, 70.36; H, 4.97%).
Reaction SMILES: C[Li].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:30])[C:17]2[C:22]([NH:23][C:24]([CH3:28])([C:26]#N)[CH3:25])=[CH:21][CH:20]=[C:19]([F:29])[N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:30])[C:17]2[C:22]([NH:23][C:24]([CH3:25])([CH3:26])[CH3:28])=[CH:21][CH:20]=[C:19]([F:29])[N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(c1nc(F)ccc1NC(C)(C)C#N)C1CCN(Cc2ccccc2)CC1
Agent: [Li]C
Solvent: Cc1ccccc1
Product: CN(c1nc(F)ccc1NC(C)(C)C)C1CCN(Cc2ccccc2)CC1

Procedure:
Methyllithium (53 ml, 74.2 mmol, 1.4M in ether) is added to toluene (15 ml) in a dry flask under a nitrogen atmosphere at -78°. 1-Benzyl-4-[N-methyl-N-(3-(1-methyl-1-cyanoethyl)amino-6-fluoro-2-pyridinyl)amino]piperidine (EXAMPLE 152, 2.83 g, 7.42 mmol) in toluene (15 ml) is cooled to -78° and cannulated into the methyllithium mixture. The mixture is allowed to warm gradually to 20°-25°, then quenched cautiously with water. The mixture is extracted with chloroform and the extract dried over sodium sulfate, filtered and concentrated. The concentrate is chromatography (silica gel, 100 g; ethyl acetate/hexane (20/80)) to give the title compound; NMR (300 MHz, CD3OD) 7.55, 7.48, 6.78, 3.68, 3.25, 3.10, 2.74, 2.20-2.30, 1.75-1.90 and 1.52δ.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC1CCCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3C)nc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (10 ml) was added 2-methylpiperidine (500 mg, 5.04 mmol) and DIEA (650 mg, 5.03 mmol). The resulting solution was stirred at 80° C. for 2 hours and then quenched by water (50 ml). The solids were collected by filtration to afford methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (520 mg, 69%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCCN1CCN(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1-[3-(Ethyloxy)-4-nitrophenyl]-4-propylpiperazine (0.422 g, 1.44 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.28 g, 0.072 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (0.295 g, 1.12 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.45-6.53 (m, 2H), 6.28 (dd, J=8.33, 2.11 Hz, 1H), 3.95 (q, J=6.96 Hz, 2H), 2.96-3.07 (m, 4H), 2.84-2.95 (m, 4H), 2.63-2.74 (m, 2H), 1.50-1.60 (m, 2H), 1.27-1.32 (m, 3H), 0.87 (t, J=7.42 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[N:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](C)Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(c1ccc(Cl)cc1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of (2R)-4-chlorophenylalanine methylester (213 mg, 1.00 mmol) in DCM (5 mL) was added dropwise TEA (280 μl, 2.00 mmol) and then methanesulfonylchloride (100 μl, 1.3 mmol) at 0° C. After 30 min, the reaction mixture was quenched with water and extracted with DCM and EtOAc. The organic solution was washed with 1N HCl, dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (280 mg, 96.1%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1N)([CH3:4])([CH3:3])[CH3:2].N([O-])=[O:16].[Na+].NC(N)=O.OS(O)(=O)=O.O>OS(O)(=O)=O.O>[C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 61.5 %

Procedure:
To a mixture of 2-tert-butyl-5-nitroaniline (1.94 g, 10 mmol) in 40 mL of 15% H2SO4 was added dropwise a solution of NaNO2 (763 mg, 11.0 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at 0-5° C. for 5 min. Excess NaNO2 was neutralized with urea, then mL of H2SO4—H2O (v/v 1:2) was added and the mixture was refluxed for 5 min. Three additional 5 mL aliquots of H2SO4—H2O (v/v 1:2) were added while heating at reflux. The reaction mixture was cooled to room temperature and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc-Hexane) to give 2-tert-butyl-5-nitrophenol (C-1-a) (1.2 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=8.6, 2.2 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H); HPLC ret. time 3.46 min, 10-99% CH3CN, 5 min run.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]1(C)C=CC=C[CH:17]=1>FC(F)(F)C(O)=O.CC(OC)(C)C>[CH2:8]([CH:9]1[CH2:10][CH2:5][CH:3]=[CH:2][O:1]1)[CH2:7][CH:6]=[CH:16][CH3:17]
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC=CCCC1CCC=CO1
Temperature: 50 °C

Procedure:
The cyclic vinyl ether (2 eq.) was added to a suspension of the hydroxy-acetophenone (10 mmol) in toluene (10 ml), followed by trifluoroacetic acid (2 or 3 drops, ˜0.01 eq.). The mixture was heated at 50° C. When the reaction was complete (TLC, 2-3 hours), it was diluted with MTBE and poured into aq. NaHCO3 (sat.). The aqueous phase was separated and extracted with MTBE, and the combined organic layers were washed with brine and dried over MgSO4. The crude, obtained after evaporation of the solvents, was purified by chromatography (SiO2, EtOAc/Hexane) to afford the desired product as a colorless to pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cc1
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(4-methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid 161 and amine 14.
Reaction SMILES: F[C:2]1([O:9][C:10]#[C:11][CH3:12])[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][CH2:3]1.[Br:13]C1C=CC(F)=CC=1O>>[Br:13][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: CC#COC1(F)C=C(F)C=CC1
Reactant: Oc1cc(F)ccc1Br
Product: C#CCOc1cc(F)ccc1Br
Yield: 87 %

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-5-fluorphenol (15 g, 78 mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6 g (87%)
Reaction SMILES: [N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH2:9][C:4]2=[N:3][N:2]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[C:35]1([NH:34][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][N:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C1=CC=C2N=NN=C2C1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzotriazole-5-carboxylic acid (856 mg), HOAt (715 mg) and EDAC (1.00 g) were dissolved in DMF (17.5 mL) and the mixture was stirred at room temperature 1 hour. A 0.5 mL aliquot of this mixture was added to aniline (13.7 μL, 0.15 mmol) and the resulting mixture was vigorously shaken at room temperature for 16 hours. 1N hydrochloric acid (2 mL) and ethyl acetate (1 mL) were added and the mixture was vigorously shaken at room temperature for 2 hours. The organic phase was isolated and concentrated in vacuo to afford the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](Cl)[CH:17]=[CH:16]2>C1COCC1>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:17]=[CH:16]2
Reactant: Oc1ccccc1
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cccc2ccc(Oc3ccccc3)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
NaH (60% w/w in mineral oil; 1.311 g, 32.8 mmol) was added to a solution of phenol (3.09 g, 32.8 mmol, Aldrich) in THF (219 ml) at 0° C.; the resulting mixture was stirred for 10 min before 8-bromo-2-chloroquinoline (178a, 5.30 g, 21.86 mmol, Biofine International, Inc., Vancouver, BC) in THF (100 ml) was added. The reaction was stirred at 0° C. for 1 h before it was warmed to RT and stirred for 3 h, then heated at reflux for 24 h. Purification by silica gel chromatography (100% hexanes to 10% EtOAc/hexanes) provided 8-bromo-2-phenoxyquinoline (178b, 41% yield) as a light yellow oil. MS (ESI, pos. ion) m/z: 300.0/302 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([N:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[N:3]=1.C(N(CC)CC)C.C1(N(C)C2N=CN=C(C(OC)=O)C=2)CCCCC1.C1(N(C)C2N=CN=C(C(OCC)=O)C=2)CCCCC1.[OH-].[Li+]>[Pd].CCO.C1COCC1.CCO.O>[CH:14]1([N:12]([CH3:13])[C:4]2[N:3]=[CH:2][N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1cc(N(C)C2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: CCOC(=O)c1cc(N(C)C2CCCCC2)ncn1
Agent: COC(=O)c1cc(N(C)C2CCCCC2)ncn1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 2-chloro-6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylate (Intermediate 9, 10.00 g; 35.2 mmol), triethylamine (14.7 mL; 105 mmol) and palladium on charcoal (750 mg) in EtOH (1 L) was stirred at RT under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo to give a mixture of methyl 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylate and ethyl 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylate. This crude was dissolved in a mixture of THF/EtOH/H2O (3/2/1, 1 L) and treated with an aqueous lithium hydroxide solution (1N, 105 mL, 105 mmol). After 1 hour, the organic solvents were evaporated in vacuo and water (900) was added. The aqueous layer was washed with DCM (200 mL), then acidified to pH 4 by addition of a HCl solution (1N). The aqueous layer was evaporated to reduce the volume by 30-50%. A precipitate appeared and was filtered to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:31])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Solvent: ClCCl
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 4-chloro-8-(2,4-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.5 g, 7.6 mmol) in DCM (100 ml) was added m-CPBA (2.2 g, 10.2 mmol). The mixture was stirred for 10 min and evaporated. Flash chromatography (EtOAc) provided the title compound as a yellow solid (2.1 g, 80%):
Reaction SMILES: C([N:4]1[C:10](=[O:11])[C@@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:8]([CH3:20])[N:7]([C:21](=[O:23])[CH3:22])[C:6]2[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:5]1=2)(=O)C.[OH-].[Na+]>CO.CCOC(C)=O>[C:21]([N:7]1[C@@H:8]([CH3:20])[C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16])[C:10](=[O:11])[NH:4][C:5]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:6]1=2)(=[O:23])[CH3:22]
Reactant: CC(=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1c2cc(C#N)ccc2NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-1,5-diacetyl-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (413 mg, 1.03 mmol) in MeOH (10.3 ml) was added 1 M aq. sodium hydroxide (1.13 ml, 1.13 mmol), dropwise. The reaction was stirred for 30 min, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-1-acetyl-8-cyano-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (144 mg, 39%) as a white solid. MS m/z 381 (MNa)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[C:44]([O:43][C:41]([N:35]1[CH2:40][CH2:39][N:38]([C:13](=[O:15])[CH2:12][CH2:11][C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)[CH2:37][CH2:36]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (2.07 g, 10 mmol), prepared as described in Example 1 above, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloide (2.3 g, 12 mmol), anhydrous 1-hydroxybenzotriazole (1.62 g, 12 mmol) and N,N-diisopropylethylamine (1.75 ml, 10 mmol) were mixed together in 50 ml of dichloromethane and stirred for one hour at room temperature. Tert-butyl 1-piperazinecarboxylate (2.24 g, 12 mmol) was added to the mixture and stirred at room temperature overnight. The reaction mixture was concentrated and the syrup was dissolved in dichloromethane then purified by flash chromatography, eluting with dichloromethane followed by (dichloromethane: methanol 50/1, 30/1) to give 4-[3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (4.45 g, 86% pure).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:2]1=2.[H-].[Na+].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](OCC)=[O:23]>C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:13])[CH2:12][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[O:23])[CH:9]=[CH:10][C:2]1=2
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccccn1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XV) (1 eq) in THF was added slowly to a suspension of NaH (1.5 eq) in THF stirred under nitrogen at room temperature. The solution was further allowed to stir at room temperature until the evolution of gas was ceased. Ethyl picolinate (XIX) (1.1 eq) was added to the solution and refluxed overnight under nitrogen. The solution was cooled, poured into ice water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography over silica gel to produce 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyridin-2-yl)propane-1,3-dione 15 as a yellow solid (71% yield), 1H NMR (CDCl3, 400 MHz): δ ppm 4.13-4.43 (m, 4H), 6.94 (d, J=8.31 Hz, 1H), 7.42 (m, 1H), 7.44 (m, 1H) 7.59 (m, 2H), 7.85 (m, 1H), 8.14 (d, J=7.81, 1H), 8.65 (m, 1H); ESIMS found C16H13NO4 m/z 284 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:24]=[CH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]=4)[CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Clc1nccnc1OC1CCCN(c2ccc3ccccc3n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nccnc2OC2CCCN(c3ccc4ccccc4n3)C2)ccn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of (racemic mixture) 2-(3-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (see PREPARATION P2.3; 340 mg, 1.0 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (219 mg, 1.0 mmol) and K3PO4 (424 mg, 2.0 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl2 (73 mg, 0.1 mmol) then the reaction mixture was stirred at 110° C. under N2 atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2 (30 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give (racemic mixture) 2-(3-((3-(2-methylpyridin-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)quinoline (200 mg, 0.50 mmol, yield 60%). ESI-MS (M+1): 384 calc. for C23H21N5O 383.
Reaction SMILES: Cl.Cl.[O:3]([CH2:7][CH2:8][NH2:9])[CH2:4][CH2:5][NH2:6].Br.Br[CH2:12][CH2:13][NH2:14].C[O-].[Na+]>C(O)C>[NH2:6][CH2:5][CH2:4][O:3][CH2:7][CH2:8][NH:9][CH2:12][CH2:13][NH2:14]
Reactant: NCCBr
Reactant: NCCOCCN
Agent: Br
Agent: C[O-]
Agent: Cl
Solvent: CCO
Product: NCCNCCOCCN
Temperature: 25 °C

Procedure:
To a mixture of 2,2'-oxy-bis(ethylamine)dihydrochloride (1) (177 mg, 1 mmol), bromoethylamine hydrobromide (2) (204.9 mg, 1 mmol), in ethanol (10 mL) was added sodium methoxide (162.6 mg, 3 mmol) at room temperature. The reaction mixture was refluxed for 48 hours under a positive flow of argon. Reaction mixture was cooled to room temperature, ethanol was evaporated on rotavapor and the crude product (135 mg) was directly taken into next step to prepare the bis-naphthalimide, compound 5.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.O.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1Sc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2 g of 2-fluoro-4-chloro-nitrobenzene in 50 ml DMF and 1.25 ml of thiophenol was added 1.9 ml triethylamine at room temperature. The mixture was stirred for one hour. One hundred mL of water was added and a yellow solid crashed out of solution. The solid was collected by filtration and dried. Yield: 50-70%. LC-MS showed a single peak with the expected (M+H+) of 267.