Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:34])=[CH:11][C:12]([F:33])=[C:13]([CH:32]=1)[O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[N:17][CH:16]=1)C1C=CC=CC=1>CO.CN(C=O)C.[Pd]>[F:33][C:12]1[CH:11]=[C:10]([CH3:34])[C:9]([OH:8])=[CH:32][C:13]=1[O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[N:17][CH:16]=1
Reactant: COCCOc1cc2nncc(Oc3cc(OCc4ccccc4)c(C)cc3F)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Oc3cc(O)c(C)cc3F)c2cc1OC
Reaction time: 9 h
Yield: 46.5 %

Procedure:
A solution of 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline (242 mg, 0.5 mmol) in a mixture of methanol (9 ml) and DMF (10.5 ml) containing 10% palladium-on-charcoal catalyst (100 mg) was stirred under hydrogen at 5 atmospheres pressure for 9 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was washed with methanol and ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline as a white solid (87 mg, 44%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.Cl.[NH:12]([CH2:14][CH2:15][CH2:16][OH:17])[NH2:13].Cl>C(O)C>[NH2:6][C:5]1[N:12]([CH2:14][CH2:15][CH2:16][OH:17])[N:13]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: NNCCCO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCCO)n1
Yield: 85.4 %

Procedure:
A solution of 4,4-dimethyl-3-oxo-pentanenitrile (0.7 g, 5.58 mmol) in ethanol (IMS grade, 5 mL) was treated with 3-hydrazino-propan-1-ol dihydrochloride (1 g, 6.13 mmol), followed by cone. HCl (0.05 mL), and the reaction mixture was heated at reflux for 18 h. The mixture was concentrated in vacuo and the residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM to afford the title compound as a white gummy solid (0.94 g, 85%). LCMS (Method 3): Rt 0.42 min, m/z 198 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([OH:10])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[S:12]([CH2:18][C:19]#[N:20])([CH2:15][C:16]#[N:17])(=[O:14])=[O:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[C:15]([C:16]#[N:17])[S:12]([CH2:18][C:19]#[N:20])(=[O:14])=[O:13])[CH:5]=[C:4]([OH:10])[C:3]=1[OH:11]
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: N#CCS(=O)(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CCS(=O)(=O)C(C#N)=Cc1cc(O)c(O)c(Br)c1
Yield: 6.3 %

Procedure:
A mixture of 500 mg of 5-bromo-3,4-dihydroxybenzaldehyde and 700 mg of sulfonly diacetonitrile in 6 ml of ethanol was refluxed with few drops of piperidine for 4 hours. Ethanol was removed in rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide about 50 mg of 2-(3-bromo-4,5-dihydroxyphenyl)-1-cyano-1-cyanomethylsulfonly ethene.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>C(#N)C>[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[C:12](=[O:17])[CH2:13]1
Reactant: CN1CCNCC1=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O

Procedure:
N,N-Diisopropylethylamine (11.5 ml) and 1-methyl-2-oxopiperazine (4.12 g) were added to a solution of 3,4-difluoronitrobenzene (1.82 ml) in acetonitrile (100 ml), and the mixture heated to reflux for 16 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 100% ethyl acetate in iso-hexane. Relevant fractions were combined and evaporated to give 3-fluoro-4-(4-methyl-3-oxopiperazin-1-yl)nitrobenzene (3.37 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Yield: 14.7 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (150 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (38.0 mg, 14.7%) as a solid.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1C[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[C:51]=1[CH2:58]C(O)=O>>[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[C:51]=1[CH2:58][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: Cc1cc(C)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,4,6-trimethylphenylacetic acid, mp 159°-161° C.
Reaction SMILES: C([CH:3]([C:9]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[S:11][N:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.C(Cl)(=O)C>C(O)C.C(OCC)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]2[S:11][N:10]=[C:9]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:13]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)C(C#N)c1nsc2ccc([N+](=O)[O-])cc12
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCOC(=O)Cc1nsc2ccc([N+](=O)[O-])cc12
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate (6.67 g, 0.0229 mol) is added to a solution of acetyl chloride (67.0 mL) in ethanol. The reaction mixture is refluxed overnight, cooled, and filtered to remove solids. The resultant filtrate is concentrated in vacuo to obtain a brown semi-solid. A mixture of the semi-solid in diethyl ether is stirred for two hours and filtered to obtain a solid. The solid is washed with diethyl ether and air-dried to give the title product as yellow crystals (1.04 g, mp 91-92° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:24]C(O)C>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CC(C)O
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F

Procedure:
To a solution of ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 200 mg) in 2-propanol (4 ml), concentrated sulfuric acid (0.2 ml) was added and the mixture was stirred under reflux for 10 days hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with dilute brine (30 ml×2) and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/4) and then crystallized from diisopropyl ether to yield isopropyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 25, 20 mg) as white powdery crystals.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2([CH2:27][CH3:28])[CH2:26][CH2:25]2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1(B(O)O)[CH2:39][CH2:38]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH:37]3[CH2:39][CH2:38]3)[CH:33]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2([CH2:27][CH3:28])[CH2:26][CH2:25]2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)N(C(=O)OC(C)(C)C)c2cc(Br)ccc23)CC1
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: Cc1ccccc1
Solvent: O
Product: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)N(C(=O)OC(C)(C)C)c2cc(C4CC4)ccc23)CC1
Temperature: 130 °C
Yield: 38.1 %

Procedure:
Under Argon atmosphere, racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (28 mg, 0.049 mmol), cyclopropylboronic acid (4.5 mg, 0.0524 mmol), Pd(PPh3)4 (5 mg), K3PO4 (50 mg) and a few drops of water were mixed in toluene (3 mL). The mixture was heated under microwave irradiation at 130° C. for 20 min. Then the solution was poured into water and the aqueous layer was extracted with EtOAc. The organic layer was dried and concentrated. The residue was purified by Prep-TLC to obtain racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (10 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[CH3:17])=[CH:29][CH:28]=1
Reactant: CC1CCCN1Cc1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CC1CCCN1Cc1ccc(N/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 14.5 %

Procedure:
To a solution of 0.2 g (0.61 mmol) of (4E)-6-iodo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione in 2 mL of N,N′-dimethylformamide is added {4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}amine (0.14 mL, 0.73 mmol). The reaction mixture is heated at 100° C. under N2. Mass spectroscopy suggested the completion of reaction after 45 min. The reaction mixture is concentrated under high-pressure vacuum. Purification is performed by silica gel chromatography using 5% MeOH/CHCl3 as solvent. Concentrating the organic layer containing product afforded 0.043 g (14.5% yield) of yellow solid: mp 157-158° C.; MS (ESI) m/z 488.4 (M+H)+1
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(N)cnc3ccsc23)C1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (197 mg, 2.21 mmol) and triethyloxonium tetrafluoroborate (395 mg, 2.08 mmol) in tetrahydrofuran (4.0 mL) was stirred at room temperature for 75 min then concentrated. The residue was dissolved in ethanol (1.5 mL) and this solution was then added to a solution of tert-butyl (3S)-3-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.24 g, 0.69 mmol) in ethanol (3.5 mL) in a vial. The resulting mixture was stirred at 80° C. for 2 h. The solvent was evaporated and the crude purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 250 mg (86%) of the desired product. LCMS calculated for C20H27N4O3S (M+H)+: m/z=403.2. Found: 403.1.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[O:9][C:3]3[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=3[N:8]=2)=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Nc1ccc(O)c(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(-c2nc3cc(N)ccc3o2)cc1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 93.9 %

Procedure:
8 mmol of 2,4-diaminophenol.2HCl and 8 mmol of 4-tert-butyl-benzoic acid were dissolved in 10 g of PPA, and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 2.0 g of 2-(4-tert-butylphenyl)benzo[d]oxazole-5-amine (Derivate #4) (yield: 94%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[N:12]=[N:13][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(-c2ccc(Nc3ccccc3)nn2)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Nc5ccccc5)nn4)cc3)c2cc1OC
Temperature: 120 °C

Procedure:
A mixture of 4-(6-phenylamino-pyridazin-3-yl)-phenol (Step 3, 0.25 g, 0.95 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.212 g, 0.95 mmol), Cu powder 0.1 g) and NaOH pellet (0.1 g) in DMF/pyridine (1.5 mL/1.5 mL) was heated in a microwave (CEM Discover, 60 W, 120° C., ramp 12 min, hold 18 min). The reaction mixture was then diluted with 50 mL of EtOAc and washed with 20 mL of water followed by brine (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column (50% EtOAc/hexane to EtOAc) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 451.2(M+H). Calc'd Exact Mass for C27H23N4O3: 450.49.
Reaction SMILES: [H-].[Na+].[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][OH:21])=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>CN(C)C=O>[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][O:21][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cc(N2CCCCCC2)c2ccc(CO)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCCCC2)c2ccc(COc3ccc(C#N)cc3)cc2n1
Temperature: 50 °C
Yield: 88.1 %

Procedure:
Sodium hydride (55-65% dispersion in mineral oil, 22 mg, 0.55 mmol) was added to a mixture of (4-azepan-1-yl-2-methyl-quinolin-7-yl)-methanol (example 3, 120 mg, 0.44 mmol) and 4-fluorobenzonitrile (54 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL). After heating 2 h at 50° C., the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded the title compound (144 mg, 87%). Light yellow solid, ISP-MS: m/e=372.3 ([M+H]+).
Reaction SMILES: [CH:1]([CH:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH2:16])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[C:28]([CH:29]=O)=[CH:27][C:26]2[N:25]([CH3:31])[C:24](=[O:32])[CH2:23][CH2:22][C:21]=2[N:20]=1.O=O>>[CH:1]([C@H:4]1[NH:9][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:7]([NH:16][CH2:29][C:28]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24](=[O:32])[N:25]3[CH3:31])=[N:20][C:19]=2[O:18][CH3:17])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCC(N)C(c2ccccc2)N1
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Agent: O=O
Product: COc1nc2c(cc1CN[C@H]1CC[C@@H](C(C)C)N[C@H]1c1ccccc1)N(C)C(=O)CC2

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-isopropyl-2-phenyl-piperidin-3-ylamine with 2-Methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde. Mass spectrum calcd for C25 H34 N4 O2 (M+1) 423; found 423.
Reaction SMILES: O[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: OCCSc1ccc(O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc(SCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of 5.0 g 4-(2-hydroxy-ethylsulfanyl)-phenol (29 mmol) in 100 ml CH2,Cl2 were added at 0° C. 2.6 ml pyridine (32.3 mmol) and 2.34 ml SOCl2 (32.3 mmol), dissolved in 10 ml CH2Cl2. The reaction mixture was stirred for 1 h at r.t. and then quenched by the addition of water. The organic phase was separated and washed twice with sat. NaHCO3-solution. The combined aqueous phases were extracted with CH2Cl2 twice and the combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to give 4.6 g product (24.3 mmol, 83%) as a yellow oil.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:44]>C(OCC)(=O)C>[CH2:1]([S:4]([CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)=[O:44])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Solvent: CCOC(C)=O
Product: C=CCS(=O)C1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Yield: 58.3 %

Procedure:
To a solution of 4.0 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-fluorophenoxy)-3-trimethylacetylthio-propenate in ethyl acetate at -78° was added a solution of 1.5 g of 80% m-chloroperoxybenzoic acid in ethyl acetate over 10 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over MgSO4, and evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 2.4 g of the title compound as a yellow oil (58% of the theoretical yield).
Reaction SMILES: O1CCCCC1[N:7]1[CH:11]=[N:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:27]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:26][C:25](=[O:34])[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)=[N:8]1.BrC1C=CC(C2N=CN(C3CCCCO3)N=2)=NC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[NH:7]1[CH:11]=[N:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:27]([CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH2:26][C:25](=[O:34])[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)=[N:8]1
Reactant: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3)cnc2N1
Agent: [Pd]
Agent: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4nc[nH]n4)nc3)cnc2N1
Temperature: 95 °C
Yield: 39 %

Procedure:
6-(6-(1-(Tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. A mixture of 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(111)-one (1 equiv), 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H -1,2,4-triazol-3-yl)pyridine (1.2 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv), tri-o-tolylphosphine (0.2 equiv), triethylamine (3 equiv) and N,N-dimethylformamide was heated at 95° C. for 3 h under nitrogen. Concentration and chromatography purification give the desired product in 39% yield. MS (ESI) m/z 463.1 [M+1]+.