Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[OH-].[Na+].C(O)C>[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:2])=[CH:26][CH:25]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: O=Cc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.75 mmol) was added to a solution of 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzaldehyde (2.2 g, 5.94 mmol) in 1N aqueous sodium hydroxide (10 ml) and ethanol (10 ml) at room temperature and stirred for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in acetic acid (10 ml) and was stirred at 80° C. for 6 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzonitrile (1.4 g, 64%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]3[C:29]([N:30]=2)=[CH:28][CH:27]=[C:26]([C:31]2([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:33][CH2:32]2)[N:25]=3)=[C:18]([F:40])[CH:17]=1>COCCOC>[F:40][C:18]1[CH:17]=[C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:21]=[CH:20][C:19]=1[C:22]1[S:23][C:24]2[C:29]([N:30]=1)=[CH:28][CH:27]=[C:26]([C:31]1([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][CH2:33]1)[N:25]=2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a slurry of NaH (0.55 g, 14 mmol) in 40 mL DME under nitrogen was added diethyl malonate (2.1 mL, 14 mmol) slowly dropwise. After addition of 1 mL, the reaction mixture was warm, so cooled to 0° C. and continued addition. To the resulting clear solution was added a slurry of 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (3.00 g, 6.8 mmol) as a solid. After 1 h, the reaction mixture was quenched with sat'd aq. Ammonium chloride and DCM, and the aq. Layer was extracted with DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography, 40 g, 0-30% EA/hexanes. Product containing fractions were combined and concentrated and triturated with hexanes to give diethyl 2-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)malonate as an off-white solid. MS (ESI) m/z: calculated: 518.2; Observed: 519.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1)O.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: CSc1ncncc1C(O)c1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CSc1ncncc1C(Cl)c1ccccc1F
Reaction time: 1 h

Procedure:
To a slurry of 9.5 g (38 mmol) of (2-fluorophenyl) (4-methylthio-5-pyrimidinyl)methanol in 50 mL of dichloromethane was added slowly with stirring 10 g (84 mmol) of thionyl chloride. The resulting solution was stirred 1 hr. and then was concentrated by evaporation under reduced pressure. The resulting amber oil was diluted with 5 mL of dichloromethane and then 100 mL of hexane. The light tan solid that formed was collected by filtration and dried under reduced pressure to obtain 10.1 g (99 percent of theory) of the title compound in crude form melting at 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[CH:24](=O)[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:24][CH2:25][CH3:26])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Reactant: CCC=O
Product: CCC=Nn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and propionaldehyde. A colorless powder (120 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][NH:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([CH2:17][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([C:34]4[CH:42]=[CH:41][CH:40]=[C:39]5[C:35]=4[CH:36]=[CH:37][NH:38]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[N:16][N:15]=2)[CH2:19]1
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)C[C@H](C)O1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4C)o2)C[C@H](C)O1
Temperature: 110 °C
Yield: 10.1 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (50 mg, 0.123 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (32.9 mg, 0.135 mmol), sodium carbonate (39.1 mg, 0.369 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride) (9.00 mg, 0.012 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane to give the title compound as a white solid (5.5 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([CH:30]2[CH2:32][CH2:31]2)[OH:29])=[CH:6][CH:5]=1.[CH3:33]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([CH:30]2[CH2:32][CH2:31]2)[O:29][CH3:33])=[CH:6][CH:5]=1
Reactant: CI
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F)C1CC1
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
Sodium hydride (60% in oil, 52.4 mg, 1.31 mmol) was added to a stirred solution of {9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}(cyclopropyl)methanol (500 mg, 1.09 mmol) in N,N-dimethylformamide (4.0 mL) at room temperature. After stirring 5 min, methyl iodide (232 mg, 1.64 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (396 mg, 0.842 mmol, 77%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN=C=S
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CCCCCCCNC(=S)NCc1ccccc1
Yield: 105.9 %

Procedure:
To a solution of 3.1 grams (0.02 mole) of n-heptyl isothiocyanate dissolved in 25 milliliters of benzene, was added 2.1 grams (0.02 mole) benzylamine. The resulting exothermic reaction resulted in a temperature rise from 24° C. to 35° C. The mixture was then refluxed for 20 minutes on the steam-bath until the mixture reached neutral pH and the mixture was evaporated under vacuum to yield 5.6 grams of n-heptyl-3-benzyl thiourea, ND30 =1.5513.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:13]=3[S:14][C:15]=2[C:16]([O:18]C)=[O:17])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:13]=3[S:14][C:15]=2[C:16]([OH:18])=[O:17])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1CCC(c2c(C(=O)O)sc3cc(C(F)(F)F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a stirred solution of 4-(2-Methoxycarbonyl-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (1.1 g, 2.7 mmol) in THF (7.0 mL) was added 1 N NaOH (2.97 mL). The resulting mixture was stirred at room temperature overnight when the mixture was diluted with water (50 mL) and washed with ether (100 mL). The aqueous layer was acidified with the addition of 3 N HCl and the product was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated yielding 960 mg (92%) of the desired product as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH+:8]([O-])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C[Si]([C:21]#[N:22])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:21]([C:6]1[N:1]=[C:2]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=[CH:4][CH:5]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)[NH+]([O-])Cc1ccccn1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
tert-Butyl 2-pyridylmethylcarbamate N-oxide (3.0 g, 13.3 mmol) was dissolved in nitroethane (50 ml), and trimethylsilyl cyanide (2.8 g, 28.6 mmol) and N,N-dimethylcarbamoyl chloride (1.7 g, 16.2 mmol) were added thereto. The mixture was stirred at room temperature for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.8 g, 58%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC1C=C(C=CC=1)CNC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>CN(C=O)C>[CH2:30]([NH:37][C:27]([C:26]1[C:20]2[NH:19][C:18]([C:12]3[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:22][C:21]=2[CH:23]=[CH:24][CH:25]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid benzylamide was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid benzylamide. LC/MS calcd for C28H24ClN5O2 (m/e) 497.0, obsd 498 (M+H).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[C:12]([CH3:24])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.N>CO.[Pd]>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[N:11]=[C:12]([CH3:24])[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Agent: N
Solvent: O=CO
Solvent: CO
Product: Cc1nc2c(cc1CCC(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 86.4 %

Procedure:
To a stirred suspension of 2-anilino-6-[(E)-3-hydroxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propanoicacid (34.5 mg, 86%): LCMS RT: 2.31 min, MH+: 400.4, Rf=0.61 (4:1 EtOAc:MeOH).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:13])[CH3:12])[CH:4]=[CH:3][CH:2]=1.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Si:14]([O:13][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)=[CH2:12])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(=O)c1cccc2cccnc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cccnc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(quinolin-8-yl)ethanone (200 mg, 1.169 mmol) and TEA (0.2 mL, 1.520 mmol) in DCM (2 mL) at 0° C. was added TBSOTf (339 mg, 1.286 mmol), and the resulting mixture was stirred at 0° C. for 1 h. The mixture was diluted with sat. aq. NaHCO3 and extracted with EtOAc (2×5 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline (300 mg) as a black solid (used without further purification): 1H NMR (400 MHz, DMSO-d6): δ 9.07 (1H, dd, J=1.6 Hz & 2.4 Hz), 8.23 (1H, dd, J=2 Hz & 6.4 Hz), 8.00 (1H, dd, J=1.6 Hz & 5.6 Hz), 7.84 (1H, dd, J=1.6 Hz & 6.8 Hz), 7.59 (1H, t, J=7.6 Hz), 7.49 (1H, dd, J=4 Hz & 4.4 Hz), 5.43 (1H, s), 5.02 (1H, s), 1.01 (9H, s), 0.20 (6H, s). m/z (ESI, +ve) 285.9 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[O:6])[CH2:4][CH3:5].[CH2:7]=[CH:8][CH:9]=[CH2:10].C1(C=CC(O)=CC=1)O>>[CH2:2]([C:3]([CH:4]1[CH2:10][CH2:9][CH:8]=[CH:7][CH2:5]1)=[O:6])[CH3:1]
Reactant: C=CC=C
Reactant: C=CC(=O)CC
Agent: Oc1ccc(O)cc1
Product: CCC(=O)C1CC=CCC1
Reaction time: 5 h
Yield: 76 %

Procedure:
50 g of pent-1-en-3-one and 50 g of butadiene are reacted, in the presence of 1 g of hydroquinone, in a 250 ml shaken bomb, at 100° C. After 5 hours, the bomb is cooled and the product is distilled. 55 g=76% of cyclohex-3-enyl ethyl ketone, of boiling point 78°-81° C./10 mm Hg, are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].CN(C)C=[O:15]>>[Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([OH:15])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Cl)c(C#N)c(Cl)n1
Reactant: CN(C)C=O
Product: Cc1cc(O)c(C#N)c(Cl)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 2,4-dichloro-6-methylnicotinonitrile (12.0 g, 64.2 mmol), CsOAc (37.0 g, 193.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80° C. overnight under N2. The mixture was partitioned between water (800 mL) and ethyl acetate (800 mL), the organic layer was dried and concentrated to afford 2-chloro-4-hydroxy-6-methylnicotinonitrile (9.0 g brown solid, 84.1% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[CH2:43][CH2:42][N:41]([C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH2:40][CH2:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCN(Cc3ccccc3)CC1)O2
Yield: 68.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 506 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.02 mmol), 365 mg CDI (2.25 mmol) and 386 mg 1-benzylpiperazine (2.2 mmol) yielded 568 mg of (4-benzylpiperazin-1-yl)(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methanone as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:20][O-:21].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([O:21][CH3:20])=[CH:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(C)C)cc2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
N-(4-Isopropylphenyl)-6-chloropyridine-3-carboxamide (1.00 g) was dissolved in THF (10 mL) and sodium methoxide (0.21 g) was added. The mixture was stirred at 50° C. for one day. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g).
Reaction SMILES: Br[C:2]1[CH:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:6][CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.O>COCCOC.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.[Fe+2].Cl[Pd]Cl>[CH:9]1([O:8][C:7]2[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5][N:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)C1=CNC(OC2CCCC2)C(Br)=C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2ccncc2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 30.8 %

Procedure:
Methyl 5-bromo-6-(cyclopentyloxy)-1,6-dihydropyridine-3-carboxylate (2.50 g, 7.94 mmol) was dissolved in DME (10 mL) and pyridin-4-ylboronic acid (813 mg, 6.61 mmol), DPPF-PdCl2 (108 mg, 0.13 mmol, Strem) and water (0.5 mL, 28 mmol) were added. The mixture was stirred at 40° C. for 4 h. The reaction mixture was cooled to RT, diluted with H10 and extracted 3× with EtOAc. The combined organic extracts were washed 1× with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 g pre-packed column, elution 0-30% EtOAc:hexanes) to give the title compound (608 mg, 31%). MS m/z: 299 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:47]=[CH:46][C:8]2[C:9](=[O:45])[N:10]([C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:36])=[CH:31][N:30]=5)[C:25](=[O:43])[N:24]([CH3:44])[CH:23]=4)[C:15]=3[CH:16]=[O:17])[CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C)C.C1COCC1>[C:1]([C:5]1[CH:47]=[CH:46][C:8]2[C:9](=[O:45])[N:10]([C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[C:26]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:36])=[CH:31][N:30]=5)[C:25](=[O:43])[N:24]([CH3:44])[CH:23]=4)[C:15]=3[CH2:16][OH:17])[CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(N3CCOc4cc(C(C)(C)C)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2cccc(N3CCOc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
To 2-(8-tert-Butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde (0.27 mmol) in isopropanol (5 mL) and THF (10 mL) at 0 C with stirring was added sodium borohydride (21 mg, 2 eq) and then the ice bath was removed and the resulting mixture was stirred at room temperature for 45 minutes. TLC analysis indicated that the reaction was complete so the mixture was diluted with ethyl acetate (150 mL) and water (50 mL). The layers were partitioned, then separated and the organic layer was further washed with water (3×50 mL) and then finally washed with brine ((1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. Purification by Thin Layer Chromatography on silica gel eluting with 10% methanol in dichloromethane afforded the title compound as a light grey powder (94 mg), (M+H)+=638.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:11](Br)Br.Cl.C(=O)([O-])[O-:16].[Na+].[Na+]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:11]=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c(C(Br)Br)c1
Agent: Cl
Agent: [Na+]
Product: O=Cc1cc(C(=O)O)ccc1Br
Temperature: 70 °C

Procedure:
4-Bromo-3-(dibromomethyl)benzoic acid (3.7 g) was added to a solution of aqueous sodium carbonate (16 g in 100 ml) and the mixture heated at 70° C. for 12 hrs. The pH of the cooled reaction was adjusted to pH5 using hydrochloric acid (2N) and the mixture extracted with ethyl acetate, to give, after evaporation of the solvent in vacuo, 4-bromo-3-formylbenzoic acid.