Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([C:11]1([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C-:22]#[N:23].[K+].Cl>O.CO>[CH2:4]([C:11]1([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][C:14]([N:2]([CH3:3])[CH3:1])([C:22]#[N:23])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CNC
Reactant: CN(C)CC1(Cc2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)CC1(Cc2ccccc2)CCC(C#N)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
40% aqueous dimethylamine solution (2.8 mL, 22.1 mmol), 4-benzyl-4-((dimethylamino) methyl)cyclohexanone (1.13 g, 4.60 mmol) and potassium cyanide (0.70 g, 11.0 mmol) were added to a mixture of 4N hydrochloric acid (3 mL) and methanol (1.05 mL) with ice cooling. The mixture was stirred for 2 d at room temperature and then after adding water (200 mL) was extracted with ether (4×150 mL). After the solution was concentrated, the residue was taken up in dichloromethane (200 mL) and dried overnight with magnesium sulphate, filtered and the solvent was removed in a vacuum. The nitrile was obtained as an oil which was crystallised through.
Reaction SMILES: OO.[C:3]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([OH:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1)=[O:9].S([O-])([O-])=O.[Na+].[Na+].[C:41]([OH:45])([CH3:44])([CH3:43])[CH3:42]>>[C:3]([O:23][CH:24]1[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH2:42][C:41]([OH:45])([CH3:44])[CH3:43])[C:28]([CH3:31])([CH3:30])[CH2:29]1)(=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([O:19][CH2:42][C:41]([OH:45])([CH3:44])[CH3:43])[C:13]([CH3:21])([CH3:20])[CH2:12]1)=[O:9]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethylpieridin-4-yl) adipate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqeuous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:22]([OH:24])=O)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([N:14]1[CH2:19][CH2:18]C(F)(F)[CH2:16][CH2:15]1)=[O:13])=[CH:8]2.ClC1C=C(C(O)=O)C=C2C=1[NH:33][C:32]([C:35](O)=O)=[CH:31]2.[CH:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:43])[CH3:42].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:22]([N:47]2[CH2:48][CH2:49][N:44]([CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46]2)=[O:24])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([N:14]1[CH2:15][CH2:16][N:33]([CH:32]([CH3:35])[CH3:31])[CH2:18][CH2:19]1)=[O:13])=[CH:8]2
Reactant: O=C(O)c1cc(Cl)c2[nH]c(C(=O)O)cc2c1
Reactant: O=C(O)c1cc(Cl)c2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2cc(Cl)c3[nH]c(C(=O)N4CCN(C(C)C)CC4)cc3c2)CC1

Procedure:
The title compounds were synthesized in analogy to example 1, from 7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indole-5-carboxylic acid hydrochloride and 7-chloro-1H-indole-2,5-dicarboxylic acid (intermediate c), 1-isopropylpiperazine (commercially available), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide. The products were separated by silica gel chromatography using dichloromethane:methanol (19:1 v/v) as eluant.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([S:29]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([N:24]6[CH2:28][CH2:27][CH2:26][CH2:25]6)(=[O:30])=[O:31])[CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: O=S(=O)(c1cccc(B(O)O)c1)N1CCCC1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(S(=O)(=O)N5CCCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-(pyrrolidinylsulfonyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 33 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.78 min (Method A); M+H=503 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.16-8.11 (m, 2H), 8.02-7.96 (m, 1H), 7.94-7.89 (m, 1H), 7.83-7.78 (m, 1H), 7.77-7.71 (m, 2H), 7.69-7.65 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.21-3.14 (m, 4H), 1.95 (s, 3H), 1.70-1.63 (m, 4H))
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:16][CH2:15][CH2:14][C@H:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCC[C@H]1C(OC(C)(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:18]1([NH:17][CH2:2][C:3]([N:5]2[CH2:16][CH2:15][CH2:14][C@H:6]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CBr
Reactant: Nc1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CNc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1-(bromoacetyl)-L-proline, 1,1-dimethylethyl ester (2.1 g., 7.5 mmole) in distilled tetrahydrofuran (40 ml.) is added aniline (1.5 g., 15 mmole) and the reaction mixture is stirred overnight under nitrogen. The reaction mixture is diluted with ethyl acetate (200 ml.), washed with saturated sodium bicarbonate (2×50 ml.) and water (twice), dried (Na2SO4), and concentrated in vacuo into a dark oily residue (4.0 g.). Flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride) affords 2.2 g. of 1-N-phenylglycyl)-L-proline, 1,1-dimethylethyl ester as a dark oil which solidifies upon drying in high vacuum.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=2)[CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:17][CH:16]=2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][I:32]>CN(C)C=O>[I-:32].[CH3:31][N+:20]1([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[CH:11]=[CH:10][C:9]3[CH:28]=[CH:29][CH:30]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)=[CH:27][CH:26]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CI
Reactant: O=C(C=Cc1cccc(-c2ccccc2)c1)Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C=Cc3cccc(-c4ccccc4)c3)cc2)CCCCC1
Product: [I-]

Procedure:
A solution of 1—(4—(3-phenylcinnamoylamino)benzyl)piperidine (0.32 g) and methyl iodide (0.15 ml) in dimethylformamide (5 ml) was stirred over night under nitrogen atmosphere at room temperature. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol to give 1-methyl-1—(4—(3-phenylcinnamoylamino)benzyl)piperidinium iodide (Compound 85) (0.26 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19]([C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(=O)c2cc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2[nH]1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A mixture of 1.5 g of 2-Butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone, 3.0 g of triphenylmethyl chloride and 3 ml of triethylamine in methylene chloride is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and washed with water. The organic layer is dried with Na2SO4 and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 40% ethyl acetate-hexanes to give 1.0 g of the desired product as a solid, m.p. 182° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=3)(=[O:42])=[O:41])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(=O)(=O)c3cccc(F)c3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and 3-fluorobenzene-1-sulfonyl chloride to give 5,7-difluoro-2-(4-(3-fluorophenylsulfonyl)-piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.96 (br s, 3H), 3.03 (t, J=4.4 Hz, 4H), 3.14 (br s, 4H), 3.34-3.36 (m, 4H), 3.68 (t, J=4.4 Hz, 4H), 6.47 (s, 1H), 7.13-7.19 (m, 1H), 7.25-7.28 (m, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.60-7.65 (m, 3H), 7.71-7.77 (m, 2H,), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=599.4 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H, J=2.3 Hz), 7.48 (s, 1H), 7.4 (m, 1H), 7.39 (s, 1H), 7.37 (m, 2H), 7.24 (t, 1H, J=7.2 Hz), 6.92 (d, 1H, J=7.9 Hz), 6.06 (s, 1H), 3.31 (q, 2H, J=6.4 Hz), 2.94 (d, 2H, J=10.8 Hz), 2.79 (s, 3H), 2.53 (q, 1H, J=6.1), 2.47 (tt, 1H, J=4.2, 11.4 Hz), 2.29 (t, 2H, J=7.2 Hz), 1.99 (t, 2H, J=11.4 Hz), 1.81 (m, 2H), 1.69 (dt, 2H, J=2.4, 11.6), 1.59 (q, 2H, J=6.6 Hz), 1.24 (d, 6H, J=6.5 Hz); ESMS m/e: 557.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13][C:14]1[C:19]([CH:20]=O)=[C:18]([O:22][CH3:23])[N:17]=[CH:16][CH:15]=1.O.C(=O)=O.II>CO.CN(C=O)C>[CH3:7][O:6][C:4]([C:3]1[C:2]2[NH:1][C:20]([C:19]3[C:18]([O:22][CH3:23])=[N:17][CH:16]=[CH:15][C:14]=3[I:13])=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COc1nccc(I)c1C=O
Reactant: COC(=O)c1cccc(N)c1N
Agent: II
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2nc(-c3c(I)ccnc3OC)[nH]c12
Temperature: 25 °C
Yield: 59 %

Procedure:
In a 250 mL round-bottomed flask, methyl 2,3-diaminobenzoate (1.5 g, 9.03 mmol) was combined with methanol (25 mL) to give a yellow solution that was stirred under nitrogen and cooled in a water/dry ice bath. To this was added drop wise 4-iodo-2-methoxynicotinaldehyde (2.37 g, 9.03 mmol) dissolved in methanol (15 mL) and DMF (10 mL). During the addition more methanol (25.0 mL) was added to the reaction. The reaction was kept in the water/dry ice bath for 2.5 hr, allowed to warm to room temperature over 3 hr, and then cooled in a water/dry ice bath. To this was added drop wise iodine (1.49 g, 5.87 mmol) dissolved in methanol (15 mL) and then the reaction was allowed to warm to room temperature overnight. The reaction was concentrated, diluted with ethyl acetate (200 mL) and saturated Na2S2O3 (200 mL) and mixed. Significant insoluble material was present and the mixture was filtered. The resulting solid was washed with ethyl acetate and water. The filtrate was separated and the resulting aqueous layer was extracted with ethyl acetate (100 mL) and DCM (3×150 mL). The organic layers were washed with saturated Na2S2O3 and brine, combined, dried over MgSO4, and concentrated as a red oil/solid. The insoluble solid from the original extract was washed with DCM (5×100 mL) and the filtrate was concentrated as a dark red/black solid. The liquid extracted crude and the solid extract crude were dissolved in minimal DCM, combined, and purified by flash chromatography (silica gel, 120 g, 0% to 60% ethyl acetate in hexanes) to give 2-(4-iodo-2-methoxy-pyridin-3-yl)-3-H-benzoimidazole-4-carboxylic acid methyl ester, as a purple solid, 0.73 g LC/MS calcd for C15H12IN3O3 (m/e) 409.0, obsd 410.0 (M+H); 1H NMR (DMSO-d6) δ: 12.68 (s, 1H), 8.05 (d, J=5.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.88-7.95 (m, 1H), 7.67 (d, J=5.3 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H). The original insoluble solid remaining after being extracted with DCM was subsequently extracted with boiling methanol (5×20 ml). The methanol filtrate was concentrated and dried, yielding additional product (83% pure by LCMS), as the sodium salt (assumed) and as a dark purple solid, 0.57 g. The remaining original insoluble solid after the DCM and methanol extractions yielded additional product (90% pure by LCMS), as the sodium salt (assumed) and as a purple solid, 0.88 g. The combined yield was 59%.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[OH-:11].[Na+].[CH2:13]=O.S(=O)(=O)(O)O>O>[OH:10][CH2:9][C:2]1[O:3][C:4]([CH2:13][OH:11])=[C:5]([OH:8])[C:6](=[O:7])[CH:1]=1
Reactant: [OH-]
Reactant: C=O
Reactant: O=c1cc(CO)occ1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1cc(CO)oc(CO)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Kojic acid, 28 g, was suspended in 100 ml of water and a pH of the suspension was adjusted to 10.5 with 50% sodium hydroxide. After 16 ml of 35% formalin was added to the suspension, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to 5° C. and its pH was adjusted to 2.0 with 50% sulfuric acid. Then, the reaction solution was concentrated to about 50 ml and the resulting crystals were taken out by filtration, washed with a small quantity of chilled water and dried to give 28 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>CN(C=O)C>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[C:8](=[O:14])[NH:9][C:10]1=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: Cc1ccsc1-c1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccsc1-c1cn(CCCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
To a solution of 5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 26, 250 mg, 1.2 mmol) in DMF (10 mL), 60% NaH (58 mg, 1.44 mmol) was added portionwise. The reaction was then heated to 70° C. and this temperature was maintained for 1.5 hour. After cooling to room temperature, (4-iodo-butoxy)-tert-butyl-dimethyl-silane (452 mg, 1.44 mmol) was then added dropwise and the reaction was stirred for 24 hours. Water (30 mL) was added and the product was extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85) followed by DCM/MeOH (70:30) to give the title compound as a yellow oil (110 mg, 23% yield).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:12])[CH:5]=1.[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[CH2:24].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:6]2[N:7]=[C:8]([CH3:10])[N:9]=[C:4]([C:3]3[CH2:24][CH:23]([CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]4)[O:1][N:2]=3)[CH:5]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: COc1ccc(CNC(=O)c2cc(C=NO)nc(C)n2)cc1
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)OC(C)(C)C)CC4)C3)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a cold solution of (6-((hydroxyimino)methyl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.2 g, 0.66 mmol, Preparation #B.1.1) and tert-butyl 4-vinylpiperidine-1-carboxylate (0.168 g, 0.799 mmol, Preparation #E.1.2) in chloroform (20 mL) was added iodobenzene diacetate (0.343 g, 1.06 mmol) in one portion. The mixture was allowed to warm to RT and stirred for about another 1 h. The reaction mixture was quenched with water (20 mL) and the product was extracted with chloroform (2×20 mL). The organic layer was washed with water (2×15 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by column chromatography using silica gel (60-120 mesh) eluting with 50% n-hexane and EtOAc. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford tert-butyl 4-(3-(6-(4-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate 0.1 g (29%). MS m/z: 510 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:17](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:17][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1)C(=O)c1cccn1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc2c(c1)C(=O)c1cccn1CC2
Reaction time: 2 h

Procedure:
A solution of 9-amino-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in triethyl orthoformate (2.14 g.; 10 mmoles in 80 ml) is refluxed for 5 hours. The volatiles are removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol is stirred in an ice bath as sodium borohydride (0.88 g.; 0.024 moles) is added over a period of 10 minutes. The mixture is stirred for a period of 2 hours. After concentration of the ethanol, the residue is dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH:13]([N:19]3[CH2:20][CH2:21][N:16]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:31]=4[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:17][CH2:18]3)[CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1cccc2c(CC(C)=O)coc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cccc2c(CC(C)N3CCN(c4cccc5cccnc45)CC3)coc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, the reaction mixture was neutralized with 10% NaHCO3 and extracted with chloroform. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 60 mg (14%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.14 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.13˜7.56 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.46˜6.80 (m, 8H); 4.01 (s, 3H); 3.51˜1.60 (m, 11H); 1.14(d, J=6.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N[C@H:16](C(O)=O)CCSC>COCCOC>[CH3:16][C:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: O=C1CCCC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(c2ccccc2)CCCC1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a slurry of 60% NaH (125 mg, 3.12 mmol) in DME (3571 μL) at 0° C. was added 2-phenylcyclopentanone (500 mg, 3.12 mmol). After stirring for 1 h, Met (898 μL, 14.36 mmol) was added, and the solution heated to reflux for 2 h. The reaction was poured onto ice and extracted 3 times into Et20. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Applied to Silica gel and eluted with an EtOAc/Hex gradient to afford 2-methyl-2-phenylcyclopentanone (401.7 mg, 2.305 mmol, 73.9% yield). LC-MS (M+H)+=175.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.29-7.37 (4H, m), 7.20-7.24 (1H, m), 2.54 (1H, dt, J=12.51, 6.26 Hz), 2.34 (2H, t, J=7.63 Hz), 1.82-2.05 (3H, m), 1.38 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:17]#[N:18])[NH:13][C:14](=[O:16])[CH3:15])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:19](=O)([O:25]C(C)(C)C)[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[BH4-].[Na+].C(OCC)(=O)C>CO.O>[C:14]([NH:13][CH:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:16])[CH3:15]
Reactant: CC(=O)NC(C#N)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)NC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
5.00 g of N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl](cyano)methyl]acetamide (0.018 mol), 7.86 g (0.036 mol) of diterbutyl carbonate, 4.28 g (0.018 mol) of nickel chloride (II)-hexahydrate are stirred in 25 mL of methanol at room temperature. 3.40 g (0.09 mol) of sodium borohydride are added portionwise. The reaction mixture is stirred overnight. 200 mL of ethyl acetate are added, followed by 50 mL of water. After separation, the aqueous phase id extracted twice 50 mL of ethyl acetate.