Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[C:20]2[C:15](=[C:16]([Br:25])[CH:17]=[C:18]([C:21]([O:23]C)=O)[CH:19]=2)[N:14]=[CH:13][CH:12]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([Br:25])[CH:17]=2)[N:14]=[CH:13][CH:12]=[C:11]3[Br:10])[OH:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1cc(Br)c2nccc(Br)c2c1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc(Br)c2nccc(Br)c2c1
Reaction time: 2 h

Procedure:
A solution of (4-chlorophenyl)magnesium bromide (2.02 mL, 1.0 M in THF) was dropwise added to a suspension of methyl 4,8-dibromoquinoline-6-carboxylate (0.2 g, 0.58 mmol) in THF (5 mL) at room temperature. The resulting mixture was slowly dissolved and became a clear solution after 30 min. During this period of time, cooling was needed, when the temperature of the reaction mixture rose above room temperature. After 2 hr, the reaction was quenched with ice water and saturated NH4Cl followed by EtOAc. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (25-30% EtOAc/hexanes) chromatography to yield bis(4-chlorophenyl)(4,8-dibromoquinolin-6-yl)methanol. (M+H)+: 536, 540, 541
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Br[CH:15]([C:20]1[CH:28]=[C:27]([O:29][CH3:30])[C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)C>[Br:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:20]3[CH:28]=[C:27]([O:29][CH3:30])[C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(Br)c1cc(OC)c2c(c1)OCO2
Reactant: Brc1ccc2cc[nH]c2c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1c[nH]c2cc(Br)ccc12
Yield: 88.9 %

Procedure:
Methyl magnesium bromide (3.6 ml of 3M solution in diethyl ether) was added dropwise to a stirred solution of 6-bromo-indole (2.13 g, 10.9 mmol) in toluene (20 ml) under a nitrogen atmosphere. After 20 minutes the reaction mixture was transferred via a cannula, over ˜10 minutes, to a stirred solution of methyl 2-bromo-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (from step (b), 2.2 g, 7.26 mmol) in toluene (20 ml) at ambient temperature. After a further 2 hours the mixture was poured into a mixture of diethyl ether and aqueous ammonium chloride. The organic layer was separated and dried (magnesium sulphate), and the solvent was removed in vacuo. The residue was flash chromatographed using dichloromethane as eluant to give the subtitle compound (2.7 g).
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[F:12][C:13]1[C:18]([C:19]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=C[C:23]=2[F:24])=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>ClCCl>[F:24][C:23]1[C:7]([CH:6]=[O:10])=[CH:21][NH:20][C:19]=1[C:18]1[C:13]([F:12])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(F)c1-c1cccnc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c(-c2cccnc2F)c1F
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a solution of N,N-dimethylformamide (717 mg) in dichloromethane (20 mL) was added oxalyl chloride (1.13 g) under ice-cooling under an argon atmosphere, and the mixture was stirred for 10 min. To the obtained suspension was added a solution of 2-fluoro-3-{3-fluoro-1-[tris(1-methylethyl)silyl]-1H-pyrrol-2-yl}pyridine (1.50 g) in dichloromethane (5 mL) and the mixture was stirred under refluxing conditions for 10 hr. The reaction mixture was cooled under ice-cooling, 1 mol/L aqueous sodium hydroxide solution (30 mL) was added and the mixture was stirred for 15 min. The solvent was evaporated to a half volume under reduced pressure and the residue was partitioned by adding ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was washed with diisopropyl ether (30 mL) and filtered by suction to give the title compound as a colorless solid (yield 726 mg, 78%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:40][CH:39]=2)=[CH:34][C:33]=1[C:49]1[CH:58]=[CH:57][C:56]2[C:55]([CH3:60])([CH3:59])[CH2:54][CH2:53][C:52]([CH3:62])([CH3:61])[C:51]=2[CH:50]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:40][CH:39]=2)=[CH:34][C:33]=1[C:49]1[CH:58]=[CH:57][C:56]2[C:55]([CH3:60])([CH3:59])[CH2:54][CH2:53][C:52]([CH3:61])([CH3:62])[C:51]=2[CH:50]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
6.8 ml (6.8 mmol) of a solution of tetrabutylammonium fluoride (1M) are added to a solution of 2.8 g (4.5 mmol) of ethyl 4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 4 h at ambient temperature. The reaction is stopped by adding 20 ml of water and the mixture is then extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvents are evaporated off. The crude obtained in the form of an oil is chromatographed on silica gel (heptane/ethyl acetate: 70/30), to give 2.10 g of ethyl 4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in the form of a colorless oil (yield=93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.CC(OC(C)=O)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2nc(O)ccc2c1
Yield: 67 %

Procedure:
A solution of 6-methoxyquinoline 1-oxide (300 mg, 1.71 mmol) in Ac2O (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product which was purified by silica gel column (PE/EtOAc=1/2) to give 6-methoxyquinolin-2-ol (200 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([Cl:28])=[N:25][O:26][CH3:27]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([Cl:28])=[N:25][O:26][CH3:27]
Reactant: Oc1cccc(Cl)c1
Reactant: CON=C(Cl)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.2 %

Procedure:
3-Chlorophenol (3.09 g, 0.024 mol), dimethyl-formamide (20 ml) and potassium carbonate (4.15 g, 0.03 mol) were added to 2-chloromethyl-α-methoxyiminobenzyl chloride (4.36 g, 0.02 mol), and the mixture was stirred at room temperature for 4 days. After completion of the reaction, ether (250 ml) was added, and the mixture was washed with brine (200 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (5.66 g, 91.2%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[N:10]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]4/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=5[O:24][CH2:25][C:19]=4[CH:18]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: Clc1nccc2[nH]c(C3CCC3)nc12
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCC4)nc4c(Cl)nccc43)cc2COc2cc(F)ccc21
Yield: 91.5 %

Procedure:
[step 3] Using 4-chloro-2-cyclobutyl-1H-imidazo[4,5-c]pyridine (41 mg, 0.196 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (70 mg, 0.196 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (87 mg, 91%) was obtained.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23](N)=[CH:22][C:21]=2[O:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:20]1[C:21]2[CH:22]=[CH:23][C:25]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][C:27]=2[O:28][CH2:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCO5)c3c2s1
Yield: 49 %

Procedure:
Prepared from VII and 3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 9:1). Yield: 49%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 2894, 2226, 1734, 1706, 1645, 1609, 1581, 1555, 1499, 1471, 1377, 1354, 1304, 1264, 1236, 1211, 1188, 1162, 1125, 1086, 1037, 972, 938, 924, 859, 829, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.14 (m, 1H), 7.76 (m, 1H), 6.94 (d, 2H, J=9.0 Hz), 6.72 (m, 1H), 6.02 (s, 2H); HRMS calcd for C17H9N5O2S (M+H+): 348.0555, found 348.0566.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:21]([Cl:34])[CH:20]=1)=[O:4].[C:35](O)(=[O:38])[CH:36]=[CH2:37].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:34][C:21]1[CH:20]=[C:19]([NH:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([NH:5][C:3]([CH2:2][NH:1][C:35](=[O:38])[CH:36]=[CH2:37])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)CN
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)NCC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Yield: 27 %

Procedure:
170 mg of 2-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acetamide as a starting material was dissolved in 5 ml of THF, and cooled to 0° C. The solution was reacted with 0.04 ml of acrylic acid, 0.06 ml of pyridine and 134 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 5 hours. The reacted solution was extracted with chloroform after adding saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate methanol=10:1) to obtain the title compound (51 mg, 27%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 54.9 %

Procedure:
A mixture of 0.15 g (0.48 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.078 g (0.57 mmole) of 4-amino-benzoic acid in 15 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH2:9][OH:10])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: OCCN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CCO)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-ethanol (0.15 g, 0.6 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.11 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified on silica. 1H-NMR (CDCl3) δ:1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10–2.60 (8H, m), 3.20–3.40 (6H, m), 3.50 (2H, m), 5.20 (2H, br, s), 6.15 (1H, t), 6.70 (1H, t), 7.18–7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.26 min.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.Cl>C1C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[Cl:14])[C:4]([CH2:8][CH2:9][CH3:10])=[N:3]1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCc1cc(=O)n(C)[nH]1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCc1nn(C)c(O)c1Cc1ccccc1Cl
Temperature: 50 °C
Yield: 9.2 %

Procedure:
1.4 g. of 1-methyl-3-n-propyl-5-pyrazolone is dissolved in 10 ml. of dioxane with heating and then 1.5 g. of calcium hydroxide is added to the resulting solution. 1.75 g. of 2-chlorobenzoyl chloride is added dropwise with stirring at 50° C. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and 100 ml. of a 2 N hydrochloric acid solution is added thereto. The mixture is extracted with 70 ml. of chloroform and an organic layer is separated. The layer is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off from the layer to give 2 g. of brown oily residue. The residue thus obtained is dissolved in a small amount of benzene and adsorbed on a silica gel column, which is then eluted with benzene: ethanol (50:1) to give 0.6 g. of crystals. The crystals are recrystallized from methanol-water (7:3) to give 0.25 g. of the desired product as colorless columns having a melting point of 125°-126° C. Yield 9.2%
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(F)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2F)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 2,4-difluorophenol (10 g, 77 mmol), PPh3 (30.2 g, 115 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (30.9 g, 154 mmol) in THF (400 mL) was added DEAD (18.3 mL, 115 mmol) at 0° C. dropwise. After the addition was completed, the resulting mixture was allowed to stir at 40° C. for 16 h. The mixture was poured into water and extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash silica gel chromatography, eluting with 80:1 PE:EtOAc, gave tert-butyl 4-(2,4-difluorophenoxyl)piperidine-1-carboxylate as an oil (20 g, 83%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1.[CH3:16]I>[Ag]=O.O1CCCC1>[CH3:16][O:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1
Reactant: CI
Reactant: CC(=O)NC1CCC(=O)c2ccccc21
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CO[C@@H]1CC[C@@H](NC(C)=O)c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of racemic N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide (3.9 g) and 150 ml. tetrahydrofuran (THF) is stirred and 17 ml. of methyl iodide and 24.4 g. of freshly prepared silver oxide are added over a 4-hour period, under a nitrogen atmosphere. After 16 hours, an additional 10 ml. of methyl iodide and 11.4 g. of silver oxide are added over a 4-hour period and stirring is continued for 2 days. The mixture is filtered through a layer of celite and the filter cake washed with THF (2 × 75 ml.). The filtrate and wash solution are combined and evaporated to dryness in vacuo to afford 4.3 g. of solid. The solid is recrystallized from hexane/ether to afford 2.4 g. of title compound, melting point 97°-100° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:30].[CH3:31][CH:32]([CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:33](O)=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:30].[ClH:30].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:33](=[O:34])[CH:32]([CH3:31])[CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CCN1CCOCC1)C(=O)O
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)C(C)CCN3CCOCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C

Procedure:
A combination of 5.0 g. (12.6 mmole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 2.82 g. (12.6 mmole) of α-methyl-γ-morpholinobutyric acid hydrochloride, 2.78 g. (13.5 mmole) of dicyclohexylcarbodiimide and 250 ml. of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was cooled and the by-product of dicyclohexylurea was removed by suction filtration. The solvent was removed and the residue dissolved in a mixture of methylene chloride/cyclohexane and again filtered to remove a small amount of insoluble material. After evaporation of the solvents, the material was dissolved in methylene chloride and converted to the dihydrochloride salt by the addition of ethereal hydrogen chloride. The solvents were removed and the residue was recrystallized from a methylene chloride/diethyl ether mixture to give 4.2 g. (52%) of colorless crystals, m.p. 188°-192° C. The sample was shown to be free of starting material by thin layer chromatography (10% MeOH/CHCl 3), and the infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH:8]([NH2:12])([CH2:10][CH3:11])[CH3:9].[OH-].[Na+]>O>[CH:8]([NH:12][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)([CH2:10][CH3:11])[CH3:9]
Reactant: BrCC1OCCO1
Reactant: CCC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)NCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and sec-butylamine (120 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-sec-butyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1.N1CCCCC1>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:7]3/[C:8](=[O:11])[NH:9][C:10]4[C:6]/3=[CH:5][CH:4]=[CH:3][C:2]=4[NH2:1])[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: Nc1cccc2c1NC(=O)C2
Solvent: C1CCNCC1
Solvent: CO
Product: Nc1cccc2c1NC(=O)/C2=C/c1ccc2cn[nH]c2c1
Temperature: 60 °C
Yield: 28 %

Procedure:
A 13 mg (0.0877 mmol) solution of 7-aminooxindole (T. Nakashima & I. Suzuki, Chem. Pharm. Bull. (1969) 11, 2293) and 1H-indazole-6-carbaldehyde (14 mg, 0.0965 mmol) in MeOH (1.0 mL) was treated with piperidine (˜1 uL, 0.00877 mmol) and the reaction was heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with 95:5 CH2Cl2/MeOH. The resulting precipitate was filtered and washed with 95:5 CH2Cl2/MeOH to obtain the title compound as a orange powder (6.7 mg, 28%). NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.94-7.87 (m, 3H), 7.46 (d, J=8.19 Hz, 1H), 7.31 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.89 Hz, 1H), 6.81 (t, J=7.79 Hz, 1H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.11.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:18](O)[CH:19]=[CH2:20].OS(O)(=O)=O>>[CH2:20]([C:2]([C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4])=[O:1])[CH:19]=[CH2:18]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CCO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 85 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
D-Arabinose (100 g, 666 mmol) and Na2SO4 (100 g, 703 mmol) were suspended in allyl alcohol (1 L, 14.65 mol) at room temperature; to this suspension was added concentrated H2SO4 (10.4 mL, 187 mmol). The reaction was stirred at 85° C. for 12 h, filtered, and the precipitate was washed with allyl alcohol (2 times 300 mL). The combined filtrates were concentrated in vacuo and purified by silica gel flash chromatography (DCM to 4:1 DCM:MeOH) to give 32 as an off-white solid (75 g, 394 mmol, 60%).