Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:43][N:41]([CH2:40][C:39]1[N:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[N:36]=[N:37][CH:38]=1)[CH3:42]
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N4CCOCC4)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M24) (138 mg, 0.218 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (37 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C.[CH:8]([N-]C(C)C)(C)C.[Li+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29]Br)=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.O>O1CCCC1>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:8][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:24][CH:23]=2)=[CH:19][CH:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1ccc(Oc2ccc(CCBr)cc2)cc1
Reactant: Cc1ccccn1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Oc2ccc(CCCc3ccncc3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 0.308 g. of picoline in 20 mL of tetrahydrofuran, which was cooled to -78° C., was added 1.6 mL of lithium diisopropyl amide, and the mixture was stirred at -78° C. for 30 minutes. The mixture was then allowed to warm to -10° C. for 2 hours, then cooled again to -78° C. There was then added a solution of 1.0 g. of 1-(4-chlorophenoxy)-4-(2-bromoethyl)benzene in 20 mL of tetrahydrofuran. This mixture was stirred for 30 minutes at -78° C., then allowed to warm to room temperature and stirred overnight. 50 mL of water was added dropwise and the tetrahydrofuran was removed by reducing pressure. The residue was extracted with ethyl acetate, which was concentrated to dryness. The product was purified by HPLC (silica gel 70% pentane; 30% ethyl acetate over 180 minutes) to give 0. 107 g. of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[OH-:31].[Na+].Cl.[NH2:34]O>O.C(O)C>[NH2:2][C:1](=[N:34][OH:31])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:20]([CH:21]([CH3:22])[CH3:23])[CH:24]([CH3:25])[CH3:26])=[O:19])=[CH:27][CH:28]=2)=[CH:29][CH:30]=1
Reactant: [OH-]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1)C(C)C
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)cc2)cc1)C(C)C

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)-pentyloxy]-N,N-bis(1-methylethyl)benzamide (300 mg, 0.73 mmol) in 2 mL of water and 8 mL of ethanol is treated with sodium hydroxide (32 mg, 0.81 mmol) and hydroxylamine hydrochloride (56 mg, 0.81 mmol). After refluxing overnight, the reaction is partitioned between dichloromethane and brine. The organic phase is dried over sodium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (10 g) with 70-80% ethyl acetate/hexane as the eluent to afford 4-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-N,N-bis -(1-methylethyl)benzamide as colorless crystals, m.p.=146°-149° C.;
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:8]([C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:12]=[CH:11][CH:10]=1)=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1nc(-c2cccc(SCc3ccccc3)n2)sc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2cccc(S(=O)Cc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
2-(6-Benzylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.18 g, 0.50 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.50 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.057 g, 30%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=[O:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(CCN)=CC=1)(OC)=O.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[NH2:47])=[CH:41][CH:40]=1)([O:37][CH3:38])=[O:36]>>[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([NH:47][CH2:17][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=2)[OH:16])[CH3:48])=[CH:41][CH:40]=1)([O:37][CH3:38])=[O:36]
Reactant: O=CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared as a mixture of diastereoisomers by the process of Example 25, replacing phenyl glyoxal by 4-benzyloxy-3-nitrophenyl glyoxal and 2-(4-carbomethoxyphenyl)ethanamine by 2-(4-carbomethoxyphenyl)-1-methylethanamine. τ (CDCl3) 8.93 (3H, d, J=6 Hz), 6.70-7.80 (7H, m), 6.14 (3H, s), 5.40 (1H, m), 4.81 (2H, s) 2.30-3.10 (10H, m), 2.02 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.CO.CCCCCC>CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CNC(C)C
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CNC(C)C)c1C
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A suspension of 71 mg of N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-2'-[[(1-methylethyl)amino]methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (prepared as in Step (A) of Example 43) was heated to reflux in ~3 ml of EtOAc. MeOH was added dropwise until complete dissolution occurred. Hexane was added to the hot mixture to the point of slight turbidity. After cooling to room temperature and standing several hours, the crystals were filtered and dried to afford 39 mg (55%) of the title compound of this Example as a colorless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:34])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].O.NN>>[ClH:1].[ClH:1].[NH2:23][CH2:22][C:14]1[N:13]=[C:12]([N:11]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH3:10])=[C:2]([Cl:1])[CH:3]=2)[CH3:34])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CCOc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1Cl
Agent: NN
Solvent: O
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1Cl
Product: Cl

Procedure:
The title compound was synthesized as a pale yellow-green solid (83 mg; 91%) in a manner analogous to that found in Example 254 from 2-{4-[(3-chloro-4-ethoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (104 mg, 0.220 mmol) and hydrazine monohydrate (85 μL, 1.8 mmol). 1H NMR (DMSO-d6) δ 8.62 (m(br), 3H), 7.87 (m, 1H), 7.81 (m, 1H), 7.64 (m, 1H), 7.35-7.28 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 4.36 (m, 2H), 4.17 (q, J=6.9 Hz, 2H), 3.69 (s, 3H), 1.39 (t, J=6.8 Hz, 3H); LC-MS (ESI+; 343 ([M+H]+)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH3:54])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:53]([O:52][C:48]1[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:54]
Reactant: CCOc1cccc(OB([O-])[O-])c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-ethoxyphenyl borate (115 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(3-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 117) (180 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)C.[CH3:22]I.[C:24](=[S:26])=[S:25]>>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:24](=[S:26])[S:25][CH3:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSC(=S)NCCNC(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (15.5 cc) is added to a solution of 2-tert.-butoxycarbonylamino-ethylamine (17.62 g) in 95% strength ethanol (110 cc), and carbon disulphide (6.65 cc) is introduced dropwise in the course of 10 minutes, whilst maintaining the temperature at between 20° C. and 25° C. The mixture is stirred for 1 hour 30 minutes at 22° C. Methyl iodide (6.85 cc) is then added and the mixture is stirred for 1 hour 30 minutes at 22° C. It is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), the residue is taken up in ethyl acetate (200 cc), and the organic phase is washed with water (3×100 cc), dried over sodium sulphate, filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). Methyl N-(2-tert.-butoxycarbonylamino-ethyl)-dithiocarbamate (23.2 g) is obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:30])=[O:10])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(O)(C)C>[ClH:1].[CH3:8][C:6]1[N:7]=[C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=[CH:4][C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][C@@H:12]1[CH3:30])=[O:10]
Reactant: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Reactant: C1COCCN1
Solvent: CC(C)O
Product: Cc1nc(N2CCOCC2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Product: Cl
Temperature: 120 °C
Yield: 53.4 %

Procedure:
(2S)-1-[(6-Chloro-2-methyl-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 24) (67 mg, 0.15 mmol) was weighed into a microwave vial, and dissolved in isopropanol (1.4 ml). Morpholine (0.253 ml, 2.90 mmol) was added and the clear solution was heated in the microwave to 120° C. for 4 h with stirring. LCMS analysis showed ˜40% conversion. Further morpholine (0.126 ml, 1.45 mmol) was added and the stirred reaction was heated to 120° C. for 6 h. LCMS analysis showed ˜79% conversion. The reaction mixture was concentrated to give the crude material as a colourless gum (87 mg). This was purified by MDAP to give the free base of the title compound as a colourless gum (44 mg).
Reaction SMILES: C(O[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[CH:9]=1)=O)(=O)C.[C:21]([C:24]1[C:25]([C:31]([F:34])([F:33])[F:32])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=1)(=[O:23])[NH2:22].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:10]1[CH:9]=[C:8]([C:6]2[N:22]=[C:21]([C:24]3[C:25]([C:31]([F:32])([F:34])[F:33])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=3)[O:23][CH:5]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)COC(C)=O)cc([N+](=O)[O-])c1OC
Reactant: NC(=O)c1ccc[n+]([O-])c1C(F)(F)F
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COc1cc(-c2coc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoethyl acetate (4.24 g, 15 mmol) in xylene (30 mL) were added 3-carbamoyl-2-(trifluoromethyl)pyridine 1-oxide (3.40 g, 16.5 mmol) and boron trifluoride etherate (0.18 mL, 15 mmol). The resulting yellow solution was heated to reflux for 18 hours and then cooled to room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and the dried over anhydrous magnesium sulphate, filtered and evaporated. The pure 3-(4-(3,4-dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine 1-oxide was obtained by column chromatography over silica gel (petroleum ether/ethylacetate 2:1) as a pale yellow solid, 2.58 g (42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1ccccc1Cl
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 82.6 %

Procedure:
To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2 mmol) in 25 mL of anhydrous DMF was added potassium carbonate (3.09 g, 22.4 mmol), followed by 2-chlorobenzaldehyde (1.26 mL, 11.3 mmol). The mixture was then heated under nitrogen atmosphere at 70° C. for 5 hours. The reaction mixture was then allowed to cool to room temperature and partitioned between ether and water. The aqueous layer was extracted with ether once and the combined organic layer was washed with water and brine, dried over sodium sulfate and condensed in vacuo. The crude product was purified via silica gel flash chromatography, eluting with 5-10% ether/hexanes, to give 2.62 g (9.251 mmol, 83%) of the desired aldehyde as a colorless oil, which solidified slowly upon standing at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14]([F:16])=[C:13]1[C:8]([CH2:9][CH:10]([CH3:17])[CH2:11][O:12]1)=[CH:7]2.[CH2:18]([Li])[CH2:19][CH2:20]C.CC(C)([O-])C.[K+].C(Br)CC>O1CCCC1>[F:1][C:2]1[C:3]([CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=[C:6]2[C:15]=1[C:14]([F:16])=[C:13]1[C:8]([CH2:9][CH:10]([CH3:17])[CH2:11][O:12]1)=[CH:7]2
Reactant: [Li]CCCC
Reactant: CC1COc2c(cc3cccc(F)c3c2F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCBr
Solvent: C1CCOC1
Product: CCCc1ccc2cc3c(c(F)c2c1F)OCC(C)C3
Temperature: -95 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
The 8,9-difluoro-3-methyl-1,2,3,4-tetrahydro-1-oxaanthracene (1.5 g) obtained in this way was dissolved in 40 ml of tetrahydrofuran and admixed at −75° C. with 7 mmol of n-butyllithium. After stirring for a further 30 minutes, a solution of 7 mmol of potassium tert-butoxide in 20 ml of tetrahydrofuran was added dropwise. After cooling to −95° C., 15 mmol of propyl bromide were added dropwise. After 2 h, the temperature was cooled to −70° C., the mixture was stirred at this temperature for a further 1 h and was then allowed to come to 0° C. overnight. The mixture was added to 200 ml of ice-water and extracted twice with 100 ml each time of tert-butyl methyl ether, and the organic phases were combined, washed with water and saturated sodium chloride solution and dried. The solvent was distilled off under reduced pressure and the brown residue was chromatographed through 500 g of silica gel using heptane/toluene (9:1, v/v). 0.42 g of 8,9-difluoro-3-methyl-7-propyl-1,2,3,4-tetrahydro-1-oxaanthracene was obtained as a colorless syrup.
Reaction SMILES: O=[C:2]([CH3:25])[C:3](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[CH3:26]/[C:27](/[NH2:31])=[CH:28]\[C:29]#[N:30]>C1(C)C=CC=CC=1>[C:29]([C:28]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:3]([C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])=[C:2]([CH3:25])[NH:31][C:27]=1[CH3:26])#[N:30]
Reactant: C/C(N)=C\C#N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)C(C(=O)NCC(=O)OC(C)(C)C)=C(C)N1
Yield: 98.7 %

Procedure:
A toluene solution containing 348 mg (1 mmol) of t-butyl 2-[N-[3-oxo-2-(3-nitrobenzylidene)butanoyl]amino]acetate and 123 mg (1.5 mmol) of 3-aminocrotonitrile was refluxed for 4 hours. The reaction mixture was chromatographed on a silica gel column for purification, whereby 407 mg (98.7%) of t-butyl 2-[N-(5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)pyridine-3-carbonyl)amino]acetate was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([CH3:24])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([CH3:24])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3O
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a cooled suspension of 3.6 g of 9-benzylamino-3,4-dihydro-6-methylacridin-1(2H)-one in 80 ml of tetrahydrofuran was added 6 ml of 1M solution of lithium aluminum hydride in THF. This was stirred for 1 hour, and thereafter quenched with 7 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate and the combined organics were dried over anhydrous magnesium sulfate. The resulting solid was triturated with ethyl ether to obtain 3.15 g of a solid, mp 148°-153° C. This was recrystallized from toulene (70 ml) to obtain 2.5 g of an analytically pure solid, mp 149°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1Oc2ccc(Cl)cc2C1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.204 mol of 5-chloro-2,3-dihydro-2-oxo-3-phenylbenzofuran in 200 ml of anhydrous dimethylformamide is added to a suspension of 0.204 mol of sodium hydride in 100 ml of anhydrous dimethylformamide. The medium is maintained with stirring at room temperature for one hour, 0.224 mol of benzyl bromoacetate is then added slowly and the medium is left for 12 hours at room temperature. The reaction mixture is concentrated under vaccuum and hydrolyzed using one liter of water, the aqueous phase extracted with twice 250 ml of benzene, the organic phase dried over anhydrous sodium sulfate and the solvent evaporated off. The residue is washed with isopropyl ether and then filtered. 0.173 mol is thereby obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[O:9][C:8]([C@H:10]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][CH2:13][CH2:12][N:11]3C(OC(C)(C)C)=O)=[N:7][N:6]=2)[CH2:2]1.[C:29](Cl)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[C:29]([N:1]1[CH2:4][CH:3]([C:5]2[O:9][C:8]([C@H:10]3[C@@H:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:14][CH2:13][CH2:12][NH:11]3)=[N:7][N:6]=2)[CH2:2]1)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](c2ccccc2)[C@@H]1c1nnc(C2CNC2)o1
Reactant: CCCCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1CC(c2nnc([C@@H]3NCCC[C@@H]3c3ccccc3)o2)C1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of tert-butyl cis-2-(5-azetidin-3-yl-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (3C.3, 20.0 mg, 0.05 mmol) in dichloromethane (1 ml) was added valeryl chloride (0.007 ml, 0.06 mmol) and triethylamine (0.007 ml, 0.05 mmol). The reaction was allowed to stir for 0.5 h. TFA (0.3 ml) was added to the reaction and allowed to stir for an additional 1 h. The reaction was concentrated and purified via reverse phase preparative HPLC. Product containing fractions were treated with aqueous sodium bicarbonate. The product was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to yield cis-2-[5-(1-pentanoylazetidin-3-yl)-1,3,4-oxadiazol-2-yl]-3-phenylpiperidine (52%). 1H NMR (400 MHz, CD3OD) δ 7.22-7.08 (m, 5H), 4.59 (d, J=5.2 Hz, 1H), 4.47 (dt, J=4.4 Hz, 1H), 4.23 (q, J=9.3 Hz, 1H), 4.11 (dd, J=9.0, 5.8 Hz, 0.5H), 4.05 (dd, J=8.4, 5.6 Hz, 0.5H), 3.95 (m, 1H), 3.84 (m, 1H), 3.33 (m, 2H), 2.89 (m, 1H), 2.34 (m, 1H), 2.10 (m, 2H), 1.92 (m, 2H), 1.74 (m, 1H), 1.54 (quint, J=7.5 Hz, 2H), 1.35 (m, 2H), 0.93 (dt, J=7.4, 2.9 Hz, 3H).