Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:12][C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:9][CH:10]=C)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+].Cl.[OH2:31]>O1CCOCC1.C(O)(C)(C)C.CO.[Os](=O)(=O)(=O)=O>[CH2:19]([O:21][C:19]([C:13]1([NH:12][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][OH:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O
Reactant: C=CCC(NC1(C(=O)O)CCCCC1)C(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [BH4-]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCO)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (1-tert-butoxycarbonylbut-3-enylamino)-cyclohexanecarboxylic acid (0.5 g, 1.29 mmol) in dioxane (5 mL) and water (5 mL) was added a 2.5 weight % solution of osmium tetroxide in tert-butanol (0.05 mL). After 20 minutes, sodium periodate (0.88 g, 4.13 mmol) was added in small portions over another period of 20 minutes. The mixture was stirred at room temperature for 6 hours and was quenched by addition of a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum to give an oil. The oil was dissolved in methanol (12 mL) and sodium borohydride (137 mg, 3.61 mmol) was added. The mixture was stirred overnight. A 1M aqueous solution of hydrochloric acid was added and, after stirring for 10 minutes, the solvent was removed under vacuum. The residue was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was washed with brine dried over magnesium sulfate, and concentrated under vacuum to give an oil. The oil was chromatographed on silica gel eluting with 10% ethyl acetate in methylene chloride to provide 1-(1-tert-butoxycarbonyl-3-hydroxy-propylamino)cyclohexanecarboxylic acid benzyl ester as an oil, 469 mg (66%).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13][O:14]C1C=CC=CC=1C(OC)=O>>[CH3:13][O:14][C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=1[C:9]([NH2:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: COC(=O)c1ccccc1OC
Product: COc1ccccc1C(C)(C)N
Yield: 81 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 2-methoxybenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 81%.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S([CH2:28][N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:16]([O:15][C:13]([C:12]1[C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:30][NH:29][CH:28]=1)=[O:14])[CH3:17]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c[nH]cc1-c1cccc2ccccc12
Yield: 76.7 %

Procedure:
500 mg (1.89 mmol) of ethyl 3-(naphthalen-1-yl)acrylate prepared in EXAMPLE 80-1) and 368 mg (1.89 mmol) of tosylmethylisocyanide were dissolved in 10 ml of tetrahydrofuran. 255 mg (2.27 mmol) of potassium t-butoxide dissolved in tetrahydrofuran (10 ml) was slowly added thereto and the mixture was refluxed for 30 minutes. 10 ml of water was added to the reaction solution to stop the reaction and the solvent was removed under reduced pressure. The residue was extracted with diethylether, washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: ethyl acetate/hexane=1/3, v/v) to give 385 mg (1.45 mmol, Yield 77%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:15])[N:3]=1.[CH3:16][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([Si:11]([CH3:13])([CH3:12])[CH3:14])=[C:4]([F:15])[N:3]=1.[F:1][C:2]1[N:3]=[C:4]([F:15])[C:5]([Si:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][C:7]=1[C:8]([O:10][CH3:16])=[O:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: C[Si](C)(C)c1cc(C(=O)O)c(F)nc1F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc([Si](C)(C)C)c(F)nc1F
Temperature: 25 °C

Procedure:
2,6-Difluoro-5-(trimethylsilyl)pyridine-3-carboxylic acid (1.17 g, 5.05 mmol) was dissolved in a mixture of DCM (20 mL) and MeOH (5 mL) and treated with (trimethylsilyl)diazomethane (2.0 m in diethyl ether, 5.0 mL, 10.00 mmol). [2,6-Difluoro-5-(trimethylsilyl)pyridine-3-carboxylic acid was synthesized according to M. Schlosser and T. Rausis, Eur. J. Org. Chem., 2004, pp 1018-1024]. The derived solution was maintained at rt for 1 hour. Evaporation under reduced pressure and purification using the by silica gel chromatography (hexane to ethyl actetate gradient) gave the desired methyl 2,6-difluoro-5-(trimethylsilyl)nicotinate.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Br:38][CH2:39][C:40](Br)=[O:41].O>C1COCC1>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([C:40](=[O:41])[CH2:39][Br:38])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: O=C(Br)CBr
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)N1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 162 mg, 0.38 mmol) was dissolved in THF (3 ml) and triethylamine (0.059 ml, 0.42 mmol) added. The reaction mixture was cooled to 0° C. then bromoacetyl bromide (0.037 ml, 0.42 mmol) added, then the mixture warmed to room temperature. A further 1.1 equivalents of triethylamine (0.059 ml), and bromoacetyl bromide (0.037 ml) were added and the reaction mixture stirred at room temperature for 15 minutes. The reaction mixture was poured into water, extracted with ethyl acetate (×3), dried (MgSO4), and concentrated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:19]([O:21]C)=[O:20].[I-].[Li+].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc2cc(NC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
Methyl N-(3,4-Dichlorobenzyl)-5-acetylaminoindole-2-carboxylate (88 mg) and lithium iodide (300 mg) were dissolved in pyridine and heated at reflux for 8 hours, then cooled to room temperature and poured into 2M HCl and extracted with diethyl ether. Combined organic extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography using DCM-2% methanol as eluent to give the desired end product as a white solid (19 mg, 22%), mp 245-246°; NMR δ (CD3SOCD3) 2.02 (s, 3H), 5.82 (s, 2H), 6.90 (d, 1H), 7.20-7.55 (m, 5H), 8.02 (s, 1H), 9.83 (s, 1H); M/z (+) 377 (MH+), 278.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[N:15]=1.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=[C:31]([CH3:39])[C:28]=1[CH:29]=[O:30]>O1CCCC1.O>[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=[C:31]([CH3:39])[C:28]=1[CH:29]([C:19]1[C:14]([Cl:13])=[N:15][C:16]([Cl:24])=[CH:17][C:18]=1[C:20]([F:21])([F:22])[F:23])[OH:30]
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(C(O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
14 ml (20 mmol) of n-butyllithium (1.5 M hexane solution) was dropwise added at 0° C. to a solution having 2.9 ml (21 mmol) of diisopropylamine dissolved in 62 ml of tetrahydrofuran, followed by stirring for 30 minutes. The solution was cooled to −20° C., a solution having 4.0 g (19 mmol) of 2,6-dichloro-4-trifluoromethylpyridine dissolved in 5 ml of tetrahydrofuran was added thereto, followed by stirring for 5 minutes, and a solution having 3.8 g (18 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 7 ml of tetrahydrofuran was added thereto, followed by stirring for 1.5 hours. 30 ml of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 6.2 g (yield 81%) of (2,3,4-trimethoxy-6-methylphenyl)(2,6-dichloro-4-trifluoromethyl-3-pyridyl)methanol (brown oily substance).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)=[O:5].Br.Br[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: BrCCNCCBr
Reactant: Nc1ccc(NC(=O)CCBr)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CCBr)Nc1ccc(N2CCNCC2)cc1
Yield: 29.5 %

Procedure:
A mixture of 14.0 g of N-(β-bromopropionyl)-p-aminoaniline, 18 g of bis(β-bromoethyl)amine monohydrobromide and 70 ml of methanol was stirred under reflux for 15 hours. After cooling, the reaction mixture was added 3.06 g of potassium carbonate and stirred under reflux for 8 hours. After cooling, crystals which formed were collected by filtration and washed with methanol to give 5.3 g of N-(β-bromopropionyl)-p-piperazinylaniline. Production of the compound was confirmed by IR and NMR spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.C(N(C(C)C)CC)(C)C.[CH:30]#[C:31][CH2:32][CH2:33][CH2:34][CH3:35].[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:30]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[C:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC#Cc1cc(OC)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a degassed solution of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.72 g, 2.30 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.23 mmol), CuI (44 mg, 0.23 mmol), diisopropylethylamine (1.41 mL, 8.02 mmol) in DMF (10 mL) at room temperature was added 1-hexyne (0.55 mL, 4.60 mmol). The mixture was stirred at room temperature overnight. Poured into saturated aqueous NH4Cl (15 mL), the mixture was extracted with EtOAc. The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by flash chromatography over SiO2 eluted with a gradient from hexanes to 5% EtOAc in hexanes to give 0.55 g (98%) of 78 as a light brown oil. 1H NMR (400 MHz, CDCl3): δ 0.95 (t, J=7.2 Hz, 3H), 1.45-1.58 (m, 2H), 1.60-1.70 (m, 2H), 2.48 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.9 Hz, J2=2.6 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].[C:14]1([CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:14]1([C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][NH:13][C:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[OH:1])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1c(O)sc2ccccc12
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC=C(c1ccccc1)c1ccccc1)c1c(O)sc2ccccc12
Temperature: 150 °C

Procedure:
A stirred mixture of 2-hydroxybenzo(b)thiophene-3-carboxamide (0.485 g, 0.0025 m), diphenylacetaldehyde (0.51 g, 0.0026 m), p. toluenesulfonic acid hydrate (30 mg), and dried toluene (15 ml) is set in an oil-bath at 100° C., the bath temperature raised to 150° C., and the mixture heated under reflux until thin-layer chromatography of the mixture indicates completeness of reaction. The cooled reaction mixture is concentrated in vacuo and the residue chromatographed on silica gel (v/v 10-50% CH2Cl2 in hexane) to yield N-(2,2-Diphenylethenyl)-2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)[CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[CH:20]=[C:19]2[CH:24]([CH3:26])[CH3:25])=[O:13].[H][H].N#N>C(O)C.[Pd].C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[CH:20]=[C:19]2[CH:24]([CH3:26])[CH3:25])=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reaction time: 0.17 h
Yield: 103.4 %

Procedure:
1,1-Dimethylethyl 4-[7-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1-methyl-3-(1-methylethyl)-1H-indol-5-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (0.27 g, 0.507 mmol) was dissolved in ethanol (10 mL) and placed in a funnel under a N2 stream for 10 min. Palladium on carbon (0.081 g, 0.076 mmol) was added and the reaction placed alternatingly under N2 and H2 via a 3-way valve. Switched atmosphere to hydrogen (balloon) and stirred at RT overnight. Placed reaction back under N2, diluted with DCM, and added Celite. The mixture was stirred for 5 min, then filtered through analytical grade Celite and washed with 10% MeOH. Solvent was removed in vacuo giving a residue that was dried on hi-vacuum for 1 h to give 1,1-dimethylethyl 4-[7-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1-methyl-3-(1-methylethyl)-1H-indol-5-yl]-1-piperidinecarboxylate (0.28 g, 0.524 mmol, 103% yield). MS (ES) [M+H]+ 535.0.
Reaction SMILES: [CH3:1][C:2]1[C@H:8]2[C@H:5]([CH2:6][C:7]2=O)[CH2:4][CH:3]=1.[H-].[Na+].COP([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(OC)=O>O1CCCC1>[CH3:1][C:2]1[C@H:8]2[C@H:5]([CH2:6][C:7]2=[CH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@H]2CC(=O)[C@@H]12
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CC[C@H]2CC(=CC(=O)OC(C)(C)C)[C@@H]12
Reaction time: 2 h

Procedure:
(±)-(1S,5R)-4-methylbicyclo[3.2.0]hept-3-en-6-one (1.10 g, 9.0 mmol) was added to a reaction solution prepared in advance by adding sodium hydride (>65% oil, 342.8 mg, 9.0 mmol) to a tetrahydrofuran solution (10 mL) of tert-butyl dimethoxyphosphorylacetate (2.08 g, 9.3 mmol) under ice cooling, and the mixture was further stirred for 2 hours. The reaction solution was separated into aqueous and organic layers by the addition of a saturated aqueous solution of ammonium chloride and saturated saline. The aqueous layer was subjected to extraction with ethyl acetate. These organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.59 g, 80%, E/Z mixture).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[CH3:24][C:25]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26]1>>[Br:1][C:2]1[C:3]([N:27]2[CH2:28][CH2:29][C:25]([OH:30])([CH3:24])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC1(O)CCNC1
Agent: Cl
Product: CC1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and 3-methylpyrrolidin-3-ol hydrochloride to afford a white solid. UPLC-MS (Condition 1) tR=2.79 min, m/z=460.9/461.9 [M+H]+, m/z=458.0/460 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 3H) 1.76-1.93 (m, 2H) 3.63 (d, 1H) 3.68 (d, 1H) 3.70-3.76 (m, 1H) 3.88-3.97 (m, 1H) 4.82 (s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.33 (d, J=2.20 Hz, 1H) 8.67 (d, J=2.20 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C@H:13]1[C@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([CH2:26][O:27]CC2C=CC=CC=2)[S:15][CH:14]1[N:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37])C1C=CC=CC=1>ClCCl>[CH:14]1([N:35]2[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]2=[O:37])[S:15][C@H:16]([CH2:26][OH:27])[C@@H:17]([OH:18])[C@@H:13]1[OH:12]
Reactant: Nc1ccn(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of boron trichloride (1 M solution) in dry dichloromethane (7 mL, 7 mmol) cooled to −78° C., was added dropwise over a period of 30 min, a solution of compound 7 (265 mg, 0.5 mmol) in dry dichloromethane (10 mL). Stirring was continued overnight at −20° C. The solvent was removed in vacuo and the residue was coevaporated with dichloromethane (4×20 mL) The residue was neutralized with saturated NaHCO3 (25 mL) and washed with chloroform (15 mL). The aqueous layer was applied to a cation exchange (H+) column and eluted with water to remove salts and then eluted with 1N NH4OH to obtain the desired compound 8 (110 mg, 85%) MS z/e 260 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[CH:4][C:3]=1[NH2:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:20][C:3]2[CH:4]=[C:5]([O:8][CH2:9][C:10]3[C:11]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:7][C:2]=2[Br:1])=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Nc1cc(OCc2ccc3ccccc3c2)ccc1Br
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: S=C(Nc1cc(Cl)cc(Cl)c1)Nc1cc(OCc2cccc3ccccc23)ccc1Br
Yield: 37.6 %

Procedure:
A solution of 2-bromo-5-(2-naphthylmethoxy)phenylamine (100 mg, 0.3 mmol) and 3,5-dichlorophenylisothiocyanate (60 mg, 0.3 mmol) in 10 mL of dichloromethane was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and the residue recrystallized from ethyl acetate/hexane to give 60 mg of product in (38%) yield as a white solid: mp 149-151° C. 1H NMR (400 MHz, Me2SO-d6) δ5.56 (s, 2H); 7.02 (dd, 1H, J=3.0, 8.9); 7.29 (d, 1H, J=3.0); 7.35 (t, 1H, J=1.8); 7.49-7.69 (m, 7H); 7.93-7.99 (m, 2H); 8.07-8.10 (m, 1H); 9.78 (s, 1H); 10.10 (s, 1H). Anal. Calcd for C24H17BrCl2N2OS: C, 54.16; H, 3.22; N, 5.26; S, 6.02; Cl, 13.32; Br, 15.01. Found: C, 54.17; H, 3.32; N, 5.28; S,6.10; Cl, 13.31; Br, 15.00.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 325 g of 4-cyanophenol, 346 mL of benzyl chloride and 758 g of potassium carbonate in 1.2 L of NMP was heated at 95° C. with stirring for 1.5 hrs. The reaction mixture was cooled to room temperature and poured into 5 L of cold water. The resulting white solid was collected, washed with water and hexanes and dried at 70° C. in vacuo giving 570.0 g of 4-benzyloxybenzonitrile.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:3][N:2]=1)=[O:19])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCCC(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCCC(C)C)[nH]n1
Yield: 73.1 %

Procedure:
Hydrazine hydrate (0.943 mL, 1.91 mmol) was added to a stirring room temperature solution of 16 (0.4354 g, 1.91 mmol) in EtOH (1.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes: 2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.3132 g (63.1%) of 17. 1H (CDCl3, 400 MHz): δ 9.60 (1H, broad s), 6.58 (1H, s), 4.34 (2H, q, J=7.2 Hz), 2.66 (2H, t, J=7.7 Hz), 1.67-1.57 (2H, m), 1.58 (1H, m), 1.36 (3H, t, J=7.2 Hz), 1.24-1.15 (2H, m), 0.85 (6H, d, J=6.5 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.22, 106.59, 61.17, 38.58, 27.99, 27.20, 26.57, 22.72, 14.48 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 22.72, 14.48; CH2 carbons: 61.17, 38.58, 27.20, 26.57; CH carbons: 106.59, 27.99 ppm. HPLC: 10.072 min.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9](O)=[O:10].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:8]=1[C:9]([N:3]([O:4][CH3:5])[CH3:2])=[O:10]
Reactant: CNOC
Reactant: Nc1c(Cl)ccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Yield: 73 %

Procedure:
N,O-dimethlyhydroxylamine hydrochloride (3.28 g, 33 mmol) and 2-amino-3,6-dichlorobenzoic acid (4.76 g, 22 mmol) were dissolved in DMF (110 ml). At r.t. under nitrogen and stirring, first N-methyl morpholine (10 g, 99 mmol) and then HBTU (12.5 g, 33 mmol) were added, and the reaction was stirred at r.t. overnight. The reaction was poured onto water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was treated with heptane and little diethyl ether to yield 4 g of the product. The mother liquor was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to give another batch of the title compound as an off-white solid (5.52 g, 100%).