Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:31]1[N:36]([CH3:37])[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=1>O1CCCC1>[CH3:37][N:36]1[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=[C:31]1[N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[CH2:18]1
Reactant: CN1CCN(c2ccc(C3CCCNC3)cc2)CC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C3CCCN(c4nc(-c5ccncc5)cc(=O)n4C)C3)cc2)CC1
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine trihydrochloride salt (0.4 g, 1.08 mmol) and triethylamine (0.6 g, 5.93 mmol) in tetrahydrofuran (10 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.22 g, 0.99 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 3-methyl-2-(3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidin-1-yl)-6-(piridin-4-yl)-3H-pyrimidin-4-one (0.31 g, 0.70 mmol; 71%) as white crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCOCC1
Reactant: BrCCCOCc1ccccc1
Product: c1ccc(COCCCOC2CCOCC2)cc1
Yield: 24 %

Procedure:
Using tetrahydro-4-pyranol (0.693 mL, 7.27 mmol) and [(3-bromopropoxy)methyl]benzene (1.93 mL, 10.9 mmol), the desired title compound (437 mg, yield 24%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.CO[CH:12](OC)[CH2:13][NH2:14].ClC(OCC)=O.C(OP(OCC)OCC)C>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:9][C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[CH:7]=[N:14][CH:13]=[CH:12]2
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(CN)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCOC(=O)Cl
Agent: CCOP(OCC)OCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cnccc2c1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
Para-tolualdehyde (53 mL, 0.486 mol) was stirred in a solvent of chloroform (900 mL). Aminoacetaldehyde dimethyl acetal (59.3 mL, 0.486 mol) was slowly added thereto, followed by stirring at 90° C. until about one-half of the reaction solution was evaporated. The reaction solution was cooled to room temperature, and the resulting yellow reaction solution was dissolved in chloroform (400 mL), followed by cooling the solution to 0° C. or below. Ethyl chloroformate (48 mL, 0.486 mol) and triethylphosphite (104 mL, 0.583 mol) were slowly added to the reaction solution. The reaction solution was stirred for 24 hours at room temperature. The reaction solution was cooled to 0° C. or below, slowly added with titanium tetrachloride (213.6 mL, 1.94 mol), and refluxed for 12 hours or more. The reaction solution was cooled to room temperature, and stirred for 12 hours or more. The reaction mixture was poured to an ice water to separate the organic layer and the aqueous layer, and the aqueous layer was washed with dichloromethane. A saturated sodium tartrate solution was added to the aqueous layer, adjusted to pH 9 by adding ammonia water, and subjected to extraction with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (46.3 g, 66%).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]([CH2:25][C:26]([O:28]CCC2C=CC(O)=C(O)C=2)=[O:27])[C:5]([C:21]([O:23]C)=[O:22])=[CH:6][O:7][C@H:8]\1[O:9][C@@H:10]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]([OH:19])[C@H:11]1[OH:20].[OH-].[K+]>CO.Cl>[CH3:1]/[CH:2]=[C:3]1\[C@H:4]([CH2:25][C:26]([OH:28])=[O:27])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][O:7][C@H:8]\1[O:9][C@@H:10]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]([OH:19])[C@H:11]1[OH:20]
Reactant: C/C=C1/[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)OC=C(C(=O)OC)[C@H]1CC(=O)OCCc1ccc(O)c(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C/C=C1/[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)OC=C(C(=O)O)[C@H]1CC(=O)O
Temperature: 10 °C

Procedure:
Oleuropein (1 g) is dispersed in 50 ml of methanol. The solution is cooled to about 10° C. and treated with stirring with about 2 g of potassium hydroxide pellets. The mixture is allowed to warm to room temperature and after about 6 hours, the reaction mixture is diluted with about 60 ml of 6 N HCl (pH about 7.5) and evaporated to dryness. The chromatographic purification of the product mixture provides oleoside [Formula I; R=glycosyl, R1=methyl]. The purified oleoside is formulated into a solid oral dosage form containing about 250 mg of oleoside. Alternatively, oleoside is dissolved in sterile isotonic saline at a concentration of about 5 mg per ml to provide a parenteral dosage form for use in accordance with the method of this invention.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.I.[CH3:16][S:17][C:18](=[NH:24])[NH:19][N:20]=[C:21]([CH3:23])[CH3:22]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:24][CH:18]([S:17][CH3:16])[N:19]([N:20]=[C:21]([CH3:23])[CH3:22])[C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)N(C(=O)Cl)c1ccc(Cl)cc1
Reactant: CSC(=N)NN=C(C)C
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(c2ccc(Cl)cc2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-(4-chlorophenyl)-bis(chlorocarbonyl)-amine and acetone-S-methyl-isothiosemicarbazone hydroiodide with addition of triethylamine, yielded 1-(4-chlorophenyl)-3-isopropylideneamino-4-methylmercaptotetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 142°-144° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH:23]1([NH:26][C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24]1>>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:33]([C:32]4[CH:31]=[CH:30][C:29]([C:27]([NH:26][CH:23]5[CH2:25][CH2:24]5)=[O:28])=[CH:36][CH:35]=4)[NH:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: N#Cc1ccc(COc2ccc3nc(-c4ccc(C(=O)NC5CC5)cc4)[nH]c3c2)cc1

Procedure:
Compound 669 was prepared according to the procedure similar to that described in Scheme III from 1-(4-cyanobenzyl)oxy-3,4-dinitrobenzene and 4-(cyclopropylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H20N4O2: 409.16; found: 409.04.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:5]2[CH2:6][CH2:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9](=[O:14])[C:10]=2[C:11]=1[O:12][CH3:13].[CH3:29][O-].C[O-].[Mg+2].CO.IC>CN(C=O)C>[CH3:13][O:12][C:11]1[C:2](=[O:1])[N:3]([CH3:29])[C:4]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[C:5]2[C:10]=1[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc(CN2CCc3c(C(=O)N(C)C)nc(O)c(OC)c3C2=O)cc1
Reactant: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CN2CCc3c(c(OC)c(=O)n(C)c3C(=O)N(C)C)C2=O)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-hydroxy-4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (5.00 g) in DMF (50 mL) was added magnesium methylate (14.3 mL of a 6-10% methanol solution), and the reaction was heated to 50° C. for 1 hour. The reaction was treated with iodomethane (17.66 mL) and allowed to stir at 50 degrees for 1.5 hours. The reaction was quenched with 15 mL 10% aq KHSO4 and concentrated in vacuo to remove the methanol. The mixture was diluted with 300 mL chloroform and the phases were separated. The aqueous layer was washed twice more with chloroform. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The remaining solid was purified on an Isco automated system affixed with a Biotage Flash 40 (L) (120 g) cartridge eluted with 0-10% MeOH in EtOAc over 20 minutes and hold at 10% MeOH for 45 minutes. The product eluted last, pure by HPLC/MS and NMR.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.[ClH:28].O1CCOCC1>CO>[ClH:28].[NH:17]1[CH2:18][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=[C:2]([Br:1])[N:7]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(Br)nc(Nc2ccc(C3CNC3)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 298b (690 mg, 1.6 mmol) and HCl/1,4-dioxane (8M, 8 mL) in methanol (30 mL) was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 298c (100 mg, 17%). MS: [M+H]+ 335.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:12]([CH3:16])[CH2:13][CH:14]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:25][NH:26][CH2:14][CH2:13][CH:12]([CH3:16])[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: CN
Reactant: CC(CC=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the aldehyde from Step (a) (0.55 g, 1.47 mmol) and methylamine (2M solution in THF, 1.48 ml, 2.95 mmol) in dry dichloromethane (5 ml) was added acetic acid (0.5 ml) followed by sodium triacetoxyborohydride (0.63 g, 2.95 mmol). The mixture was stirred at room temperature for 16 hours before quenching with saturated aqueous sodium bicarbonate solution (10 ml) and separating the phases. The organic phase was dried (MgSO4) and evaporated under reduced pressure to yield as a mixture of diastereoisomers (3RS, 4RS)-N-methyl-[4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methyl-butyl]amine as a gummy yellow solid, which was carried on to the next stage without further purification.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[NH2:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[N:12]=[C:2]=[O:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 0 °C

Procedure:
The mixture of trichloromethyl chloroformate (530 ml, 4.4 mol) and toluene (4 liters) were put in a 10-liter three-neck flask as equipped with a stirrer, a dropping funnel, and a reflux condenser, and cooled to 0° C. To the solution was dropwise added a toluene solution (1 liter) containing 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.0 kg, 2.86 mol) and triethylamine (20 ml) over a period of 8 hours. After addition, the reaction solution was stirred under heat at about 100° C. After reaction, toluene was removed by distillation, and the impurities as precipitated out were removed by filtration. As a result, 2-fluoro-4-chloro-5-cyclopentyloxyphenylisocyanate was obtained almost quantitatively. Spectral data and other data of the product are those as shown in Example 24.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:7]1[CH:29]=[CH:28][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)#[N:6].FC(F)(F)C(O)=O>O>[NH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:29][CH:28]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C#N)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OCCCC2CCNCC2)cc1
Reaction time: 0.33 h
Yield: 103.7 %

Procedure:
To a chloroform (100 mL) solution of 14.0 g of tert-butyl 4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate was dropwise added 40 mL of trifluoroacetic acid under cooling with water over a period of 10 minutes. This mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 35 minutes. After distilling off the solvent under reduced pressure, chloroform and water were added. A sodium hydroxide aqueous solution was added thereto for adjustment to pH 13.0. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, which was then washed with a sodium hydroxide aqueous solution and dried with potassium carbonate, followed by distilling off the solvent under reduced pressure to provide 10.3 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile as pale yellow solid form.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][C@H:25]2[NH2:28])=[CH:21][CH:20]=1.Cl.FC(F)(F)C1C=C2C(CC[C@H]2N)=CC=1>>[OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12]([NH:28][C@H:25]1[C:26]3[C:22](=[CH:21][CH:20]=[C:19]([C:18]([F:17])([F:29])[F:30])[CH:27]=3)[CH2:23][CH2:24]1)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cn1c(=O)c(O)c(C(=O)Cl)c2ccccc21
Reactant: N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Agent: Cl
Product: Cn1c(=O)c(O)c(C(=O)N[C@@H]2CCc3ccc(C(F)(F)F)cc32)c2ccccc21
Yield: 20 %

Procedure:
Following the procedure described for Example 3, Example 192 (4 mg, 9.94 μmol, 20% yield) was prepared as an off-white powder by using 3-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl chloride (see Example 3C) and (R)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-amine (Intermediate 15). LCMS=2.07 min, [M+1]=403.1 (Method A); Orthogonal HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=9.47 min, 98%}; Xbridge {RT=8.63 min, 92%}. 1H NMR (500 MHz, MeOD) δ ppm 7.80 (1 H, s), 7.64 (1 H, d, J=8.3 Hz), 7.48-7.57 (3 H, m), 7.44 (1H, d, J=8.0 Hz), 7.31 (1 H, t, J=7.4 Hz), 5.76 (1 H, t, J=7.4 Hz), 3.81 (3 H, s), 3.08-3.18 (1 H, m), 2.98-3.06 (1 H, m), 2.67-2.74 (1 H, m), 2.05-2.13 (1 H, m).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]1[C:11]([NH2:13])=O)=[O:4].N1C=CN=C1.O=P(Cl)(Cl)Cl.[NH4+].[Cl-]>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]1[C:11]#[N:13])=[O:4]
Reactant: C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Temperature: -35 °C
Reaction time: 1 h

Procedure:
(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carboxylic acid amide (0.25 g, 1.2 mmol) and imidazole (85 mg, 1.25 mmol) ware mixed in pyridine (5 mL). The mixture was cooled to −35° C. and POCl3 (0.18 mL, 1.8 mmol) was added slowly. The mixture was stirred at −35° C. for 1 h. Saturated NH4Cl (20 mL) was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The oil was purified by flash chromatography (hexane: EtOAc, 2:1) to yield the title compound. MS (DCI) m/z 187 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH:13]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:12]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) in 150 mL toluene at ambient temperature was added carbethoxymethylenetriphenyl phosphorane (17.4 g, 50 mmoL.). The mixture was warmed to 50° C. and allowed to stir for 16 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure and purified by column chromatography (Si2O, 50% hexanes in EtOAc) to provide the title compound (2.2 g, 13 mmol, 26% yield). MS (DCI/NH3) m/z 171 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=O)[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:10])[CH:5]=[C:4]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH:3]=1
Reactant: NC(=O)c1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc(Br)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc(Br)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
1.76 g (0.0044 mol) of 6-bromo-4-(4-nitrobenzenesulphonyl)-pyridine-2-carboxamide were suspended in 11 ml of dioxane/THF 1:1, treated with 1.34 ml (0.0096 mol) of triethylamine and cooled to 0° C. 0.69 ml (0.00496 mol) of trifluoroacetic anhydride was slowly added dropwise to this suspension and the mixture was left to warm to room temperature and stirred for 1 hr. The reaction mixture was partitioned in ethyl acetate and water and the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There were obtained 1.40 g (87%) of 6-bromo-4-(4-nitrobenzenesulphonyl)-pyridine-2-carbonitrile as yellowish crystals; m.p.: 158-160° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]C)=[O:16])[C@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.O.Cl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A solution of 0.016 g (0.034 mmole) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxy-carbonylmethyl)-3-(S)-phenylmorpholine (from Example 46) in 2 mL of THF and 0.5 mL of water was treated with 0.027 mL (0.067 mmole) of 2.5N aqueous sodium hydroxide and the mixture was stirred at room temperature for 5 hr. The mixture was treated with 2 drops of 2N aqueous HCl and 3 mL of water and the solution was extracted with 15 mL of 1:1 hexanes:ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chormatography on 13 g of silica eluting with 250 mL of 100:3:0.1 methylene chloride:methanol:acetic acid then 100 mL of 50:2:0.1 methylene chloride:methanol:acetic acid to give 0.014 g (90%) of an oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.[OH-].[K+]>[Cu].C1C2C(CCCC2)CCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:23][CH:22]=1
Reactant: Brc1ccc(Br)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Product: Brc1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 25.1 %

Procedure:
A mixture of 9.2 g (38 mmol) of 9H-tribenz[b,d,f]azepine (synthesized in accordance with J. Org. Chem., vol. 56, p. 3906 (1991)), 44.8 g (190 mmol) of 1,4-dibromobenzene, 5.6 g (100 mmol) of potassium hydroxide, 1.6 g (25 mmol) of copper powder, and 50 ml of decalin was heated at an external temperature of 200° C. for 36 hours in a nitrogen stream while stirring. The reaction mixture was worked up in the same manner as in Example 1, and the resulting crude product was purified by silica gel column chromatography to give 3.8 g (25%) of 9-(4-bromophenyl)-9H-tribenz[b,d,f]azepine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH2:20][CH2:19][CH2:18]3)O1.Br[C:27]1[C:28]2[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=2[S:30][C:31]=1[CH:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34]>O.CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:38]([O:37][CH:32]([C:31]1[S:30][C:29]2[CH:42]=[CH:43][CH:44]=[CH:45][C:28]=2[C:27]=1[C:15]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=1)[C:33]([O:35][CH3:36])=[O:34])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C(OC(C)(C)C)c1sc2ccccc2c1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1sc2ccccc2c1-c1ccc2c(c1)CCCO2
Temperature: 110 °C
Yield: 53.6 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (33 mg, 0.3 mmol), palladium tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (78 mg, 0.3 mmol) were added to a solution of methyl (3-bromo-benzo[b]thiophen-2-yl)-tert-butoxy-acetate (21d) (100 mg, 0.28 mmol) in a mixture of water (1 mL) and N,N-dimethylformamide (3 mL). The mixture was heated at 110° C. for 1 hour. The mixture was then cooled at room temperature, concentrated and water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product as a white solid (60 mg, 0.15 mmol, 54%).