Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[C:17]12([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:30][CH2:29][C:28]([NH:27][C:17]23[CH2:24][CH:23]4[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]4)[CH2:18]2)[CH2:26]3)=[O:31])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)NC23CC4CC(CC(C4)C2)C3)cc(C(C)(C)C)c1O

Procedure:
Following the method of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole), the title compound of Example 5 (1.03 g, 0.005 mole) and triethylamine (0.5 ml) were stirred in methanol (100 ml) for 12 hours at room temperature under argon. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl aceate/hexane, filtered and dried in vacuo, m.p. ca. 172.5°-173.5° C.
Reaction SMILES: O[CH2:2][C@@H:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F.F.F.C(N(CC)CC)C.[F:31]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CCN(C(C)C)C(C)C>C1(C(F)(F)F)C=CC=CC=1>[F:31][CH2:2][C@@H:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Agent: F
Solvent: CCN(C(C)C)C(C)C
Solvent: FC(F)(F)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1[C@H](CF)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of (S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (1.5 g, 5.61 mmol) in PhCF3 (18.71 mL) was added triethylamine trihydrofluoride (5.48 mL, 33.7 mmol), perfluorobutanesulfonyl fluoride (1.019 mL, 5.67 mmol), DIEA (14.70 mL, 84 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then more perfluorobutanesulfonyl fluoride (1.019 mL, 5.67 mmol) was added. After 5 h, the reaction mixture was quenched with NaHCO3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% EtOAC in heptane) yielding (S)-2-(2-fluoro-1-phenylethyl)isoindoline-1,3-dione (30% yield). LCMS (m/z): 270.1 (MH+), 0.96 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[N:13]/[S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Mg]Br>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:13][S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(/C=N/S(=O)C(C)(C)C)C1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 3-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.87 mmol) in CH2Cl2 (4 mL) at 0° C. was added dropwise methylmagnesium bromide (3.0 M in Et2O, 0.35 mL, 1.04 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 273 mg of 3-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester as an off-white foamy solid which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]C1COCCO1>>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrC1COCCO1
Reactant: COC(=O)Cc1ccc(C(C)=O)cc1
Product: COC(=O)Cc1ccc(C(=O)CBr)cc1

Procedure:
Prepared from methyl 4-acetyl-phenylacetate and bromodioxan.
Reaction SMILES: [C:1]([N:8]([CH2:15][C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:21])=[CH:18][CH:17]=1)[CH2:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)(OC(C)(C)C)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1C=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:34]=[CH:35][C:16]([CH2:15][N:8]([CH2:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:1][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)=[CH:17][CH:18]=1)[CH2:29][CH3:30]
Reactant: O=Cc1ccccn1
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ccccn2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 39.5 h

Procedure:
The compound (39.8 mg) obtained in Example 1-3 and pyridine-2-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.1 mg) were dissolved in anhydrous methanol (2.0 ml). The solution was added with sodium cyanoborohydride (18.9 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 39.5 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and then washed with a 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. Subsequently, the residue was distilled off and the residue was then treated with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (7.00 mg) of the subject compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[O:11]C=CC=2)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[Mn]([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O>[NH2:1][C:2]1[C:3]([C:10]([OH:11])=[O:16])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(Cl)nc(-c2ccco2)c1N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Cl)nc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
3-Amino-6-chloro-2-(2-furanyl)-4-methylpyridine (400 mg) was dissolved in acetone (10 mL) and cooled in an ice bath to 0° C. A solution prepared of potassium permanganate (909 mg) in water (15 mL) was added drop wise to this solution. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled again to 0° C. and a second portion of potassium permanganate (600 mg) in water (10 mL) was added and the cool bath removed. After stirring for 2 hours, the reaction mixture was filtered through a pad of celite, the filter cake was washed carefully with water, methanol and ethyl acetate and concentrated to approx. 10 mL on a rotary evaporator. 2N Sodium hydroxide solution was added to adjust the pH-value to −12 and the aqueous layer was washed 2× with MTB-ether. The aqueous layer was then adjusted to pH ˜2 by addition of 6N hydrochloric acid and extracted 3× with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 262 mg of the title compound of the formula
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:6]1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH2:4][N:5]1[C:6]2[C:22]3[N:23]([CH3:30])[C:24]4[C:29]([C:21]=3[C:20]3[C:19](=[O:31])[NH:18][C:17](=[O:32])[C:16]=3[C:7]=2[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]1=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)#[N:2]
Reactant: COc1ccc2c(c1)c(C1=C(c3cn(C)c4ccccc34)C(=O)NC1=O)cn2CCC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c1c3c(c4c5ccccc5n(C)c4c1n2CCC#N)C(=O)NC3=O
Yield: 54.2 %

Procedure:
500 mg (1.18 mmol) 3-[1-(2-cyanoethyl)-5-methoxy-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in 50 ml toluene are heated under reflux for 30 minutes with 225 mg (1.18 mmol) p-toluenesulphonic acid hydrate and 315 mg (1.39 mmol) 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). After cooling, the reaction mixture is evaporated in a vacuum and the residue is stirred with 100 ml 0.1N sodium hydroxide solution. The aqueous suspension is saturated with sodium chloride and extracted twice with, in each case, 100 ml tetrahydrofuran. The tetrahydrofuran solutions are washed twice with, in each case, 100 ml saturated sodium chloride solution. The residue is chromatographed on silica gel with toluene/acetone (4:1 v/v). The fraction with the Rf 0.3 is isolated, stirred up with diisopropyl ether and the crystals formed are filtered off. There are obtained 270 mg (54% of theory) 13-(2-cyanoethyl)-6,7,12,13-tetrahydro-3-methoxy-12-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in the form of yellow crystals which decompose from about 260° C. with the evolution of gas.
Reaction SMILES: C1(C)C(C)=CC=CC=1.C1([SnH](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[N:38][C:39](=[C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:46][C:45]([CH3:54])([CH3:53])[NH:44]2)[C:40]([NH2:42])=[O:41])=[CH:33][CH:32]=1)(=[O:30])[CH3:29]>C(#N)C>[C:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]=[N:38][CH:39]([CH:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:46][C:45]([CH3:54])([CH3:53])[NH:44]2)[C:40]([NH2:42])=[O:41])=[CH:35][CH:36]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: CC(=O)c1ccc(N=NC(C(N)=O)C2NC(C)(C)Cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere, 2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia) is dissolved in acetonitrile, and the obtained product is added with xylene in which triphenyl tin hydride (Aldrich, Corp., USA) is dissolved, and the mixture is refluxed. The refluxed product is cooled to room temperature and an insoluble matter is separated by filtration. The solvent is removed from the filtrate by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 1H-indazole-5-carboxylic acid (6.0 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (5.4 g, 1.5 eq), HOBt (6.0 g, 1.2 eq) and EDCI (8.5 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (15 g, 4.0 eq) dropwise at 0° C. After addition, the mixture was stirred at rt overnight, concentrated, and purified by column chromatography to give the desired product (4.4 g, 58%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.56 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[N:21]1[CH:26]=NC=N[CH:22]=1>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][NH:21][CH:26]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1F
Reactant: c1ncncn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc(-c2ccccc2F)c1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of sodium ethoxide in ethanol (20%, 1270 μl) was added to a solution of ethyl 4-(2-fluorophenyl)-3-oxobutanoate (697 mg) and 1,3,5-triazine (277 mg) in ethanol (8.0 ml) at room temperature, and the mixture was stirred at 85° C. for four hours. The solvent was distilled off under reduced pressure, followed by dilution with water. A 1 N aqueous hydrochloric acid solution was added, and the precipitated solid was collected by filtration and washed with ethyl acetate to give 406 mg of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:14][CH3:15])[N:5]2[CH:16]=[CH:17][N:18]=[C:4]2[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.[Pd].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>[CH3:15][NH:14][C:6]1[N:5]2[CH:16]=[CH:17][N:18]=[C:4]2[N:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CNc1c(-c2ccccc2)c(Cl)nc2nccn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CNc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 550 mg of the product of step 1 and 350 mg 4-formylphenylboronic acid in 10 ml 1,2-dimethoxyethane are, 55 mg tetrakis(triphenylphosphine) palladium(0) and 4 ml of a 10% w/w sodium carbonate solution are added and the resulting mixture is heated by microwave for 2 h. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate and evaporated. The residue is suspended in ethyl acetate and the resulting mixture is stirred for 2 h at room temperature. The product is collected by filtration and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:14][C@@H:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(N[C@@H](C)C(=O)OC)nc(Cl)n1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (5.175 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.497 g, 25.05 mmol) and iPr2NEt (9.6 mL, 55.1 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 30-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a thick yellow-orange oil (4.194 g, 15.33 mmol, 61% yield). LC/MS: m/z=274.2 [M+H]+.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=C(Cl)C=C(Cl)C=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][CH:38]1[CH2:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:46]([C:47]3[CH:52]=[C:51]([Cl:53])[CH:50]=[C:49]([Cl:54])[CH:48]=3)[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:53][C:51]1[CH:52]=[C:47]([C:46]2[C:40]3[O:39][CH:38]([CH2:37][NH2:34])[CH2:42][C:41]=3[CH:43]=[CH:44][CH:45]=2)[CH:48]=[C:49]([Cl:54])[CH:50]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3cc(Cl)cc(Cl)c3)c2O1
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)cc(Cl)c4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: NCC1Cc2cccc(-c3cc(Cl)cc(Cl)c3)c2O1
Yield: 49 %

Procedure:
Treatment of (±)-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.498 mmol) with sodium azide (0.08 g, 1.25 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphosphine (0.26 g, 0.997 mol) generally according to the procedure described for Example 21 afforded 0.08 g (49%) of (±)-1-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 165-168° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.27; H, 3.95; N, 4.23.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22]>>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]([F:22])([F:24])[F:23])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile was prepared from vanillin and 4-fluoro-3-trifluoromethylbenzonitrile following General Procedure A. 1H NMR (400 Hz, CDCl3) δ 10.00 (s, 1H), 8.00 (m, 1H), 7.68 (dd, 1H), 7.58-7.53 (m, 2H), 7.29 (d, 1H), 6.75 (d, 1H), 3.83 (s, 3H); LC/MS (m/z) [M+1]+322.1 (calculated for C16H11F3NO3, 322.06).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5]Br.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5][O:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(CF)(CF)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CF)(CF)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
171.2 g (0.79 mol) of 3,3-bisfluoromethyl-1-bromo-butan-2-one were added dropwise to a stirred mixture of 102 g (0.79 mol) of p-chlorophenol and 110 g (0.79 mol) of powdered potassium carbonate in 500 ml of acetone at 20° to 30° C. The mixture was subsequently stirred at 40° C. for 4 hours, the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 190.5 g (90% of theory) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-butan-2-one of boiling point 113°-117° C./0.1 mm Hg were obtained. ##STR74##
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:13][C:14]#[N:15])[CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCNCC1
Reactant: N#CCBr
Product: CN(C)CCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Dimethyl-(2-piperazin-1-yl-ethyl)-amine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=197.2.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH2:33]([N:35]([CH2:39][CH3:40])[C:36](Cl)=[O:37])[CH3:34]>>[CH2:33]([N:35]([CH2:39][CH3:40])[C:36]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:37])[CH3:34]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-diethylcarbamoyl chloride. Off-white solid. MS (m/z): 534.3 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]([O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])(=[O:13])/[CH:14]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=O
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCC/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of valeraldehyde (5.81 g) in THF (100 mL) was added tert-butoxycarbonylmethylenetriphenylphosphorane (25.4 g) and the reaction mixture stirred for 16 h at rt. The solvents were evaporated, the residue slurried in diethyl ether and filtered. The filtrate was evaporated and the residue purified by chromatography eluting with 3% EtOAc in isohexane to give the subtitle compound 8.5 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25]Cl)[CH3:22]>CC(N(C)C)=O>[CH2:21]([N:23]([CH2:27][CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: Oc1ccccc1CCCCc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCOc1ccccc1CCCCc1ccccc1
Yield: 98.2 %

Procedure:
Following a procedure similar to that described in Example 2, 340 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 140 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 310 mg of 2-diethylaminoethyl chloride hydrochloride were reacted in 20 ml of dimethylacetamide. The crude product, extracted following the procedure of Example 2, was purified by column chromatography through silica gel, using a 30:1 by volume mixture of methylene chloride and methanol as the eluent, to give 480 mg (yield 98%) of the title compound as an oil.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[Br:11]NC(=O)CCC(N)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: NC(=O)CCC(=O)NBr
Reactant: c1cnc2c(n1)CCCC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrC1CCCc2nccnc21
Yield: 61.8 %

Procedure:
To a solution of commercially available 5,6,7,8-tetrahydroquinoxaline (3.08 g, 23.0 mmol) in CCl4 (200 mL) was added N-bromosuccinamide (4.09 g, 23.0 mmol) and a catalytic amount (56 mg) of benzoyl peroxide. The reaction mixture was heated at reflux for 17 hours. Saturated sodium bicarbonate solution was added (100 mL), the layers were separated and the aqueous phase was extracted with CH2Cl2 (2×200 mL). The organic extracts were dried and concentrated. The crude material contained 1:3:1 ratio (GC) of starting material, mono- and dibromo products which were separated by column chromatography on silica gel using a mixture of 1:1 EtOAc:hexanes to give 5-bromo-5,6,7,8-tetrahydroquinoxaline (3.03 g, 54%) as a brown liquid: 1H NMR (CDCl3): δ 1.99-2.03 (m, 1H), 2.20-2.49 (m, 3H), 2.97-3.10 (m, 1H), 3.11-3.20 (m, 1H), 5.48 (t, 1H, J=1.5 Hz), 8.40 (s, 2H). It should be noted that this material is unstable when exposed to air over 2-3 days and was used immediately in the next reaction.