Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+:4]([C:7]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:8]=1F)([O-:6])=[O:5]>C(COC)OC>[CH3:1][S:2][C:8]1[C:7]([N+:4]([O-:6])=[O:5])=[CH:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: C[S-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(NC(C)=O)cc1[N+](=O)[O-]

Procedure:
At room temperature, 50.0 g of sodium thiomethoxide are suspended in 500 ml of dimethoxyethane and 99.1 g (0.5 mole) of 2-nitro-4-acetylaminofluorobenzene are added, in portions, over 30 min, while the temperature is maintained between 25° and 27° C. by means of an ice cold water bath.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:22](=[O:23])[C:21]([S:18]([NH:17][C:16]1[CH:25]=[CH:26][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)(=[O:20])=[O:19])=[CH:7]2
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(NS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 175-177° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:24])=[CH:25][CH:26]=2)[CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cc2)cn1
Yield: 13 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using tetrahydro-pyran-4-ylamine instead of cyclopropylmethylamine, to the title compound (16 mg, 13%) which was obtained as an off-white solid. MS: m/e=428.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].[Se](=O)=[O:23]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Yield: 60.7 %

Procedure:
The compound (16.00 g, 57.07 mmol) obtained in Step 2 was dissolved in 1,4-dioxane. Selenium dioxide (63.33 g, 570.07 mmol) was added thereto and refluxed for 10 hrs, followed by cooling. The resulting mixture washed with 1M sodium bicarbonate, and successively extracted with diethyl ether. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 10.198 g of the titled compound (yield: 61%) as a red solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:8][N:7]=[CH:6][C:5]=1[O:19][C:20]1[CH:21]=[C:22]([NH:26]C(=O)OC(C)(C)C)[CH:23]=[CH:24][CH:25]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[O:19][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cncc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
840 mg of tert-butyl [3-({4-carbamoyl-5-[(2-fluoro-4-iodophenyl)amino]pyridin-3-yl}oxy)phenyl]carbamate (1.488 mmol, 1 eq.) were dissolved in 8 mL dichloromethane under a nitrogen atmosphere. Then 1.6 ml of TFA were added and the brownish solution was stirred at room temperature for 18 hours. Then 4 ml of saturated aqueouse NaHCO3 solution was added and the mixture was stirred for 4 hours while a suspension was forming, that was filtered off. Drying of the precipitate in vacuo yielded 615 mg of the analytically pure target compound (1.488 mmol, 87% yield) as a yellowish solid.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6]1)(=O)C.O=CC(Cl)(Cl)Cl.C(N(CC)CC)C.C(C(C)=O)C(C)C>O>[OH:4][CH:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6]1
Reactant: COC(=O)CCC#CCCC1=CC(OC(C)=O)CC1=O
Agent: O=CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COC(=O)CCC#CCCC1=CC(O)CC1=O
Yield: 86 %

Procedure:
A mixture (9.45 g) of the compound [IX-1] and the racemic 4-hydroxycyclopentenone obtained in Example 7, chloral (0.24 g) and triethylamine (0.43 g) is reacted at 60° C. for 5 hours. After completion of the reaction, to the mixture are added methyl isobutyl ketone (30 ml) and water (20 ml). The organic layer is separated and washed successively with 1% aqueous hydrochloric acid solution and water, and methyl isobutyl ketone is distilled off therefrom to give 4-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) (8.13 g, yield; 86%).
Reaction SMILES: [O-:1][C:2]#[N:3].[O-:4]C#[N:6].[NH4+].[NH2:8][C:9]([NH2:11])=[O:10].C(=O)=O.N>>[NH2:8][C:9]([NH2:11])=[O:10].[C:2](=[O:4])([O-:1])[NH2:3].[NH4+:6]
Reactant: N#C[O-]
Agent: N
Agent: NC(N)=O
Agent: O=C=O
Product: NC(=O)[O-]

Procedure:
A number of cyanate compounds (for purposes of this disclosure, a term used generically for compounds having an OCN or NCO moiety such as cyanates or isocyanates) have significant commercial applications. For example, ammonium cyanate or its equivalent urea is employed in a number of large scale uses. Urea is used as a main constituent in fertilizers, as a monomer in the production of plastics, and as an ingredient in animal feed. The large quantities of urea used are synthesized commercially by contacting carbon dioxide and ammonia at high pressure, typically 200 to 400 atms. and at temperatures between 140° to 210 degrees C. to form ammonium carbamate, which is then decomposed into urea and water with a yield of 50%. The high pressures and incomplete conversion of CO2 and NH3 necessitate the use of expensive, sophisticated reaction and separation equipment. Production of smaller quantities is, therefore, not fiscally acceptable.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH:19]([C:21]2[N:26]3[N:27]=[CH:28][N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)[CH3:20])=[CH:16][CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([C:21]2[N:26]3[N:27]=[CH:28][N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)[CH3:20])=[CH:30][CH:31]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(OC(C)c2ccnc3ncnn23)cc1
Solvent: ClCCl
Product: CC(Oc1ccc(S(C)=O)cc1)c1ccnc2ncnn12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperbenzoic acid (0.63 g) in dichloromethane (30 ml) was added dropwise at -78° C. to a stirred solution of 7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine (0.89 g, prepared in a similar manner to that described in Example 9) in dichloromethane (30 ml). The reaction mixture was stirred at -78° C. for 2 hours, washed with a 10% aqueous solution of sodium hydrogen carbonate followed by water. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using as eluent a mixture of dichloromethane and ethanol (in the ratio of 95:5 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.76 g, (m.p. 89°-102° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>C(O)CCC>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:26][C:25]4[CH:27]=[CH:28][C:29]([F:30])=[C:23]([Cl:22])[CH:24]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: CCCCO
Product: CCOC(=O)c1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Temperature: 145 °C
Reaction time: 2 h

Procedure:
3.6 g (12 mmol) 4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) are suspended in 80 ml n-butanol and treated with 3.5 g (24 mmol) 3-chloro-4-fluoro-aniline. The mixture is heated to 145° C. under stirring. After 30 min a clear brown solution is obtained which turns into a thick suspension after 2 h. After a total of 3 h the reaction mixture is cooled in an ice bath and the product collected by filtration; m.p.>300° C.; Rf(dichloromethane/ethanol 95:5 plus 1% conc. ammonia)=0.29; HPLC tR=11.66 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1.[H-].[Na+].I[CH2:31][CH3:32].O>CN(C=O)C>[CH2:31]([O:1][CH2:2][C:3]1[C:4]([C:24]([F:26])([F:25])[F:27])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])[CH:7]=1)[CH3:32]
Reactant: CCI
Reactant: NC(=O)c1c(NC(=O)Cn2cc(CO)c(C(F)(F)F)n2)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 65 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 2-(2-(4-(hydroxymethyl)-3-(trifluoromethyl)pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (20 mg, 0.05 mmol) in DMF (2 mL) was added NaH (7 mg, 0.29 mmol) under an atmosphere of N2. The reaction mixture was stirred at RT for 30 min before addition of iodoethane (20 mg, 0.13 mmol). The reaction mixture was heated at 65° C. for 3 h then left to stand at RT overnight. Water (2 mL) was added and the reaction mixture extracted with EtOAc (3×5 mL). The combined EtOAc layers were washed with water (3×10 mL), brine (10 mL), dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative reverse phase HPLC to give the desired product as a clear gum (6.7 mg, 0.016 mmol, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][OH:5].[C@H:11]1([N:20]=[C:21]=S)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C.O>[Cl:10][C:6]1[C:3]2[CH2:4][O:5][C:21]([NH:20][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[N:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: S=C=N[C@@H]1CCc2ccccc21
Reactant: Nc1cccc(Cl)c1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 23 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
To a stirred solution of commercially available 2-amino-6-chlorobenzyl alcohol (CAS-no. 39885-08-0) (315 mg, 2 mmol) in tetrahydrofuran (4 ml) at 23° C. was added commercially available (R)-(−)-1-indanyl isothiocyanate (CAS-no. 737000-97-4) (324 ul, 2 mmol) and the mixture was stirred at 23° C. for 18 h, then at reflux for another 3 h. Cooled to 23° C., the solvent was removed in vacuum, the residue was dissolved in acetonitrile (4 ml), added dicyclohexylcarbodiimide (DCC) (619 mg, 3.0 mmol) and refluxed for 2 h. Cooled to room temperature, diluted with ethyl acetate and water, added little 1 M NaH2PO4.2H2O solution to achieve pH 4, separated phases, washed organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a yellow foam, which was purified by silica gel flash chromatography with n-heptane and ethyl acetate to give the title compound as a light yellow oil (215 mg, 36%), MS (ISP) m/e=299.1 [(M+H)+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)cn4)nn23)no1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(COS(C)(=O)=O)cn4)nn23)no1
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (1.07 ml, 13.9 mmol) was added to a stirred suspension of {6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridin-3-yl}methanol (2.78 mmol), Et3N (1.94 ml, 13.9 mmol) in CH2Cl2 (100 ml) under nitrogen. The reaction mixture was stirred overnight and then diluted with CH2Cl2. The resulting solution was washed with H2O (100 ml), 1 N HCl (100 ml), NaHCO3 (sat., 100 ml) and brine (100 ml). The solution was then dried MgSO4) and concentrated under reduced pressure. The resultant mesylate was used without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[C:27]([CH3:33])=[CH:26][N:25]=3)[NH:18][C:17]=2[CH:16]=[C:15]([CH3:34])[C:14]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[OH-].[Na+]>C(Cl)Cl.O>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[C:27]([CH3:33])=[CH:26][N:25]=3)=[O:9])[NH:18][C:17]=2[CH:16]=[C:15]([CH3:34])[C:14]=1[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCOc1c(C)cc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCOc1c(C)cc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
m-Chloroperbenzoic acid, 91% (1.13 g, 0.0059 mol) dissolved in CH2Cl2 (25 ml) and cooled to -10° C. was added under stirring to 4,6-dimethyl-5-heptyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (2.7 g, 0.0059 mol) dissolved in CH2Cl2 (50 ml) maintaining the temperature at -5° C. Stirring was continued at -5° C. for 10 min. The two phases were separated and then NaOH (0.26 g, 0.0066 mol) dissolved in water (50 ml) was added under vigorous stirring. The two phases were separated. The organic phase was dried (Na2SO4), filtered and the solvent evaporated off giving a residual oil, which according to NMR included 30% of unreacted starting material. The oil was chromatographed on a silica column using CH3OH--CH2Cl2 5:95 as eluant and then the product was recrystallized from CH3CN giving the desired product in crystalline form (0.85 g, 32%), m.p. 116° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[NH4+].OCC(CO)O>O1CCCC1.B(OC)(OC)OC.[Zn]>[CH2:21]([O:20][C:18](=[O:19])[CH:17]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)c1ccc(-c2ccccc2)cc1

Procedure:
6.45 g (0.1 mole) of activated zinc metal (20 mesh) is placed in a flask fitted with a septum inlet and a magnetic stirrer. The system is maintained under a nitrogen atmosphere and kept at a temperature of 25° C. on a water bath. A solution of 19.6 g (0.1 mole) of 4-acetylbiphenyl in 75 ml of dry tetrahydrofuran and 75 ml of trimethyl borate (distilled from calcium hydride) is injected and the mixture stirred. 11.1 ml (0.1 mole) of freshly distilled ethyl bromoacetate is injected in one shot and the mixture stirred at 25° C. for 12 hours. A mixture of 25 ml of concentrated ammonium hydroxide and 75 ml of glycerine is added, and the aqueous phase is separated and extracted thrice with 25 ml portions of diethyl ether. The combined organic extracts are dried over anhydrous magnesium sulphate and the diethylether removed on a rotary evaporator, the residue is vacuum distilled and the fraction distilling at 0.125 mn at 171°-172° C. is collected. Recrystallisation from petroleum ether yields the heading compound, substantially in trans form.
Reaction SMILES: [N:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:15][CH2:14]1.C(O)(=O)C>C(O)C>[N:1]1([N:11]=[C:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)CC1
Reactant: NN1CCCc2ccccc21
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCCC(=NN2CCCc3ccccc32)CC1
Yield: 99.5 %

Procedure:
A solution of 3,4-dihydro-1(2H)-quinolinylamine (2.97 g, 20.1 mmol), benzyl 4-oxo-1-azepanecarboxylate (4.96 g, 20.1 mmol), and glacial acetic acid (0.2 ml) in ethanol (200 ml) was allowed to reflux for 2.5 hours. The reaction was then cooled and evaporated in vacuo. The hydrazone product was purified by flash chromatography (90 g SiO2, 1% MeOH/CH2Cl2) providing benzyl 4-[3,4-dihydro-1(2H)-quinolinylimino]-1-azepanecarboxylate (7.55 g) as an oil. To a solution of benzyl 4-[3,4-dihydro-1(2H)-quinolinylimino]-1-azepanecarboxylate (6.79 g, 17.99 mmol) in ethanol (200 ml) was added trifluoroacetic acid (6.22 g, 53.96 mmol). The reaction was heated and allowed to stir at reflux for 2.5 hours, at which time it was cooled to rt., evaporated, and extracted into dichloromethane. This extract was washed with water, brine, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. Crystallization from ethyl acetate/hexanes provided 2.93 g of the title compound (mp 131-133° C.). 1H NMR (CDCl3) δ 7.38, 7.29, 7.00, 6.86, 5.19, 3.98, 3.78, 2.97, 2.24; IR (drift) 2947, 1699, 1473, 1420, 1358, 1260, 1250, 1235, 1216, 1101, 997, 764, 757, 746, 703 cm−1.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][OH:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O.C(Cl)Cl>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([O:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: OCC1CN(c2ccccc2)CCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 20 h

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinemethanol (7.8 g, 27.6 mmol) in dimethylformamide under nitrogen and add 60% sodium hydride (1.22 g, 30.4 mmol). Stir for 20 h as solid slowly dissolves. Add 1-fluoro-4-nitrobenzene (4.29 g, 30.4 mmol) and stir at room temperature. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction, add water (100 mL) to the reaction mixture andextract with methylene chloride (2×100 mL). Remove the solvent in vacuo and recrystallize the residue from ethyl acetate/hexanes (1/1) (80 mL) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(CSCC(O)CC(NS(=O)(=O)c2ccc(-c3ccc(OC)cc3)cc2)C(=O)O)cc1

Procedure:
Example 50 is prepared from 4-methoxy-α-toluenethiol and 1d using the procedure described for compound 20.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:8]=[C:9]([O:21][CH2:22][CH3:23])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[Cl:12].CN(C)CCN(C)C.CN([CH:35]=[O:36])C.[NH4+].[OH-]>C1COCC1>[Cl:12][C:11]1[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([O:21][CH2:22][CH3:23])=[N:8][C:7]=1[CH:35]=[O:36]
Reactant: CN(C)C=O
Reactant: CCOc1nc(Br)c(Cl)n1COCC[Si](C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1nc(C=O)c(Cl)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.2 mL) was added to a solution of intermediate (26a) (1.0 g, 2.8 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.5 mL, 3.1 mmol) in THF (8 mL) at −78° C. DMF (0.3 mL, 3.4 mmol) was added after 3 minutes. The mixture was stirred at −78° C. for 1 hour. The mixture was allowed to warm to room temperature over 30 minutes. Saturated aq. NH4OH (1 mL) was added and the mixture was concentrated in vacuo. The mixture was extracted with DCM (2×30 mL) and 0.5M PO3H4 (10 mL). The combined organic fractions were washed with sat. aq. NaHCO3 (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography (EtOAc:hexane) afforded intermediate (26b) (600 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23])=S)[CH:2]=[CH2:3].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[N:13]=[C:14]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)ccc1NC(=S)Nc1ccccc1Br
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reaction time: 0.25 h
Yield: 146 %

Procedure:
To a stirred solution of N-(2-Allyloxy-4-cyanophenyl)-N′-(2-bromophenyl)-thiourea (900 mg, 2.32 mmol) and triethylamine (1 ml, 6.95 mmol) in methylene chloride was added dropwise at 0° methanesulfonyl chloride (360 μL, 4.64 mmol) under Ar. The reaction was stirred for 15 minutes at 0° and tlc showed no starting material present. The reaction mixture was chromatographed on silica gel eluting with methylene chloride to afford the title compound as a yellow solid (1.2 g, >100%). This was used in the next reaction without further purification.