Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CCO)c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
Methyl 2-{[3-(2-hydroxyethyl)phenoxy]methyl}benzoate (0.5 g, 1.75 mmol), 4-(benzyloxy)phenol (0.35 g, 1.75 mmol) and triphenylphosphine (0.5 g, 1.92 mmol) was added to a dry round bottomed flask and fitted with septum. Dry toluene (10 ml) was added and N2 was flushed through the mixture for 5 minutes. Diisopropyl (E)-diazene-1,2-dicarboxylate (0.39 g, 1.92 mmol) was added dropwise and the solution was stirred at room temperature. After three hours another equivalent of reagents was added and stirred for one hour. After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.319 g methyl 2-[(3-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoate (yield 39%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:45])[N:13]([C:16]1[C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][C:19]=2[N:18]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:17]=1)[CH2:14][CH3:15])([CH3:10])([CH3:9])[CH3:8].[C:46](=[O:56])([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[NH2:47].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1>[C:7]([O:11][C:12](=[O:45])[N:13]([C:16]1[C:20]2[CH:21]=[N:22][C:23]([NH:47][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:56])=[CH:24][C:19]=2[N:18]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:17]=1)[CH2:14][CH3:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: NC(=O)OCc1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ncc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A 20 mL microwave vial was charged with cesium carbonate (907 mg, 2.78 mmol), tert-butyl(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (500 mg, 0.928 mmol), benzyl carbamate (421 mg, 2.78 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (34.9 mg, 0.065 mmol) and BrettPhos-G3-Pd (58.9 mg, 0.065 mmol). Dioxane (10 ml) was added, the vial was flushed with argon, capped and the contents heated to 100° C. with stirring for 16 h. The reaction mixture was diluted with DCM/i-PrOH (4:1, 50 mL) and washed with brine (2×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 24 g prepacked) eluting with ethyl acetate/hexanes to afford tert-butyl(6-(((benzyloxy)carbonyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (225 mg, 0.344 mmol, 37.1% yield) as a white solid. MS ESI calc'd. For C40H40N5O4 [M+H]+ 654. found 654.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]([F:17])([F:16])[C:13](O)=O>>[CH3:10][O:9][C:3]1[C:2]2[NH:1][C:13]([C:12]([F:17])([F:16])[F:11])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(N)c1N
Reactant: O=C(O)C(F)(F)F
Product: COc1cccc2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,3-diaminoanisole (1.0 g) in trifluoroacetic acid (15 ml) was refluxed for 5 h and then stirred at room temperature overnight. Excess trifluoroacetic acid was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (50 ml) and water (50 ml). Drying over anhydrous sodium sulfate and removal of the solvent in vacuo gave a brown residue. Purification by column chromatography eluting with 50% ethyl acetate in hexane gave the title compound as a yellow solid (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[Li+].[OH-].O.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Temperature: 45 °C

Procedure:
Phenylmethyl 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 66; 381 mg, 0.82 mmol) was redissolved in tetrahydrofuran (4 ml) and LiOH (64 mg, 2.67 mmol) and water (1 ml) were added. The solution was heated at 45° C. for 90 minutes, 2M hydrochloric acid (1.33 ml, 2.66 mmol) was added and the solvent removed in vacuo. The solid was partitioned between 2M HCl (5 ml) and ethyl acetate (40 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a brown solid. 381 mg.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][N:9]([CH3:11])[CH3:10].N[C:27]1[CH:28]=C(C=[C:35](S(=O)(=O)N)[C:36]=1CC1C=CC=CC=1)CN(C)C.Cl.Cl.[OH-].[Na+].CCCC(Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.COCCOC.O.C(OCC)(=O)C>[CH2:15]([C:14]1[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:12][C:7]([CH2:8][N:9]([CH3:10])[CH3:11])=[CH:6][C:5]=1[NH:4][CH2:28][CH2:27][CH2:36][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)Cc1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Agent: CCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCCCNc1cc(CN(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1
Reaction time: 2 h

Procedure:
To a vigorously stirred mixture of (3-amino-4-benzyl-5-sulfamylbenzyl)dimethylamine dihydrochloride hemihydrate (4.0 g; prepared as described in Example 209), 2 N sodium hydroxide (60 ml) and methylene chloride (40 ml) a solution of n-butyryl chloride (1.1 g) in methylene chloride (12 ml) is dropwise added during 30 minutes keeping the temperature at 0°-5° C. by external cooling. After additional stirring at 22°-25° C. for 2 hours, the organic layer is separated, washed with water and dried in the presence of magnesium sulphate. The methylene chloride is then removed in vacuo to yield crude (4-benzyl-3-n-butyrylamido-5-sulfamylbenzyl)dimethylamine as an oil. The crude amine is dissolved in dry 1,2-dimethoxyethane (50 ml) and the resulting solution is dropwise added at 100° C. during 45 minutes to a stirred mixture of lithium aluminium hydride (2.0 g) and 1,2-dimethoxyethane (40 ml). After additional refluxing and stirring for 16 hours, the mixture is cooled, and ethyl acetate (4 ml) followed by water (8 ml) are very cautiously added. The mixture is stirred for a further 30 minutes and is then heated on a steam-bath and filtered hot. The filtercake is carefully washed with hot 1,2-dimethoxyethane (3 portions of 25 ml), whereafter the combined filtrates are evaporated in vacuo to yield crude (4-benzyl-3-n-butylamino-5-sulfamylbenzyl)dimethylamine. After recrystallization from ethanol it is obtained with a melting point of 111°-113° C. The material (IR, analysis) is identical with the material prepared as in Example 172.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1S[CH2:14][C:15](=O)[N:16]=1.SC1[C:30]([OH:31])=[CH:29]C=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[C:30]([OH:31])=[CH:29][CH:14]=[CH:15][N:16]=1
Reactant: Oc1cccnc1S
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(OCCCCCCSc2ncccc2O)c(Cl)c1

Procedure:
Stir 300 mg. of the iodide prepared in Examples 2 or 3, 3 ml. acetonitrile 112 mg. 2-mercapto-3-pyridinol and 201 mg. cesium carbonate in a reaction flask overnight at room temperature. Remove the acetonitrile and add methylene chloride. Wash with sodium carbonate solution, water, then brine and dry over sodium sulfate. Remove the solvent then add methylene chloride, heat to dissolve the mixture, add hexane and cool to precipitate the title compound as white crystals.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][C@H:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Yield: 99 %

Procedure:
Following method 2, tert-butyl(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding tert-butyl(3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([CH3:13])[C:5]([O:14][CH2:15][C:16]#[N:17])=[CH:4][CH:3]=1.Cl.[NH:19]1CCN=[C:20]1[CH2:24]OC1C=C(NS(C)(=O)=O)C=CC=1.NC1C=C(C=CC=1)OCC#N>>[ClH:1].[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:6]([CH3:13])[C:5]([O:14][CH2:15][C:16]2[NH:19][CH2:20][CH2:24][N:17]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Reactant: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Agent: Cl
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(OCC2=NCCN2)ccc(Cl)c1NS(C)(=O)=O

Procedure:
N-[6-chloro-3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-methylphenyl]-methanesulfonamide hydrochloride was prepared from N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide in a manner similar to that described in Example 1 for the preparation of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)phenyl] methanesulfonamide hydrochloride from (3-aminophenoxy)acetonitrile.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[C@H:20]([C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[OH:22])[CH2:19][S:18][CH2:17]2)=[O:15])=[CH:9][CH:8]=1)=[O:4].I([O-])(=O)(=O)=[O:34].[Na+]>CO.O>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]2[C@H:20]([C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[OH:22])[CH2:19][S:18](=[O:34])[CH2:17]2)=[O:15])=[CH:11][CH:12]=1)=[O:4]
Reactant: CC(C)(C)C(=O)NCc1ccc(NC(=O)N2CSC[C@H]2[C@@H](O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)NCc1ccc(NC(=O)N2CS(=O)C[C@H]2[C@@H](O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4(R)-[(3,4-dichlorophenyl)-(S)hydroxymethyl]-thiazolidine-3-carboxylic acid {4-[(2,2-dimethyl-propionylamino)-methyl]-phenyl}-amide (11 mg, 0.022 mmol) in MeOH (2 ml) is added sodium periodate (4.9 mg, 0.023 mmol) in water (0.5 ml). The reaction mixture is stirred at 25° C. for 18 hrs. More aqueous sodium periodate is added by portions until almost complete conversion of the starting material. The reaction mixture is filtered on cellite and concentrated in vacuo. The residue is taken into methylene chloride, washed with water and brine, concentrated and purified by preparative reverse phase HPLC and flash chromatography (silica gel, 2% to 5% MeOH/NH3 in methylene chloride) sequentially to give the following two products isomeric at the sulfoxide center:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[C:6](OC)([O:8]C)[CH3:7].Cl.[CH2:15]([NH:17][C:18]([NH2:20])=[NH:19])[CH3:16].[O-]CC.[Na+]>>[CH2:15]([NH:17][C:18]1[N:20]=[C:5]([C:6](=[O:8])[CH3:7])[CH:4]=[CH:3][N:19]=1)[CH3:16]
Reactant: COC(C)(OC)C(=O)C=CN(C)C
Reactant: CCNC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCNc1nccc(C(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6 g of 1-dimethylamino-4,4-dimethoxypent-1-en-3-one, 3.96 of N-ethylguanidine hydrochloride and 26 ml of 20% strength ethanolic sodium ethoxide solution is heated under reflux for 2 hours. After cooling, the solid is filtered off with suction, and the filtrate is concentrated in vacuo and mixed with 20 ml of trifluoroacetic acid and 2 ml of water and stirred at room temperature overnight. Then 50 ml of water are added, the pH is adjusted to 10 with sodium carbonate, and the mixture is extracted twice with 25 ml of ethyl acetate each time. The organic phase is dried over sodium sulfate and concentrated. The resulting oily residue is purified by column chromatography (silica gel, mobile phase: methylene chloride:methanol=98:2).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[CH:16][C:13]=3[NH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([N:34]([O:36][CH3:37])[CH3:35])=[O:33]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[CH:16][C:13]=3[N:14]([CH2:31][C:32]([N:34]([O:36][CH3:37])[CH3:35])=[O:33])[CH:15]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: CON(C)C(=O)CCl
Reactant: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2cc(CO)sc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Reaction time: 48 h
Yield: 69.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.288 mmol), potassium carbonate (60 mg, 0.43 mmol) and 2-chloro-N-methoxy-N-methylacetamide (200 mg) in DMF (1.5 mL) was shaken at room temp. for 48 hrs. The mixture was diluted with water (5 mL), and the resulting solid was collected by filtration. The crude solid was recrystallized from aq. ethanol to afford title compound (90 mg). The title compound is also a compound of formula I.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:17](=[O:18])[NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)OC2CN3CCC2CC3)cc1
Yield: 93 %

Procedure:
3-Quinuclidinol and 4-tolyl isocyanate were used. Filtration of the precipitated solid from the cooled reaction mixture afforded the title compound (93%) as a white solid: mp 186.0-187.5° C.; FAB LRMS m /z (relative intensity, %) 262 (21), 261 ([MH+ ], 100).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[C@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].[OH-].[Na+:27]>C1COCC1>[C:8]([C:7]1[C@@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:5]([C:20]#[N:21])=[C:4]([C:22]([F:23])([F:25])[F:24])[N-:3][C:2]=1[CH3:1])#[N:9].[Na+:27]
Reactant: CC1=C(C#N)[C@@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)[N-]1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 41 mg (0.12 mmol) (4R)-2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 5) in THF (1 ml) under argon atmosphere was added 131 μl (0.13 mmol) 1 N aqueous sodium hydroxide solution, and the mixture was stirred under a weak argon stream for 5 days at room temperature. The resulting precipitate was dried in vacuo to yield 44 mg (100% of th.) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[Li+].[OH-]>C1COCC1.C(O)C>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 0.30 g (0.87 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 4 ml of THF and 2 ml of ethanol was added 2 ml (2 mmol) of LiOH (1N aqueous solution). The reaction mixture was stirred at room temperature for 4 hours, concentrated in vacuo to near dryness, partitioned between EtOAc and 1 ml of water and acidified to pH 4 with 10% HCl. The aqueous layer was extracted with EtOAc and then the organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound as a light yellow solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25]>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.) in toluene (200 ml.) is added p-nitrobenzoyl chloride (1.86 g.). The mixture is refluxed for 18 hours and then cooled to room temperature. The precipitate is collected by filtration, washed with hexane and dried to afford 4.15 g. (87% yield) of 3-(3-carbomethoxythioureido)-4-p-nitrobenzamidobenzophenone, m.p. 205° C., dec. at 210° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[C:28]4[NH:27][C:26](=[O:29])[O:25][C:24]([CH3:31])([CH3:30])[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:32]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[C:28]4[NH:27][C:26](=[O:29])[O:25][C:24]([CH3:31])([CH3:30])[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[O:32])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCSc3ccc(C4CCCCC4)cc3)cccc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2c(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cccc21

Procedure:
Prepared analogously to Example 2 from 8-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: ClC1N=C(C=[N:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])C(N)=NC=1Cl.ClC1C=CC=CC=1SCl.[OH-].[NH4+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:12][NH2:11]
Reactant: Nc1nc(Cl)c(Cl)nc1C=NSc1ccccc1Cl
Agent: ClSc1ccccc1Cl
Agent: [NH4+]
Agent: [OH-]
Product: NSc1ccccc1Cl

Procedure:
5,6-Dichloro-3-[(o-chlorophenyl)thioimino]methylpyrazinamine by the reaction of o-chlorobenzenesulfenyl chloride with ammonium hydroxide to form o-chlorobenzenesulfenamide, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinealdehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)OCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]#[N:12]
Reactant: N#CCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccccc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 2-bromophenol (5.1 g, 29.48 mmol, 1.00 equiv), 2-bromoacetonitrile (5.3 g, 44.19 mmol, 1.50 equiv), potassium carbonate (8 g, 57.97 mmol, 2.00 equiv), N,N-dimethylformamide (20 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting solution was diluted with 5×50 mL of EA. The organic layer was washed with 50 mL of H2O. Organic layers were collected and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 6 g (96%) of 2-(2-bromophenoxy)acetonitrile as a brown solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32].O>CS(C)=O.CCOC(C)=O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]3[C:10]([NH2:9])=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:17][CH:18]=2)=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ncccc1-c1ccc(Oc2ccc(Br)c(C(F)(F)F)c2)cc1
Temperature: 140 °C
Reaction time: 7 h
Yield: 69.2 %

Procedure:
Tripotassium phosphate (3.42 g) was added to a mixture of 4-(2-aminopyridin-3-yl)phenol (1.00 g) and 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (1.57 g) in DMSO (15 mL). The mixture was stirred at 140° C. under nitrogen for 7 hr. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) and concentrated to give 3-{4-[4-bromo-3-(trifluoromethyl)phenoxy]phenyl}pyridin-2-amine (1.52 g) as orange oil.