Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:33])[CH3:32]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15](=O)[NH:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:37]2)=CC=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15](=[S:37])[NH:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=O)CCC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2(C)C

Procedure:
(5,5-Dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-carbamic acid tert-butyl ester (1.90 g, 0.00624 mol), THF (100 mL, 1 mol), and 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (2.58 g, 6.4 mmol) were stirred at rt for 16 h. Title compound was obtained as a white solid (1.54 g, 77%), LCMS 321.21 (M+H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.O.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>C(#N)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: O=C1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g), 4-piperidone monohydrate hydrochloride (13.9 g) and triethylamine (25 ml) were added to acetonitrile (100 ml), and the mixture was stirred at a refluxing temperature for 1.5 h. 0.5 N Aqueous hydrochloric acid solution (200 ml) was added to the reaction mixture to allow crystallization to give the title compound (16.1 g), melting point: 109° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCCN1
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCCN1c1ccnc(Cl)n1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 15.9 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (2.6 g), pyrrolidin-2-one (1.0 g), cesium carbonate (11 g) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (370 mg) in toluene (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (540 mg), and the mixture was stirred in a microwave reactor at 110° C. for 1.5 hr. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (370 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([S:30][C:31]4[CH:32]=[C:33]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[CH:35][CH:36]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([S:30][C:31]4[CH:32]=[C:33]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[CH:35][CH:36]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Sc5cccc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 51.1 %

Procedure:
(S)—N-(3-((4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)phenyl)methanesulfonamide (10 mg, 0.01 mmol) was treated with trifluoroacetic acid (1 ml, 14 mmol) and a solution of ammonia (7N in methanol, 1 ml, 59 mmol) according to the method described in Example 27 to give 3 mg (37% yield) of the title compound as a white solid. Purity 99%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[CH:10][C:3]=12.[N:30]1[CH:34]=[CH:33][CH2:32][N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:30]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:9]=[CH:10][C:3]=23)[CH:32]=[N:31]1
Reactant: C1=CN=NC1
Reactant: Ic1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ncc3c(-c4cn[nH]c4)ccnc32)cc1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A mixture of 4-iodo-1-trityl-pyrazolo[5,4-b]pyridine (1.404 g, 2.880 mmol), 444,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-pyrazole (950 mg, 4.896 mmol) and tetrakis(triphenylphosphine)palladium(0) (166.4 mg, 0.1440 mmol) in DME (20 mL) was treated with Na2CO3 (5.559 g, 5.040 mL of 2 M, 10.08 mmol) and heated in the microwave for 60 minutes at 150° C. The reaction mixture was diluted with EtOAc and water and the layers separated. The organics were dried (MgSO4), filtered and concentrated and purified by column chromatography (1:1 Petroleum ether/EtOAc moving to EtOAc to) give the pure compound as a white solid (597 mg, 49% Yield). 1H NMR (DMSO, 400 MHz) δ 6.25 (1H, m), 7.20-7.25 (15H, m), 7.33 (1H, m), 7.65 (2H, m), 8.19 (1H, m), 8.71 (1H, s), 8.60 (1H, br s); MS (ES+) 428.18
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:8])([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(N)c2)c1
Yield: 87.3 %

Procedure:
To a solution of tert-butyl {3-[(3-nitrobenzoyl)amino]phenyl}carbamate (2.00 g, 5.6 mmol) in water (4 mL), methanol (22 mL) and acetic acid (8.6 mL) was added iron (0.782 g, 14.0 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 3 h. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (1.6 g, 87%). LCMS for C18H21N3O3 (M+H)+: m/z=328.1.
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.O[N:19]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C(Cl)Cl.C(N(CC)CC)C>[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([NH2:19])=[O:17]
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C1CCCCN1
Reaction time: 72 h
Yield: 89 %

Procedure:
N-benzyloxypiperidine-2-carboxylic acid (2.0 g), 1-hydroxybenzotriazole (1.6 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g) were dissolved in methylene chloride (20 mL). Concentrated aqueous ammonia (3 mL) and triethylamine (2 mL) were added to the resultant solution at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between water and methylene chloride. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. 10% Palladium-carbon (1 g, 50% wet) was added to the residue in methanol (30 mL), and the resultant mixture was stirred in a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration. The solvent was evaporated under reduced pressure, and the thus-obtained oily product was dried, to thereby give the title compound as a solid (970 mg, quantitative amount).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)CC)(=O)[CH2:13][CH3:14]>>[CH2:13]([C:14]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:12]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: CCC(=O)OC(=O)CC
Product: CCc1nc2ccc(F)cc2c(=O)o1

Procedure:
A mixture of 2-amino-5-fluorobenzoic acid (23.3 g, 0.15 mol) and propionic acid anhydride (150 mL) was heated to reflux for 3 hr, then the propionic acid anhydride was removed in vacuo to afford 2-ethyl-6-fluoro-benzo[d][1,3]oxazin-4-one 2 as a gray solid, which was used directly in the next step.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([OH:26])[CH2:22][C:21]2[CH:20]=[C:19]3[C:10]([C:11](=[O:24])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:23])=[C:9]([OH:25])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:27]([O-:30])(=[O:29])[CH3:28].[Na+]>CC(C)=O>[C:27]([O:30][CH2:2][C:3]([C:5]1([OH:26])[CH2:22][C:21]2[CH:20]=[C:19]3[C:10]([C:11](=[O:24])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:23])=[C:9]([OH:25])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)c2c1cc1c(c2O)CCC(O)(C(=O)CBr)C1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)C1(O)CCc2c(cc3c(c2O)C(=O)c2ccccc2C3=O)C1
Yield: 75.6 %

Procedure:
To a solution of 9-bromoacetyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (780 mg) in acetone (64 ml) was added sodium acetate (1.6 g) and the mixture was allowed to react at room temperature for 65 hours. After removing insoluble matters by filtration, the most part of the solvent was distilled off under reduced pressure and subjected to filtration to give yellow crystals (560 mg, 76%) of 9-acetoxyacetyl6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 203°-206° C.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br>O.[OH-].[Na+]>[C:18]1([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:25][CH:24]=3)=[N:9][N:10]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1

Procedure:
To 1-(4-methoxybenzyl)-4-phenylphthalazine (0.240 g, 0.735 mmol) was added acetic acid (1.5 mL) followed by hydrobromic acid 48% (1.50 ml, 27.6 mmol). A water condenser was attached and the mixture was heated to reflux for 3 hours. The reaction was diluted with water and neutralized with 6 N NaOH until pH˜6. Filtered the resulting solid, washed with water and dried to yield 4-((4-phenylphthalazin-1-yl)methyl)phenol as an off-white solid. MS m/z=313 [M+1]+. Calc'd for C21H16N2O: 312.37.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:6]([NH:20]C(=O)OC(C)(C)C)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(Cl)Cl.CO.Cl>O1CCOCC1>[Br:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:6]([NH2:20])=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(NC(=O)OC(C)(C)C)c(Oc3ccc(F)cc3Br)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc(Sc2cnc(N)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.7 %

Procedure:
A 250 mL flask was charged with tert-butyl 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylcarbamate (9.1 g, 17 mmol) and 1:1 mixture of CH2Cl2 and MeOH (100 mL). 4N HCl in dioxane was added (50 mL) and the reaction was stirred at ambient temperature overnight. The solvent was removed and dried on high vacuum to afford 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-amine (8.0 g, 109% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[N:4]([CH2:6][C:7]#[C:8][CH2:9]N(CC)CC)[CH3:5].N#C[Br:18]>C(OCC)C>[Br:18][CH2:9][C:8]#[C:7][CH2:6][N:4]([CH3:5])[C:3](=[O:15])[O:2][CH3:1]
Reactant: CCN(CC)CC#CCN(C)C(=O)OC
Reactant: N#CBr
Solvent: CCOCC
Product: COC(=O)N(C)CC#CCBr
Reaction time: 12 h

Procedure:
A solution of methyl[4-(diethylamino)-2-butynyl]- methyl-carbamate (4.2 g, 0.02 mol) (Example 1i) in anhydrous diethyl ether (50 ml) is added dropwise at room temperature to a stirred solution of cyanogen bromide in anhydrous diethyl ether (40 ml). The mixture is allowed to stand for 12 hours and the diethyl ether layer is separated, washed with water (40 ml), dried over magnesium sulfate, and concentrated. The resulting oil is then purified by bulb to bulb distillation under high vacuum to give methyl N-(4-bromo-2-butynyl)-N-methylcarbamate as a ight yellow oil. Azetidine (2 g, 0.032 mol) is added to a stirred solution of methyl N-(4-bromo-2-butynyl)-N-methylcarbamate (3.6 g, 0.016 mol). The mixture is kept at room temperature for one hour and then filtered. The filtrate is concentrated and the resulting oil purified by bulb to bulb distillation under high vacuum to give a light yellow oil. NMR(CDCl3): 4.10 (brs, 2H); 3.7 (s, 3H); 3.39 (brs, 2H); 2.94 (s, 3H); 2.45 (brs, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6]1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.CO>[OH:11][CH2:10][C@@H:7]1[CH2:8][CH2:9][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@H](CO)C1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a mixture of cis-3-(methoxycarbonyl)cyclopentancarboxylic acid [prepared according to the procedure disclosed by Tucjan J. J. Horonowski and Walter A. Szorek. Can. J. Chem. 66 61-70 (1988); 17.2 g, 0.1 mmol] and triethylamine (10.1 g, 0.1 mmol) in tetrahydrofuran (300 mL) was added ethyl chloroformate (10.9 g, 0.1 mmol) at about −5° C. over a period of about 30 min. The mixture was further stirred for about 15 min at about −5° C. The resultant thick slurry was filtered and the solids were washed with tetrahydrofuran. The combined filtrates were cooled to about 10° C. and sodium borohydride (14.5 g, 0.38 mol) was added with stirring in one portion. The mixture was stirred further for about 10 min and methanol (62 mL) added dropwise over a period of about 1 h at about 10° C. When methanol addition was completed, 6 N hydrochloric acid was added slowly until neutralization. An organic layer was collected and an aqueous layer was extracted thrice with ether. The combined organic extracts were dried, filtered, and concentrated. The residue was dissolved in ether (about 300 mL), and a white solid was precipitated which was removed by filtration. The filtrate was concentrated and the residue passed through a column of silica gel using about 2% methanol in chloroform. The appropriate fractions were combined and concentrated to give 12.5 g (79%) of methyl cis-3-hydroxymethylcyclopentancarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([C:29]1[O:30][C:31]2[CH:37]=[C:36]([CH2:38]Br)[CH:35]=[CH:34][C:32]=2[N:33]=1)#[N:28]>CC(C)=O.CN(C)C=O>[C:27]([C:29]1[O:30][C:31]2[CH:37]=[C:36]([CH2:38][O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]4[CH:7]=[CH:6][C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=4)[CH:15]=3)[CH:35]=[CH:34][C:32]=2[N:33]=1)#[N:28]
Reactant: Oc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: N#Cc1nc2ccc(CBr)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(COc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)cc2o1

Procedure:
To a stirred solution of the (E)-3-(7-chloro-2quinolinylethenyl)phenol (1.485 g, 5.28 mmol) in acetone (120 ml) and dimethylformamide (I5 ml) at room temperature are added successively potassium carbonate (1.09 g, 7.0 mmol) and 2-cyano-6-(bromomethyl)benzoxazole (1.25 g, 5.27 mmol). The resulting solution-suspension is refluxed for 16 hours and concentrated. Water (100 ml) and ethyl acetate (150 ml) are added. Extraction with ethyl acetate is followed by washing with water and brine, drying (MgSO4) and evaporation under reduced pressure. The residue is subjected to flash chromatography over silica gel. Elution is with 33% ethyl acetate in hexane and concentration of the appropriate fractions provides (E)-2-cyano-6-[3-(7-chloro-2-quinolinylethenyl) phenoxymethyl]-benzoxazole.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:34][O+](C)C>C(Cl)Cl>[CH3:34][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=1
Reactant: C[O+](C)C
Reactant: CCOC(=O)C(CCCC1CCCCC(=O)N1)NC(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CCCC1CCCCC(OC)=N1)NC(=O)OCc1ccccc1

Procedure:
The product of EXAMPLE 247 is treated with trimethyloxonium tetraflouroborate in CH2Cl2 by the method of EXAMPLE 26 to yield title material.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].Br.Br.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Yield: 87.2 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g), 4-(4-hydroxyphenyl)piperazine dihydrobromide (3.4 g) and sodium bicarbonate (1.3 g) in dimethylformamide (30 cc). The mixture is heated for 4 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5 - 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (90 cc), 2-(2-[4-(4-hydroxyphenyl)-1-piperazin-Yl]ethyl}naphtho[1-,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 235° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Br)([CH3:10])([CH3:9])[CH3:8].[C:12]([OH:18])(=[O:17])[CH2:13][CH2:14][C:15]#[CH:16].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C)C(=O)C>[C:12]([O:18][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:17])[CH2:13][CH2:14][C:15]#[CH:16]
Reactant: C#CCCC(=O)O
Reactant: CC(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C#CCCC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 24 h

Procedure:
Benzyltriethylammonium chloride (5.92 g), potassium carbonate (93.4 g), and t-butyl bromide (143 ml) were added to a solution of 4-pentynoic acid (2550 mg) in N,N-dimethylacetamide (230 ml), and this reaction mixture was stirred at 55° C. for 24 hours. After water was added, the reaction mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium chloride, and then filtered through silica gel. The filtrate was concentrated under reduced pressure to give the title compound (2.10 g). This compound was used in the following reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)[CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Oc3ccc4cccnc4c3)c2c2ccccc12
Yield: 68.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 182 using 83 (50 mg, 0.22 mmol) and quinolin-7-ol (63 mg, 0.43 mmol) to provide 229 (51 mg, 69% yield) as a tan solid. LC-MS (M+H=340, obsd.=340).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[S:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: COc1ccc(Cc2nc(C(=O)O)cs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid (101 mg, 0.405 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (96.5 mg, 0.410 mmol) were dissolved in acetonitrile (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (171 mg, 0.450 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a yellow solid (84.0 mg, 0.180 mmol, 43.9%). ESI-MS m/z calc. 466.6, found 467.2 (M+1)+. Retention time of 8.32 minutes. 1H NMR (400 MHz, CD3CN) δ 1.68-2.07 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.82 (s, 9H), 4.20 (s, 2H), 6.83-7.29 (m, 8H), 7.87 (s, 1H).