Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:28][C:16]1[CH:17]=[CH:18][C:19]([S:22]([C:25](=[CH:12][C:11]2[CH:14]=[CH:15][C:8]([C:4]3[S:5][CH:6]=[CH:7][C:3]=3[S:2][CH3:1])=[CH:9][CH:10]=2)[C:26]#[N:27])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Reactant: CSc1ccsc1-c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CSc1ccsc1-c1ccc(C=C(C#N)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To a stirring solution of 4-(3-methylthio-2-thienyl)benzaldehyde (1.0 mmol, prepared directly above) and p-toluenesulphonylacetonitrile (1.0 mmol) in toluene, add piperidine (0.05 mmol) and acetic acid (0.3 mmol). Heat the reaction mixture to reflux for 2 hours while using a Dean-Stark trap, remove the heat and concentrate the reaction in vacuo. The crude material can be carried on to the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([CH3:18])[C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[N:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:6][C:7]1[CH:8]=[C:9]([CH3:18])[C:10]([NH:13][C:14](=[O:17])[CH2:15][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:11][CH:12]=1
Reactant: Cc1cc(Br)cnc1NC(=O)CCl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cnc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.81 mL (9.9 mmol) pyrrolidine are added to a suspension of 2.37 g (9.0 mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-chloro-acetamide and 2.49 g (18 mmol) K2CO3 in 22.5 mL DMF and the reaction mixture is stirred for 20 h at RT. It is diluted with water, extracted exhaustively with EtOAc, the combined organic phases are washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is taken up in a little diisopropylether, cooled to 0° C., the crystals precipitated are suction filtered and dried in the air.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:38])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:37])[C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:26]3=[O:36])=[CH:21][CH:20]=2)=[N:6][CH:7]=1.C(OO)(=[O:41])C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:38])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:37])[C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][N+:33]([CH3:35])([CH3:34])[O-:41])[C:26]3=[O:36])=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: CN(C)CCN1CCCC(c2ccc(C(=O)Nc3c(O)cccc3C(=O)Nc3ccc(Cl)cn3)cc2)C1=O
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[N+](C)([O-])CCN1CCCC(c2ccc(C(=O)Nc3c(O)cccc3C(=O)Nc3ccc(Cl)cn3)cc2)C1=O

Procedure:
N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (300 mg) was dissolved in dimethylformamide (6 mL), and with cooling with ice, an aqueous 32% peracetic acid solution (135 μL) was added, followed by stirring with cooling with ice for 30 minutes. The reaction solution was put into an aqueous saturated sodium hydrogencarbonate solution (30 ml), followed by extraction with chloroform. The organic layer was dried with sodium sulfate and evaporated under reduced pressure to obtain N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylnitroryl)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (210 mg). The resulting N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylnitroryl)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (209 mg) was dissolved in dimethylformamide (3 mL), then at room temperature, water (3 ml), benzoic acid (46 mg) and an aqueous 1 M iron chloride solution (38 μL) were added, followed by stirring at room temperature for 2 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (chloroform:methanol=100:0 to 95:5). The purified product was dissolved in ethanol, and 4 M hydrochloric acid/ethyl acetate solution (1 mL) was added, followed by evaporation under reduced pressure. Ethyl acetate was added to the residue, followed by stirring at room temperature for 1 hour. The precipitate formed was collected by filtration and dried at 40° C. under reduced pressure to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(methylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]benzamide hydrochloride (108 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1NN.[OH-].[Na+].Cl[O-].[Na+].Cl>O>[Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([Cl:11])=[C:6]([Cl:10])[CH:7]=1
Reactant: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1nc(Cl)c(Cl)cc1Cl
Reaction time: 0.05 h
Yield: 110.4 %

Procedure:
A mixture was prepared by admixing 3 grams (0.01 mole) of 3,5,6-trichloro-4-hydrazinopicolinic acid with 15 milliliters of 20 percent sodium hydroxide and 20 milliliters of water. To this mixture at 30°C was added 25 milliliters (0.018 mole) of a 5.25 percent sodium hypochlorite solution. Immediate gas evolution was noted which ceased after about 3 minutes. Five minutes after the addition of the sodium hypochlorite solution, the reaction mixture was acidified to a pH of about 2 with concentrated hydrochloric acid. The mixture was extracted with methylene chloride. The methylene chloride was removed from the extract by evaporation leaving 2.5 grams of the crude 3,5,6-trichloropicolinic acid which was purified by sublimation at 130°C and 1 millimeter of mercury. There was thus obtained 2.0 grams of the purified product (88 percent of theoretical) which melted at 147°-151°C.
Reaction SMILES: N#N.[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:19])([CH3:18])[O:9][Si:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].N1C=CC=CC=1.Cl[C:27]([O:29]C=C)=[O:28]>C(Cl)Cl.C(#N)C>[C:27](=[O:28])([OH:29])[O:15][CH:14]=[CH2:13].[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][Si:10]([CH3:17])([CH3:16])[O:9][Si:8]([CH3:18])([CH3:19])[CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: C=COC(=O)Cl
Agent: C[Si](C)(CCCCO)O[Si](C)(C)CCCCO
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: C=COC(=O)O
Reaction time: 4 h

Procedure:
A 500 ml 3-neck , round bottom flask equipped with a reflux condenser, a mechanical stirrer, a thermometer, a dropping funnel and a N2 blanket, is charged with 69.5 g (0.25 mole) of 1,3-bis(4-hydroxybutyl) tetramethyl disiloxane (Silar Lab.), pyridine, 19.5 g and 300 ml of methylene chloride. The contents are cooled down to between 0 and 5 degrees C. by an ice bath. Through the dropping funnel 25.3 g (0.25 mole) of vinyl chloroformate in 50 ml of methylene chloride is added dropwise into the flask at a rate such that the temperature is maintained between 0 and 5 degrees C. The contents are then stirred for another 4 hours and then passed through a silica gel column. The eluents are condensed and injected in 6-8 gram portions into a reverse phase high performance liquid chromatography unit (Waters), using acetonitrile as solvent. Three fractions are collected. The major (center) fraction from each injection is collected and condensed to give 1,3-bis(4-hydroxybutyl)tetramethyl disiloxane monovinyl carbonate. The monovinyl carbonate product (34.8 g or 0.1 mole) is charged into a flask as already described, along with 8.0 g of pyridine, 50 mg of hydroquinone and 200 ml of chloroform. The contents are cooled down to between 0 and 5 degrees C. Through a dropping funnel, 10.5 g (0.1 mole) of methacryloyl chloride in 50 ml of chloroform is added into the flask at such a rate that the temperature is maintained between 0 and 5 degrees C. The contents are stirred continuously for 4 hours and then passed through a silica gel column. The contents are then condensed and distilled under reduced pressure to give the named product. Hydroquinone (50 mg) is added into the named product.
Reaction SMILES: O[C:2]1[CH:15]=[C:14](O)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].C(Br)CCCCCCC.[Na].OC1C(O)=C(C=CC=1)C(C1C=CC=CC=1)=O>C1(C)C=CC=CC=1.CC(CC(C)C)=O.CS(C)=O>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C(c1ccccc1)c1cccc(O)c1O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCCCCBr
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 40 °C
Yield: 35 %

Procedure:
2,4-dihydroxybenzophenone (5 g, 23 mmol) and polyethylenglycol (PEG 6000) (1 g) in toluene (25 ml) and NaOH 30% (6,26 g, 47 mmol) were loaded into a 100 ml three-necked flask. The solution was kept under reflux with Dien-Stark to remove water. The solution was cooled at 40° C. Dimethylsulfoxide (DMSO) (7 ml) and octylbromide (8 ml, 47 mmol) were added and the solution thus obtained was kept under reflux with Dien-Stark for 8 hours. NaOH 30% (30 ml) and methylisobutylketone (MIBK) (10 ml) were added. The aqueous phase containing the unreacted dihydroxybenzophenone sodium salt was separated from the solution. The organic phase was washed with water. The aqueous phase was reextracted with MIBK (10 ml). Both aqueous and organic phases were cloudy (the organic phase was filtered on silica). After removal of the solvent from the organic phase the crude product was dissolved in cool ethyl-acetate (9 ml) and methanol (65 ml) was added. The product crystallized at —5° C. The product was recrystallized from methanol at 30° C. cooling up to 10° C. (yield 35%; m.pt. 37,7-38,1° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]([CH3:20])[C:16]=2[CH:17]=[CH:18][CH:19]=1)[OH:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:10]
Reactant: COc1ccccc1C(O)c1cccc2c1ccn2C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Product: COc1ccccc1C(=O)c1cccc2c1ccn2C
Yield: 69.4 %

Procedure:
Using the procedure of Step C of Example 1, 43.7 g of the alcohol of Step B and 92.4 g of pyridinium dichromate were reacted to obtain 30.1 g of the expected product melting at 74° C. which was used as is for the following step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=1.O=[C:17]([C:23](OCC)=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC1C=C(N2C(=O)C(C(O)=O)=NC3C=CC=NC2=3)C=CC=1C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]2=[O:24])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Cc1cccc(Nc2ccccc2N)n1
Agent: Cc1ccc(-n2c(=O)c(C(=O)O)nc3cccnc32)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2ccccc2n(-c2cccc(C)n2)c1=O
Yield: 87.9 %

Procedure:
19.8 g (0.1 mol) of N-(6-methylpyridine-2-yl)benzene-1,2-diamine was dissolved in toluene (100 ml), and 19.0 g (0.11 mol) of diethyl ketomalonate and 57.1 g of 4 A molecular sieve were added thereto. The solution was heated to reflux for 3 hours while removing water using a Dean-Stark apparatus. Reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 27.2 g (yield: 89%) of ethyl 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=O)([O-:3])=[O:2].[NH3:15]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:5]=1[CH:6]=[CH:7][NH:15][C:9]2=[O:8])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: N
Solvent: CCO
Product: O=c1[nH]ccc2c([N+](=O)[O-])cccc12
Yield: 79.7 %

Procedure:
2.51 g (13.13 mmol) of 5-nitroisocoumarin is added in 100 ml of ethanol. Ammonia is pressure-forced in in an autoclave. The product precipitates and is suctioned off. 1.98 g (79.7%) of the desired compound is isolated.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]([F:33])([F:32])[C:25]1([C:29]([OH:31])=O)[CH2:28][CH2:27][CH2:26]1.[Cl:34][C:35]1[C:42]([NH:43][C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][CH2:58][CH:57]([C:61]([F:64])([F:63])[F:62])[CH2:56]4)[C:52]([Cl:54])=[CH:53][C:46]=3[N:45]=2)=[C:41]([Cl:65])[CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[Cl:34][C:35]1[C:42]([NH:43][C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][CH2:58][CH:57]([C:61]([F:64])([F:63])[F:62])[CH2:56]4)[C:52]([Cl:54])=[CH:53][C:46]=3[N:45]=2)=[C:41]([Cl:65])[CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:29]([C:25]1([C:24]([F:23])([F:33])[F:32])[CH2:26][CH2:27][CH2:28]1)=[O:31]
Reactant: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C3(C(F)(F)F)CCC3)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21

Procedure:
The title compound was prepared from TBTU (35 mg, 0.11 mmol), TEA (50 μL, 0.36 mmol), 1-trifluormethyl-cyclobutanecarboxylic acid (57 mg, 0.4 mmol) and 2,4-dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzylamine (45.3 mg, 0.1 mmol) in DMF (3 mL) analogy to example 1 step (i).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[N:17]=[C:16]4[CH2:18][CH2:19][CH2:20][CH2:21][C:15]4=[C:14]3[CH:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:23]=2)=[CH:8][CH:9]=1)=[O:4].O1C=CC=C1C(O)=O>>[CH2:24]([CH:22]1[C:14]2=[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]3=[N:17][C:13]2=[CH:12][C:11]([O:10][C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[CH:23]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCC1C=C(Oc2ccc(C(=O)OC)o2)C=C2N=C3CCCCC3=C21
Agent: O=C(O)c1ccco1
Product: CCCCCCCCC1C=C(Oc2ccc(C(=O)O)o2)C=C2N=C3CCCCC3=C21

Procedure:
Using the procedure of Example 43, 6.3 g of the methyl ester from Example 110 was saponified to 5-(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-7-yl)oxy]-2-furancarboxylic acid (4.3 g; 70.6%) as a white solid after crystallization from ethyl acetate, mp 142°-144° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29](C#N)[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].[OH-].[Na+]>CO.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:4][CH3:3])[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(C#N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CO
Product: COc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
A solution of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2 carbonitrile trifluoroacetate (0.13 g, 0.00023 mol) in MeOH (2.0 mL) was treated with 1N NaOH (0.5 mL). After stirring at room temperature for 3 h, it was heated at 60° C. for an additional 3 h and left overnight room temperature. The resulting solution was diluted with acetonitrile, and purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z=452) were combined and freeze dried to afford the title compound (0.015 g) as a white powder: 1H NMR (CD3OD) δ8.84 (d, 1H, J=5.2 Hz) 7.62 (d, 1H, J=5.2 Hz), 7.05 (m, 2H), 6.57 (s, 1H), 5.49 (s, 2H), 5.32 (s, 2H), 3.96 (s, 3H), and 2.49 (s, 3H); ES-HRMS m/z 452.0440 (M+H C19H17N3O3BrF2 requires 452.0416).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[OH:8][CH:1]([CH:10]1[CH2:11][CH2:12][CH2:13][O:14][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCO1
Product: O=C1OCCCC1C(O)c1ccccc1

Procedure:
Employing a procedure which is similar to that described in Example I, benzaldehyde is reacted with δ-valerolactone to produce 2-(1-hydroxy-1-phenylmethyl)-δ-valerolactone. ##STR8##
Reaction SMILES: ClC1C=C(C=CC=1)C[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:7]1.[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O.O>[N:35]([CH2:17][CH2:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][N:7]=[C:8]2[S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.25 g, 0.49 mmoles) and sodium azide (0.04 g, 0.58 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.23 g, 0.44 mmoles).
Reaction SMILES: [CH2:1]([C:3]1[O:7][CH:6]=[N:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[F:29][C:30]([F:38])([F:37])[C:31]([C:33]([F:36])([F:35])[F:34])=[O:32]>O1CCCC1>[CH2:1]([C:3]1[O:7][C:6]([C:31]([C:33]([F:36])([F:35])[F:34])([C:30]([F:38])([F:37])[F:29])[OH:32])=[N:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCc1ocnc1-c1ccc(SC)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1oc(C(O)(C(F)(F)F)C(F)(F)F)nc1-c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2.50 g (11.4 mmol) of 5-ethyl-4-(4-methylthiophenyl)oxazole and 2.0 ml (13.3 mmol) of tetramethylethylenediamine in 50 ml of tetrahydrofuran at -78° C. was added dropwise 12.6 ml (20.2 mmol) of n-butyl lithium (1.6M in hexane). The resulting solution was stirred for 1 hour at -78° C., and then 3.5 ml (31 mmol) of hexafluoroacetone was added dropwise. The mixture was stirred for 1 hour at -78° C. and then quenched by the rapid addition of 30 ml of sodium bicarbonate solution. After warming to 25° C., the organic and aqueous phases were separated and the aqueous phase was extracted with tetrahydrofuran. The combined organic phases were then washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was dissolved in a mixture of 100 ml of ethanol and 20 ml of 4N hydrochloric acid; and the solution was stirred overnight at 25° C. The solution was concentrated in vacuo to remove the ethanol and the resulting aqueous mixture was extracted with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (elution-benzene) to provide 3.28 g of 5-ethyl-4-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)oxazole-2-methanol as a light orange oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C(C)C)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 3.5 days at 35° C., from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(propane-2-sulfonyl)-piperazin-1-yl]-methanone (example 15) and 3-chlorophenylboronic acid to afford the desired product as a colorless foam (65%). MS (ISP): 600.4 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH:10]([C:12]1[N:16]([CH2:17][CH2:18][C:19]#[N:20])[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[N:13]=1)[CH3:11].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.O>[CH3:11][CH:10]([C:12]1[N:16]([CH2:17][CH2:18][C:19]#[N:20])[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[N:13]=1)[CH2:9][CH:8]=[O:7]
Reactant: CC(CCO)c1nc2ccccc2n1CCC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(CC=O)c1nc2ccccc2n1CCC#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1.0 mL of oxalyl chloride in 20 mL of methylene chloride cooled to −78° C. was added 2 mL of anhydrous DMSO. After 15 min, a solution of 1 g of 3-[2-(3-hydroxy-1-methyl-propyl)-benzoimidazol-1-yl]-propionitrile in 20 mL of anhydrous DMSO and 50 mL of methylene chloride was added keeping the temperature below −50° C. After 10 min, 10 mL of triethyl amine was added and the mixture allowed to warm to room temperature. After 15 min, the mixture was diluted with 250 mL of water, shaken and separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude 3-[2-(3-oxo-propyl)-benzimidazol-1-yl]-propionitrile was an amber resin (1.2 g), and contained only traces of the starting alcohol by TLC (90:10 methylene chloride:methanol).
Reaction SMILES: C1([C@@H]([N:9]([C@H:21]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:23]=3[CH2:22]2)[CH2:10][C@H:11]([OH:20])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C)C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:37]([O:36][C:34]([CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:24]2[CH2:25][CH2:26][CH2:27][C@H:21]([NH:9][CH2:10][C@H:11]([OH:20])[CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][C:23]=2[CH:31]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N(C[C@H](O)COc1ccccc1)[C@@H](C)c1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)COc1ccccc1)CCC2
Yield: 82.8 %

Procedure:
A mixture of (2S)-1-[N-((S)-1-phenylethyl)-((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.65 g) and 10% palladium on activated carbon (50% wet, 0.20 g) in ethanol (6 ml) and tetrahydrofuran (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed (chloroform-methanol) over silica gel to afford (2S)-1-[((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (430 mg). (2S)-1-[((6S)-3-Ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (190 mg) was treated with 4N hydrogen chloride in ethyl acetate to afford (2S)-1-[((6S)-3-ethoxycarbonyl-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (103 mg).