Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>>[C:1]1([N:7]2[C:11]3([CH2:12][CH2:13][N:14]([C:19]4[CH:20]=[CH:21][C:22]5[N:23]([C:25]([C:28]([F:29])([F:31])[F:30])=[N:26][N:27]=5)[N:24]=4)[CH2:15][CH2:16]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: O=C1NCN(c2ccccc2)C12CCN(c1ccc3nnc(C(F)(F)F)n3n1)CC2

Procedure:
A mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-phenyl-8-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.C(N(CC)CC)C>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:6](=[O:8])[CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)OCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
A tetrahydrofuran (6 L) solution of 140 g of 2-isopropoxyacetic acid and 540 mL of triethylamine was cooled to −20° C., to which a tetrahydrofuran (100 mL) solution of 145 g of 2,2-dimethylpropanoyl chloride was added dropwise, followed by stirring the reaction mixture at −10 to −20° C. for 3 hours. The reaction mixture was cooled to −30° C., to which 80 g of anhydrous lithium chloride and then 225 g of (4S)-4-benzyl-1,3-oxazolidin-2-one was added, followed by stirring the reaction mixture overnight at room temperature. The reaction mixture was filtered and subjected to vacuum concentration. The residue was dissolved in 3 L of ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution (1.5 L), and dried with anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was purified using silica gel column chromatography to obtain 196 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (5:1→2:1)-eluted fraction.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39]I)[C:22]=1[CH2:41][CH2:42][CH3:43])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:41][CH2:42][CH3:43])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCCOCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 87.1 %

Procedure:
A mixture of 1.00 g (0.0052 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.78 g (0.0052 mole) of [4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.44 g (0.010 mole) of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HPLC using 35% ethyl acetate-hexane to give 2.72 g (87% yield) of [4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])=[O:28]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: O=C1CC2(CCN1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O
Product: CC(C)(C)CC(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3) from 2-(4-(2,2,2-trifluoroethyl)phenyl)-2,8-diazaspiro[4.5]decane-1,7-dione, product of example 10 step A), and 3,3-dimethyl-butyryl chloride. MS (ESI): 425.2 (MH+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O.O.[OH-].[NH4+:29]>CO>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([C:3]([NH2:29])=[O:2])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: [NH4+]
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C(C(N)=O)CCC2c2ccc(F)cc2)cc1

Procedure:
A solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (1.3 g, 3.44 mmol) in MeOH (75 ml) and ammonium hydroxide solution (50 ml, 25%) was stirred at room temperature for 72 h. The volume of the solution was reduced to 50 ml and water (150 ml) was added. The title compound precipitated as a white solid (0.95 g, yield 76%), m.p. 137° C. and MS: m/e=363.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[FH:26].C(=O)(O)[O-].[Na+]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([F:26])[C@@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](F)[C@@H]1O
Temperature: 0 °C
Reaction time: 9 h

Procedure:
To a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (100 mg) in anhydrous diethyl ether (6 ml) cooled in an ice-bath was added 70% hydrogen fluoride-pyridine (0.24 ml). The mixture was stirred at 0° C. for 9 hours, ice was added and the reaction mixture was neutralized by addition of solid sodium bicarbonate (1.2 g) at 0° C. and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated to afford the crude title compound as an oil (65 mg). This crude material was purified by chromatography on silica gel (10 g, elution with ethyl acetate:cyclohexane, 2:8) and the resulting material (35 mg) was crystallized from a diethyl ether/pentane mixture to afford the title compound as a white solid, m.p. 98°-99° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[C:29]([SH:30])=[N:28][N:27]=[N:26]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21][S:30][C:29]3[N:25]([CH3:24])[N:26]=[N:27][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1S
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cn1nnnc1SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 33, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 1-methyl-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 58°-62° C., in an 87% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].N1C=CC=CC=1.Cl.[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(OCCO)C>[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3cccc(N(C)C)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 273.3 mg (3.0 mmol) of pyridine and 261.4 mg (1.25 mmol) of 3-dimethylaminoaniline hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 294.8 mg (73.4%) of the product as a deep greenish yellow solid, m.p. 222-225° C., mass spectrum (electrospray, m/e): M+H 319.0.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].[ClH:8].[CH:9]([O-])([O-])OC>CO>[ClH:8].[CH3:9][O:6][C:5](=[O:7])[C@H:3]([CH3:4])[NH:2][CH3:1]
Reactant: COC([O-])[O-]
Reactant: CN[C@@H](C)C(=O)O
Agent: Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)OC
Reaction time: 24 h

Procedure:
In 600 ml of methanol was suspended 53.5 g (0.52 mol) of N-methyl-L-alanine and under ice-cooling and stirring, 75 g of dry hydrogen chloride gas was dissolved. The suspension of the starting material cleared gradually with reaction time and, on stirring overnight, yielded a homogeneous solution. To the reaction mixture was added 85 g (0.8 mol) of methyl orthoformate and the mixture was allowed to stand at room temperature for 24 hours. The small quantities of insolubles were filtered off and the filtrate was concentrated under reduced pressure. By the above procedure was obtained a solid product of N-methyl-L-alanine methyl ester hydrochloride.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>>[CH3:18][C:12]1[C:11]2[N:10]=[C:5]([CH:4]3[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]3)[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C(O)C1CCNCC1
Product: Cc1cccc2[nH]c(C3CCNCC3)nc12

Procedure:
The title compound was prepared from isonipecotic acid and 2,3 diamino toluene using the method described in Description 14. MH+ 216.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCN(C(=O)C2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 94.5 %

Procedure:
To a solution of the compound (6.3 g) obtained in step 4 in ethanol (30 mL) was added 4N aqueous sodium hydroxide solution (35 mL), and the mixture was stirred at room temperature for 22 hr. The reaction mixture was concentrated under reduced pressure, and made acidic with 6N hydrochloric acid. The resultant product was extracted with ethyl acetate, the organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid (5.21 g, 95%) as a pale yellow powder.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH2:20][NH2:21])([C:16]([O:18][CH3:19])=[O:17])[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH2:20][NH:21][S:30]([CH3:29])(=[O:32])=[O:31])([C:16]([O:18][CH3:19])=[O:17])[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:3]
Reactant: COC(=O)C1(CN)CC(c2ccc(F)c(C#N)c2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(CNS(C)(=O)=O)CC(c2ccc(F)c(C#N)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-cyano-4-fluorophenyl)-5-(aminomethyl)-5-(carbomethoxy)isoxazoline hydrochloride salt (1.15 g) in CH2Cl2 (50 mL) was added triethylamine (1.27 mL) and methanesulfonyl chloride (0.31 mL). The mixture was stirred at RT under N2 for 1 h. The solvent was diluted with CH2Cl2 and washed with water, 1N aqueous HCl, and saturated aqueous NaHCO3. It was dried over MgSO4 and concentrated to a yellow solid (1.13 g). 1H NMR (CDCl3) δ 7.92 (m, 2H), 7.30 (t, 1H), 4.82 (t, 1H), 3.84 (s, 3H), 3.76-3.60 (m, 4H), 3.03 (s, 3H) ppm; ESI mass spectrum z (rel. intensity) 377.9 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH2:19]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH:19]2[C:8](=[O:10])[C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1ccsc1C(=O)O
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: COc1ccsc1C(=O)C1C(=O)N(C(N)=O)c2ccc(Cl)cc21
Yield: 29 %

Procedure:
A 2.00 g (12.69 mmoles) sample of 3-methoxy-2-thiophenecarboxylic acid (prepared according to Gronowitz, S., Arkiv. for Kemi. 12:239 (1958)) was reacted with 10 ml of thionyl chloride according to Example 32. Evaporation of excess thionyl chloride left 2.17 g of 3-methoxy-2-thiophenecarbonyl chloride as a crystalline solid, m.p. 86°-88° C. The acid chloride was coupled to 2.16 g (10.24 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 3.30 g (27 mmoles) 4-(N,N-dimethylamino)pyridine according to the procedure in Example 32. Aqueous acid quench followed by filtration gave a yellow solid which was purified by recrystallization to give 1.04 g (2.96 mmoles, 29% yield) of 5-chloro-3-(3-methoxy-2-thenoyl)-2-oxindole-1-carboxamide as a yellow solid, m.p. 272°-274° C. (acetic acid).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(Cl)Cl>CN(C=O)C>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:24]=3[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]4[NH:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:6][C:5]=12
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCCl
Reactant: c1nnc2n1CCNC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.16 g) in DMF (8 mL) was added Ag2CO3 (0.98 g) and a solution of 6-(3-chloropropoxy)-N-(4-fluorophenyl)-7-methoxyquinazolin-4-amine (0.32 g) in DMF (2 mL) at room temperature under stirring. The mixture was heated at 80° C. for 36 h under N2, and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a white solid (87.70 mg, 20.41%), HPLC: 90.53%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 450.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.02-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.12 (m, 1H), 7.26 (s, 1H), 7.29 (t, J=6.00 Hz, 1H), 7.38 (s, 1H), 7.54-7.58 (m, 2H), 7.81-7.84 (m, 1H), 8.07 (s, 1H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[CH:19]=1)=[O:12].N1C=CC=CC=1>C(Cl)Cl>[CH3:34][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=2)[CH:19]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulphonyl chloride (0.46 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-aminobenzamide, pyridine (0.56 ml) and methylene chloride (30 ml) and the resultant mixture was stirred at ambient temperature for 48 hours. The precipitate was isolated, washed in turn with methylene chloride and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (1.64 g); m.p. 239-240° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.03 (s, 9H), 7.24 (m, 2H), 7.45 (m, 5H), 7.59 (m, 1H), 7.71 (m, 1H), 7.27 (m, 1H), 7.77 (d, 1H), 7.82 (d, 1H), 9.94 (br s, 1H), 10.24 (br s, 1H); Mass Spectrum: M−H− 465.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 99 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](OC(C)=O)=[O:17]>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:16](=[O:17])[CH3:15]
Reactant: O=[N+]([O-])c1cccc2c(F)cccc12
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c(F)cccc12
Yield: 95.9 %

Procedure:
A solution of 141 mg (0.74 mmol) of compound 208A in 2 mL of AcOH was heated to reflux and treated with small portions of iron powder (118 mg, 2.11 mmol). The mixture was kept at reflux for 15 min before 73 μL (0.78 mmol) of Ac2O was added. After an additional 15 min at reflux, the mixture was cooled and filtered eluting with CH2Cl2. The filtrate was then concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 20 to 50% EtOAc in to give 145 mg (0.71 mmol, 97%) of compound 209A as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[CH:9][CH:10]=2)[S:5][CH2:4]1.I([O-])(=O)(=O)=[O:18].[Na+]>CO.O>[OH:1][CH2:2][C:3]1([CH2:15][OH:16])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[CH:9][CH:10]=2)[S:5](=[O:18])[CH2:4]1
Reactant: Cc1ccc2c(c1)SCC(CO)(CO)C2=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)S(=O)CC(CO)(CO)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,3-bis(hydroxymethyl)-7-methylthiochroman-4-one (300 mg, 1.26 mmol) in MeOH (6 ml) was admixed with a solution of sodium metaperiodate (286 mg, 1.34 mmol) in water (3 ml) and stirred at RT overnight. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, 4:1 cyclohexane/EtOAc, 1% by vol. of acetic acid), the desired product was obtained as a white solid (186 mg, 58% of theory).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]1([C:20]2NN=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C:20]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Yield: 82 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (6.81 g), 5-phenyl-1H-tetrazole (5.01 g) and pyridine (10 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration, and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with cold hexane to give methyl 4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzoate (7.88 g, yield 82%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 172–173° C.