Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:15][CH2:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([Li:32])CCC.CCCCCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Li:32])[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2(O)C=CCC2)cc1
Reactant: [Li]CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Li]C1(c2ccc(C(C)(C)C)cc2)C=CC=C1

Procedure:
A solution of 7 g of 1-(4-t-butylphenyl)cyclopent-2-en-1-ol (0.032 mole) and 0.1 g of p-toluenesulphonic acid (0.00058 mole) in 70 ml toluene was gently heated to 40° C. for 5 minutes. The mixture was washed with aqueous sodium hydroxide and subsequently with water. After drying the organic phase over magnesium sulphate for 2 hours, 20.3 ml of a solution of n-butyllithium in hexane (1.6 mole/liter, 0.032 mole n-butyllithium) was added. A precipitate was formed and the precipitate was washed three times with hexane to obtain 4-t-butylphenylcyclopentadienyllithium as an off-white solid material.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CN(C)C(=O)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and piperidine-4-carboxylic acid dimethylamide using General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid dimethylamide.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21]>>[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-phenylalanine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=148-149.5° C.). The reaction was monitored by tlc (Rf=0.24 in 50% EtOAc/hexanes) and the product was not purified.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:28][O:27]1>>[OH:32][CH2:31][C@@H:29]1[CH2:28][O:27][C:26](=[O:25])[N:30]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][N:7]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)nc1C
Yield: 50 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (540 mg) described in Preparation Example 146 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (474 mg), the title compound (295 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[C:17]([F:19])([F:20])[F:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (3.6 g, 12.6 mmol) in methanol (100 mL) and water (20 mL) at room temperature was added lithium hydroxide, monohydrate (0.583 g, 13.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The methanol was removed under reduce pressure, and the residue was diluted with water (−100 mL). Ethyl ether (200 mL) was added, and the pH of the aqueous layer was adjusted to <1 with a 1N aqueous solution of hydrochloric acid. The mixture was transferred to a separatory funnel, and after agitation, the layers were separated. The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated to afford 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (3.12 g, 12.13 mmol, 96% yield) as a white, crystalline solid. The compound had an HPLC retention time=2.58 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+Na)=279.95. 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.64 (m, 3H), and 7.70 (d, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH2:18]>C(Cl)(Cl)Cl>[OH-:18].[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17]
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: [OH-]

Procedure:
The corresponding salts of formula (V) or (VI) where M is tetrabutylammonium can be obtained from the corresponding acid, e.g. by neutralization with aqueous tetrabutylammonium hydroxide in the presence of a water immiscible organic solvent, preferably chloroform. The solvent layer is separated and the product isolated by evaporation of solvent. Alternately, the sodium or potassium salts of formula (V) or (VI) are reacted with an equimolar amount of aqueous tetrabutylammonium hydrogen sulfate in the presence of a water immiscible solvent, the precipitated alkali metal bisulfate salt removed by filtration and the product isolated by evaporation of solvent.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([C:14]2[O:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[O:18][C:19]=2[CH2:20][NH2:21])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.CCOC(C)=O>N1C=CC=CC=1.ClCCl>[C:8]1([C:14]2[O:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[O:18][C:19]=2[CH2:20][NH:21][C:1](=[O:3])[CH3:2])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1=C(c2ccccc2)Oc2ccccc2O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC1=C(c2ccccc2)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.416 ml (4.4 mmol) of acetic anhydride are slowly added to a solution of 0.88 g (3.67 mmol) of the amine obtained in Step C in 10 ml of anhydrous pyridine previously cooled to 0° C. After 1 hour of stirring under argon, the medium is diluted with dichloromethane and then acidified with a hydrochloric acid solution (1N). The aqueous phase is then extracted with dichloromethane; the organic phases are then dried over magnesium sulphate. The solvent is evaporated in vacuo; the residue obtained is then passed over a silica column (eluant:AcOEt/PE:60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]3[N:29]=[CH:30][CH:31]=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl.CN([CH:40]=[O:41])C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:40]=[O:41])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3ccnn23)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=O)cnn23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12 %

Procedure:
To tert-butyl 3-(5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (965 mg, 2.2 mmol) in DMF (8.2 mL), POCl3 (1.2 mL, 13.3 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred for 3 days at room temperature. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, tert-butyl 3-(5-(3-chlorophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was collected as a solid in 12% yield after purification by column chromatography on silica using 5% acetone/dichloromethane as the eluent. LCMS (M+1=464)
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]([C:13]#[N:14])=[C:9](SC)[N:10]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>C(#N)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]([C:13]#[N:14])=[C:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]2)[N:10]=1
Reactant: CSc1nc(Cc2ccccc2F)[nH]c(=O)c1C#N
Reactant: OCCC1CCNCC1
Solvent: CC#N
Product: N#Cc1c(N2CCC(CCO)CC2)nc(Cc2ccccc2F)[nH]c1=O
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(2-fluorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.14 g (1.1 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for six days. After cooling to room temperature, the crude product is purified by preparative HPLC. 31 mg (24% of theory) of the title compound are obtained as a colourless solid.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1.C([O-])(O)=O.[Na+].Cl[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([OH:37])=[O:36])=[CH:29][CH:28]=1)(=[O:26])=[O:25].Cl>O1CCOCC1.O>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([C:27]3[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 82.7 %

Procedure:
To a suspension of 1-(α,α,α-trifluoro-m-tolyl)piperazine hydrochloride (0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (A) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL) and the pH of the medium was brought to ˜4 with 2 N HCl. The precipitated solid was filtered, washed with water, and dried in vacuum to give the title compound (0.59 g, 82%). 1H NMR (DMSO-dc, HMDSO), δ: 2.96-3.67 (SH, m, overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz); 7.01-7.57 (4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz); 8.00 (2H, d, J=8.4 Hz); 12.71 (1H, br s).
Reaction SMILES: P(Cl)(Cl)Cl.[CH2:5]([N:12]1[C:22](=[O:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:15]2[S:16](=O)[CH2:17][CH:18]=[CH:19][N:14]2[C:13]1=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[CH2:5]([N:12]1[C:22](=[O:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:15]2[S:16][CH2:17][CH:18]=[CH:19][N:14]2[C:13]1=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)C=CCS2=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)C=CCS2
Temperature: -10 °C
Yield: 81.1 %

Procedure:
Phosphorus trichloride (0.2 ml) was added dropwise to a solution of 7-benzyl-1-oxo-9-phenyl-2H,6H-pyrimido[6,1-b]-[1,3]thiazine-6,8(7H)-dione (0.4 g) in DMF (8 ml) under stirring at -10° C. The mixture was stirred at the same temperature for 30 minutes and the resulting solution was poured to ice-water to give crystals and the crystals were collected by filtration. The resulting crude crystals were washed and recrystalized from methylene chloride-methanol to give colorless needles (0.31 g, 81%).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]N)=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=O)[CH3:21]>>[N+:17]([C:11]1[CH:10]=[C:9]([O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[C:13]2[C:12]=1[NH:15][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:21]2)([O-:19])=[O:18]
Reactant: CC(=O)c1ccccn1
Reactant: NNc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Product: O=[N+]([O-])c1cc(Oc2ccccc2)cc2cc(-c3ccccn3)[nH]c12
Yield: 12.3 %

Procedure:
(4-Phenoxy-2-nitrophenyl)hydrazine hydrochloride (10 g, 49 mmol) and 2-acetylpyridine (5.5 ml, 49 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (2 g, Yield 16%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Yield: 66.2 %

Procedure:
The general method described in Part C of Example 30 was used to cyclize ethyl 4-(3-aminoquinolin-4-ylamino)butyrate (18.0 g, 65.9 mmol) by reaction with trimethyl orthobutyrate (10.4 g, 70.2 mmol) to provide ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate (14.2 g) as a solid after chromatography on silica gel (elution with 5% methanol in dichloromethane).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]#[N:33])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]#[N:33])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N#CCCN1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCN1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), 3-(4-amino-piperidin-1-yl)-propionitrile (hydrochloride salt) (9.48 g, 50.0 mmol), diisopropylethylamine (24.5 ml, 141 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 18 h. The mixture was cooled to 25° C. and was concentrated to approximately 40 ml volume. This material was partitioned between water (2000 ml) and CH2Cl2 (3×2000 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (19.3 g, 93% over 3 steps) as a yellow-orange foam. LCMS (Method G, ESI): RT=0.69 min, m+H=455.3. This material was used in the next step below without additional characterization.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][CH2:21][CH3:22].C1C=C(Cl)C=C(C(OO)=[O:32])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([CH2:21][CH3:22])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SCC)c1CC
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)CC)c1CC

Procedure:
Prepared from product of Example 5 (7.0 g, 19.6 mmol) and MCPBA (3.98 g of an 85% mixture with MCBA, 19.6 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (6.56 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])([O-])=O>CO.[Pd]>[F:19][C:18]([F:20])([F:21])[O:17][C:13]1[CH:12]=[C:11]([C:6]2[CH:7]=[CH:8][C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(-c2cccc(OC(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cccc(OC(F)(F)F)c2)cc1N
Reaction time: 4 h
Yield: 69.4 %

Procedure:
3-Nitro-3′-trifluoromethoxy-biphenyl-4-ylamine (28.5 g) was dissolved in methanol (250 mL). To this solution, Pd—C (10%, Degussa Type, 15 g) was added, and the resulting mixture was stirred under a hydrogen atmosphere for 4 hours. The solution was filtered on celite, washed with methanol, and then concentrated to give 3′-trifluoromethoxy-biphenyl-3,4-diamine (17.8 g) which was used without further purification. 3′-Trifluoromethoxy-biphenyl-3,4-diamine (17.8 g) was taken up into methanol (100 mL), and cyanogen bromide (8.9 g) was added. The resulting mixture was stirred at room temperature for about 30 minutes. The solution was concentrated to dryness. The resulting crude product was triturated with diethyl ether (100 mL), filtered and dried to obtain 5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (21.3 g), which was used without further purification. LCMS (m/z): 293.9.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29]>C(#N)C>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: NCc1ccccc1F
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccccc1CNCCOc1cccc(-c2noc3ccsc23)c1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
Mix 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.40 g, 1.23 mmol), potassium carbonate (0.341 g, 2.47 mmol), 2-fluorobenzylamine (0.626 g, 5.0 mmol) and acetonitrile (5.0 mL) and heat at 80° C., overnight. Cool the reaction mixture and filter through a Waters Sep-Pak 1 g silica cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a solvent gradient of 40% ethyl acetate in heptane to 100% ethyl acetate to obtain the title compound (0.378 g, 83% Yield). Purity by LC/MS (APCI)=99%, [M+H]+=369.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].[CH:23]([SH:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:26][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)SC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Temperature: 0 °C

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-3-chloro-1-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate (32 mg) in anhydrous dimethylformamide (DMF, 2 ml) is cooled to -40° C. and stirred under a nitrogen atmosphere. A solution of isopropylmercaptan (8 mg) in anhydrous DMF (1 ml) containing 57% sodium hydride (4.4 mg) is added dropwise over 10 mins. The resulting solution is stirred for 2 hrs, with gradual warming to 0° C. The solution is diluted with ethyl acetate (20 ml), washed with water (5×10 ml) and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue is purified by plc on silica gel GF to yield benzyl 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.O1CCOCC1.[Cl-].[Na+].[NH2:42][NH2:43]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:5]3[C:4](=[CH:9][CH:8]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:6]=3)[N:3]=[C:2]([NH:42][NH2:43])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NN)nc(-c3cccc(Cl)c3)c2c1
Yield: 76 %

Procedure:
A mixture of 2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.0040 mol), described in International Patent Specification WO 00/39082, in hydrazine (20 ml) and dioxane (40 ml) was stirred at 70° C. for 20 minutes. Saturated sodium chloride solution was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (2.15 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH; 95/5 to 90/10; 70–200 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.5 g (76%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-hydrazino-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol, mp.186° C. (intermediate 11).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>C(O)C>[Br:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1cccs1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)C(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-ethoxyacrylate (1.1 g) in ethanol (10 ml) is added portionwise 2-aminothiophene (0.3 g). After stirring the mixture at room temperature for 30 minutes, the precipitated crystals are separated by filtration to give ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-(2-thienyl)acrylate (0.9 g).