Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12.[H-].[Na+].Br[CH2:29][CH2:30][OH:31]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[N:12]([CH2:29][CH2:30][OH:31])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1CCO
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (0.0041 M) of 11b-(2-chlorophenyl)-10-nitro-2,3,5,11b-tetrahydooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 30 ml of dry N,N-dimethylformamide was treated with 0.34 g (0.008 M) of a 57% dispersion of sodium hydride in mineral oil with stirring under nitrogen. After 30 min, 1.5 g (0.012 M) of 2-bromoethanol was added and the reaction was heated to 90° for 3 hr. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloromethane which was then washed with 50 ml of water, 25 ml of a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether, and recrystallized from a mixture of dichloromethane and methanol to give the product as pale yellow prisms, m.p. 185°-190°(dec.).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH3:5][CH:6]([CH3:15])[CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1>C(O)(=O)C>[CH3:5][CH:6]([CH3:15])[CH2:7][CH2:8][CH:9]1[CH:13]([CH:1]=[CH2:2])[CH2:12][CH2:11][C:10]1=[O:14]
Reactant: C=C[Mg]Cl
Reactant: CC(C)CCC1=CCCC1=O
Solvent: CC(=O)O
Product: C=CC1CCC(=O)C1CCC(C)C
Temperature: -25 °C
Reaction time: 4 h

Procedure:
Vinylmagnesium chloride (H2CHCClMg, 1 L) and cuprous chloride were charged to a dried flask under nitrogen and cooled to −25° C. with a dry ice bath. The resulting mixture was fed with 2-(3-methyl-butyl)-cyclopent-2-enone (226 g, 1.49 mol, obtained as detailed above) slowly for over 4 hours, aged for another 4 hours, and allowed to warm to 0° C. The reaction mixture was then poured into acetic acid solution and washed to neutral with saturated Na2CO3 solution. The distillation process provided the product 2-(3-methyl-butyl)-3-vinyl-cyclopentanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:32])C(=O)C1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:32])=[C:9]([CH3:11])[N:8]([CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1c(I)c2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of (S)-tert-butyl 2-((4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate (1.0 g, 2.86 mmol, 1.0 eq) in DMF (20 mL), NIS (0.675 g, 3.00 mmol, 1.05 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography to afford (S)-tert-butyl 2-((4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate as white solid (1.0 g, 77% in yield) which was converted to the title compound as described in Example 30 above. LCMS m/z 519.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CC([O-])=O.[Na+].C(O)C>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([O:21][N:22]=[C:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Reactant: O=C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-piperidinone (2.5 mmol) in 25 mL of DCM, was added 69b (0.43 g, 2 mmol). The mixture was stirred at room temperature for 2 h. NaOAc (0.27 g, 2 mmol) and ethanol (10 mL) were added and the reaction mixture was heated at 70° C. for 2 h. The solution was allowed to cool down to room temperature and the ethanol was evaporated. The residue was extracted with ethyl acetate, washed with water, dried and concentrated to give 0.59 g of 69c.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11]>CO.[Pd]>[CH:7]12[O:10][CH:1]([CH2:9][CH2:8]1)[CH:2]1[CH:6]2[C:5](=[O:11])[CH2:4][C:3]1=[O:12]
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Agent: [Pd]
Solvent: CO
Product: O=C1CC(=O)C2C3CCC(O3)C12
Temperature: 25 °C

Procedure:
(1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (2.1 g, 12.8 mmol), prepared in Example 1, Step 5, is dissolved in warm methanol (180 ml) and the mixture is allowed to cool to room temperature. The mixture is then hydrogenated in the presence of 5% palladium on carbon (approx. 50 mg) at 3.5 bar for 4 hours. The catalyst is removed by filtration through diatomaceous earth and the filtrate is concentrated under reduced pressure to afford (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:29][C:2]([F:28])([F:1])[C:3]([N:5]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:30][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:9][CH2:8]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)=[CH:18][CH:17]=1)=[O:4]
Reactant: Cn1cc(-c2ccc([C@@H]3C[C@H]3N(CC3CCNCC3)C(=O)C(F)(F)F)cc2)cn1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccc(-c4cnn(C)c4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (85 mg, 0.209 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 4-formylbenzoate (41.2 mg, 0.251 mmol) and sodium triacetoxyborohydride (75 mg, 0.356 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (3 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 68 mg of product as off-white solid. MS: (M+H)+=555.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28-1.53 (m, 4H), 1.56-1.76 (m, 3H), 1.80-1.96 (m, 1H), 1.98-2.11 (m, 3H), 2.44 (br. s., 1H), 2.75-2.97 (m, 3H), 3.09-3.19 (m, 1H), 7.12 (d, J=8.08 Hz, 2H), 7.41-7.55 (m, 5H), 7.91-8.03 (m, 3H)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].O>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14](=[O:16])[CH3:15])[CH2:22][CH2:21]3)[CH:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(Nc2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 1b (0.75 g, 4.1 mmol) and 2d (0.9 g, 4.1 mmol) in anhydrous NMP (2 ml) was heated to 80° C. overnight under a stream of nitrogen. After cooling water (20 ml) was added and the mixture was extracted with dichloromethane. The organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column-chromatography on silica gel using ethyl acetate as the eluent to yield 4-acetyl-N-(3-(1-acetylpiperazin-4-yl)phenyl)-2-nitroaniline as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].[NH4+].[OH-]>OS(O)(=O)=O>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([N+:25]([O-:27])=[O:26])=[C:8]([C:6]3[CH:5]=[C:4]([CH3:24])[N:3]=[C:2]([CH3:1])[CH:7]=3)[CH:17]=2)[C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14]1)[CH3:19]
Reactant: O=[N+]([O-])O
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3cc(C)nc(C)c3)cc21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cc([N+](=O)[O-])c(-c3cc(C)nc(C)c3)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 200 g. of 7-(2,6-dimethyl-4-pyridinyl)-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 440 ml of 95-98% H2SO4 was added a solution of 80 ml of 90% HNO3 in 80 ml of 95-98% H2SO4 over a period of one hour. The resulting solution was stirred at room temperature for an additional 20 minutes, then heated on a steam bath for 8 hours. The reaction mixture was allowed to stand at room temperature overnight and then poured into 6000 ml of ice water. The precipitate was collected and slurried in approximately 2000 ml water. Concentrated NH4OH was added to reach a pH of 5.5-6.0. The solid was collected and washed with a small amount of ethanol and ether. Additional material was obtained by treating the original filtrate with NH4OH as described above. Recrystallization from dimethylformamide gave several crops totalling 135 g (59%) and melting from 274° C. to 298° C. A 2.8 g sample was recrystallized from 20 ml of dimethylformamide, washed with ether and dried at 120° C. for 16 hours at 0.02 mm to produce 1.54 g of 1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-6-nitro-4-oxo-3-quinolinecarboxylic acid, m.p. 289°-291° C.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)=[O:4].Cl.[CH3:18][NH:19][C:20]([C:22]1[C:26]([NH2:27])=[CH:25][N:24]([CH3:28])[N:23]=1)=[O:21]>>[NH2:11][C:10]1[C:5]([C:3]([NH:27][C:26]2[C:22]([C:20](=[O:21])[NH:19][CH3:18])=[N:23][N:24]([CH3:28])[CH:25]=2)=[O:4])=[N:6][C:7]([CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:8][N:9]=1
Reactant: COC(=O)c1nc(C2CCCO2)cnc1N
Reactant: CNC(=O)c1nn(C)cc1N
Agent: Cl
Product: CNC(=O)c1nn(C)cc1NC(=O)c1nc(C2CCCO2)cnc1N
Yield: 64 %

Procedure:
According to the procedure described in step 2 of example 14, 3-amino-6-(tetrahydrofuran-2-yl)pyrazine-2-carboxylic acid methyl ester was reacted with 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methylamide hydrochloride to obtain the title compound as yellow solid (64%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.CN([CH:19]=[O:20])C.CCOC(C)=O>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,5-dibromo-2,4-difluorobenzene (17.5 g, 64.2 mmol) in ether (100 mL) at −78° C. was added n-BuLi (2.5 M solution, 30.8 mL, 77 mmol) over a period of 5 min, and the reaction mixture was stirred at −78° C. for 30 min. Then DMF (9.94 mL, 148 mmol) was added in one portion, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to give the title compound as a slightly yellow oil (8.5 g, 60% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 10.26 (s, 1H), 8.14 (t, J=7.5 Hz, 1H), 7.05 (dd, J=9.8, 8.0 Hz, 1H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)=[O:20])[CH3:17]>C1C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]([C:9]([C:8]2[C:7]([Cl:6])=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:24][CH:25]=1)=[O:20])[CH3:17]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)c1ccc[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.6 %

Procedure:
A solution of tin (IV) chloride (3.72 g, 5 mmol) in benzene (10 mL) was added dropwise to a mixture of 2-chloronicotinoyl chloride (2.02 g, 11 mmol) and 1H-pyrrole-2-carboxylic acid ethyl ester (0.73 g; prepared as discussed below) in dry benzene (12 mL) at 0° C. The reaction was allowed to warm up slowly to room temperature and stirred 4 hours. The reaction was concentrated, the residue was dissolved in ethyl acetate and washed with brine, dried and concentrated to give 1.53 g of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:4](=[O:5])[O:3]1.[CH2:15](O)[CH3:16]>[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[C:6]1([C:15]2[CH:16]=[N:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:11]=3[CH:2]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCO
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)c1cccc2ncc(-c3ccccc3)cc12
Reaction time: 4 h

Procedure:
50 g (0.256 mol) of 3-hydroxy-4-nitro-phthalide are hydrogenated at 20° C. and at 3 bar using 5 g of Pd/barium sulphate (5%) in 380 ml of ethanol. The mixture is filtered with suction, and 0.308 mol=38.7 ml of phenylacetaldehyde solution are added to the filtrate. The mixture is boiled for 4 hours, the quinolinecarboxylic acid precipitating. It is cooled, filtered with suction and washed with ethanol. 28.3 g (44.3% of theory) of a colorless compound of melting point>290° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:16][C:17]([N:19]([CH2:21][CH:22](OC)OC)[CH3:20])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[ClH:27]>O>[CH3:20][N:19]1[CH:21]=[CH:22][N:16]([C:4]2[CH:3]=[CH:2][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([Cl:27])[CH:14]=3)=[CH:6][CH:5]=2)[C:17]1=[O:18]
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccc(C)cc2)c(Cl)c1)OC
Reactant: Cl
Solvent: O
Product: Cc1ccc(Oc2ccc(-n3ccn(C)c3=O)cc2)cc1Cl

Procedure:
N-[3-chloro-4-[(4-methylphenoxy)]phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-[3-chloro-4-methylphenoxy]phenyl]-4-imidazolin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[CH:23][C:11]([CH2:12][O:13][C:14]([CH3:22])([C:18]([F:21])([F:20])[F:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+:26]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([CH3:22])([C:18]([F:19])([F:20])[F:21])[C:15]([O-:17])=[O:16])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1.[Na+:26]
Reactant: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)[O-])C(F)(F)F

Procedure:
A mixture of (±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid (0.36 g.), N aqueous sodium hydroxide (1.0 ml.) and water (3.0 ml.) is stirred until no more of the acid dissolves. The mixture is filtered, the filtrate is washed with ether and evaporated in vacuo. The residue is crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80° C.) to give (±)-sodium 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (0.3 g.) m.p. 271°-272° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:13](O)=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CNC.C=O>O>[CH2:13]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(CCc1ccccc1)C(=O)O
Agent: C=O
Agent: CNC
Solvent: O
Product: C=C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenylethylmalonic acid (1.8 g), 40% aqueous dimethylamine (1.08 ml, 1 eq) and 37% aqueous formaldehyde (0.64 ml, 1 eq) in water (10 ml) was stirred at room temperature overnight. After cooling at 0° C. the solid was filtered off, washed with water and dried. The white solid was heated at 170° C. for 10 minutes and cooled to room temperature. The resulting gum was dissolved in ethyl acetate (20 ml), washed with 10% potassium hydrogen sulphate solution (10 ml), water (2×10 ml), saturated brine (10 ml), dried (MgSO4) and evaporated to give crude 2-methylene4-phenylbutanoic acid. δH (CDCl3) 2.55-2.90 (4H, m, 2×CH,), 5.65, 6.85 (2H, 2×s, ##STR6## 7.25 (5H, m, Ph). The solid was dissolved in thioacetic acid (1 ml) and heated at 100° C. for 1 hour. After evaporation the gum was dissolved in ethyl acetate (10 ml) and extracted with saturated sodium hydrogen carbonate solution (2×10 ml). The combined extracts were washed with ethyl acetate (2×10 ml) and acidified with 10% potassium hydrogen sulphate solution (pH 3). The aqueous layer was extracted with ethyl acetate (2×10 ml) and the combined extracts washed with water (2×10 ml), dried (MgSO4) and evaporated to yield the title compound as a yellow oil (0.52 g, 24%); δH (CDCl3) 2.00 (2H, m, CH2), 2.71 (3H, m, CH2, CH), 3.14 (2H, m, CH2), 7.24 (5H, m, Ph). EIMS M+ 252 DCIMS MNH4+ 270.
Reaction SMILES: [F:1][C:2]([F:35])([C:31]([F:34])([F:33])[F:32])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[O:8][C:9]([F:22])([F:21])[CH2:10][O:11][CH2:12][C@@H:13]([F:20])[CH2:14][O:15][CH2:16][CH2:17][CH2:18]Cl.[CH2:36]([O:42][C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH2:36]([O:42][C:43]1[CH:48]=[N:47][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:18][CH2:17][CH2:16][O:15][CH2:14][C@H:13]([F:20])[CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:24])([F:23])[C:6]([F:26])([F:25])[O:5][C:4]([F:28])([F:27])[C:3]([F:30])([F:29])[C:2]([F:35])([F:1])[C:31]([F:34])([F:33])[F:32])([F:22])[F:21])=[CH:53][CH:54]=2)=[N:45][CH:44]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: F[C@@H](COCCCCl)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCOc1cnc(-c2ccc(OCCCOC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 8 of International Patent Publication No. WO 96/33251 by combining 3-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)propyl chloride (3.0 g, 5.1 mmol) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (1.4 g, 5.1 mmol). The resulting crude product was purified by Kugelrohr distillation (b.p. 170-80° C. at 0.01 torr).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(F)c(F)c2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,4-difluorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a slightly yellow powder (yield 67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[S:37][C:36]([C:38]2[O:42][N:41]=[C:40]([CH2:43]OS(C)(=O)=O)[CH:39]=2)=[CH:35][CH:34]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]=[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][CH2:19]3)[N:11]([CH2:43][C:40]3[CH:39]=[C:38]([C:36]4[S:37][C:33]([Cl:32])=[CH:34][CH:35]=4)[O:42][N:41]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
17.3 g (50.52 mmol) 2-(1-Cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester were dissolved in 800 mL DMF. Subsequently 10.47 g (75.8 mmol) K2CO3 and 14.84 g (50.52 mmol) methanesulfonic acid 5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl ester were added and the resulting mixture was stirred for 2 h at 80° C. The mixture was concentrated under reduced pressure. The residue was suspended in 800 mL ethyl acetate. The next day the resulting precipitate was filtered off and washed with 100 mL ethyl acetate to give 3-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid methyl ester. The filtrate was concentrated to a volume of approx. 100 mL. Again the formed precipitate was filtered off. That procedure was repeated once again. The remaining filtrate was concentrated under reduced pressure and finally purified by flash-chromatography on silica gel using ethyl acetate as eluent. The product containing fractions were concentrated under vacuo to give pure (>98%) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a light brown crystalline solid.