Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][N:4]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:10]=[CH:9][C:8]=2[C:7]2[N:20](COCC[Si](C)(C)C)[N:21]=[CH:22][C:6]=2[C:5]1=[O:31].FC(F)CN1C2C=C(C3C=CN=CC=3)C=CC=2C2NN(COCC[Si](C)(C)C)CC=2C1=O.[ClH:65].O1CCOCC1>C(Cl)Cl.C(O)(C)C>[ClH:65].[F:32][CH:2]([F:1])[CH2:3][N:4]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:10]=[CH:9][C:8]=2[C:7]2[NH:20][N:21]=[CH:22][C:6]=2[C:5]1=[O:31]
Reactant: C[Si](C)(C)CCOCn1ncc2c(=O)n(CC(F)F)c3cc(-c4ccncc4)ccc3c21
Agent: C[Si](C)(C)CCOCN1Cc2c(c3ccc(-c4ccncc4)cc3n(CC(F)F)c2=O)N1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=c1c2cn[nH]c2c2ccc(-c3ccncc3)cc2n1CC(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg, 0.22 mmol) in 2 mL of DCM is added a 4M solution of anhydrous hydrogen chloride in dioxane (1.10 mL, 4.38 mmol) at room temperature. After stirring at room temperature for 24 hours, the mixture is filtered. The solid obtained is taken up in isopropanol, filtered off and dried under vacuum to give 74 mg of a white powder (hydrochloride, yield: 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[O:23]1[CH2:27][CH2:26][NH:25][C:24]1=[O:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:17]1([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:25]2[CH2:26][CH2:27][O:23][C:24]2=[O:28])[CH:3]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOC2=O)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), oxazolidin-2-one (322 mg, 2.5 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (498 mg, 80%) as a white solid: LC/MS m/e calcd for C21H22N2O4 (M+H)+: 367.42, observed: 367.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H][H]>[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:7][N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: Cc1nnc2ccc(-c3ccc([N+](=O)[O-])cc3)cn12
Agent: [Pd]
Product: Cc1nnc2n1CC(c1ccc(N)cc1)CC2

Procedure:
3-Methyl-6-(4-nitrophenyl)-1,2,4-triazolo[4,3-a]pyridine is treated with hydrogen in the presence of palladium on carbon to give the product of the Example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(Cl)(Cl)Cl>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc(Nc2c(C#N)cnc3cc(C#C[Si](C)(C)C)sc23)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), (trimethylsilyl)acetylene (237 μL, 1.67 mmol), 12.5 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(I) iodide in 3.5 mL of triethylamine and 12 mL of benzene is heated at reflux for 20 hours. The mixture is cooled to room temperature and 50 mL of chloroform are added. The mixture is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered through a celite pad and concentrated in vacuo. The resulting brown solid is suspended in diethyl ether. The solids are collected by filtration and washed with diethyl ether to yield 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 169–171° C.; 1H NMR (CDCl3) δ 0.26 (s, 9H), 3.88 (s, 3H), 6.79 (s, 1H), 6.89 (s, 1H), 7.51 (s, 1H), 7.56 (s, 1H), 8.65 (s, 1H); MS 444.1, 446.1 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:34])=[O:35])=[CH:31][CH:32]=1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 509 [M+H]+, 507 [M−H]−, 1H-NMR (DMSO-d6) δ 1.14 (3H, t, J=7.5 Hz), 2.62 (2H, q, J=7.5 Hz), 2.72 (2H, t, J=7.1 Hz), 3.18-3.30 (2H, m), 6.60 (1H, t, J=5.7 Hz), 7.19 (1H, tt, J=7.3, 1.3 Hz), 7.28-7.38 (6H, m), 7.64-7.70 (2H, m), 7.76-7.80 (2H, m), 7.88 (2H, dt, J=11.2, 2.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Product: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Temperature: 135 °C

Procedure:
2 g (0.0103 mol) of ethyl p-methoxyphenylacetate and 9.1 g (10.6 ml, 0.0618 mol) of dimethylformamide diethylacetal were mixed in a 100 ml balloon flask provided with reflux cooler, magnetic stirring and thermometer. The thus obtained solution was heated to reflux (135° C.) for 20 hours. Then the dimethylformamide diethylacetal and the unreacted ethyl p-methoxyphenylacetate were removed by distillation under vacuum, the desired product being obtained as distillation residue. 2,14 g of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)acrylate were thus obtained (Yield: 83%).
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[OH-].[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23].C(C1C=C(C(C(=O)C)C(=O)C)C=C(C(C)(C)C)C=1O)(C)(C)C>>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])[CH2:4][CH:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(=O)C(C(C)=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O

Procedure:
A mixture of N,N-dimethyl-2,6-di-t-butyl-4-aminomethylphenol (2.63 g, 10 mmols), sodium hydroxide (0.6 g, 15 mmols) and acetylacetone (24 mmols, 10% solution) was refluxed for 3 hours in a glass reaction vessel. Acetylacetone was distilled under reduced pressure to afford an oily residue containing 3-(3',5'-di-t-butyl-4'-hydroxyphenyl)-2,4-pentanedione (80% by VPC). Crystallization from ethanol:water afforded a single crop of 3-(3',5'-di-t-butyl-4'-hydroxybenzyl)-2,4-pentanedione (65%, overall yield, 97% pure).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:7][C:6]2[CH:17]=[CH:18][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(COc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OCc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of [4-(4-trifluoromethyl-phenoxymethyl)-phenyl]-methanol (intermediate 14.1.2, 0.34 g, 1.2 mmol) in dichloromethane (10 mL) were added triethylamine (0.34 mL, 2.4 mmol) and methanesulfonyl chloride (0.19 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 36 h under nitrogen atmosphere. The reaction mixture was washed with water, the organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH:1]([C:4]1([C:29]#[N:30])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:10]=2)[C:5]1=[O:28])([CH3:3])[CH3:2].C(=O)=O.CO.C(#N)C>>[CH:1]([C@:4]1([C:29]#[N:30])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[N:10]=2)[C:5]1=[O:28])([CH3:3])[CH3:2]
Reactant: CC(C)C1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: O=C=O
Solvent: CC#N
Solvent: CO
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 10.6 %

Procedure:
3-Isopropyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (85 mg) obtained in Example 5 was resolved by SFC (column: CHIRALCEL OJH, 20 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol/acetonitrile 660/170/170), and the compound having a longer retention time was recrystallized (hexane/ethyl acetate) to give the title compound (9 mg).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:10][CH3:11])([CH2:8][OH:9])[CH2:4][O:3]1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>CO>[OH:3][CH2:4][C:5]([CH2:8][OH:9])([CH2:10][CH3:11])[CH2:6][OH:7]
Reactant: CCC1(CO)COC(C)(C)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 21 h
Yield: 179.7 %

Procedure:
7.8 g (17 mmol) of the crude sulfonate 6 prepared in step 2 are introduced into 60 ml of methanol, and 3 N hydrochloric acid is added dropwise until the pH is less than 5. 400 mg of p-toluenesulfonic acid are subsequently added, the mixture is stirred at room temperature for 21 hours, and methanolic potassium hydroxide solution is added until the mixture is slightly alkaline (pH≈8 to 9). The solvent is removed by distillation in vacuo, and the residue which remains is separated by column chromatography on silica gel using dichloromethane as the eluent, giving 4.1 g of a colorless oil 7.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[C:10]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[C@H:16]([C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[CH2:42][C:43](O)=[O:44])[CH2:31][CH2:30]2)=[O:28])[CH2:15]1)([CH3:13])([CH3:12])[CH3:11].CN.Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:10]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[C@H:16]([C:27]([N:29]2[CH2:30][CH2:31][CH:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[CH2:42][C:43]([NH:4][CH3:1])=[O:44])[CH2:33][CH2:34]2)=[O:28])[CH2:15]1)([CH3:12])([CH3:11])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)N1C[C@@H](C(=O)N2CCC(c3ccc(Cl)cc3CC(=O)O)CC2)[C@H](c2ccc(F)cc2F)C1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h

Procedure:
N,N-diisopropylethylamine (0.166 mL, 0.953 mmol) was added to a stirred suspension of [2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-chlorophenyl]acetic acid (1-10) (40.0 mg), methylamine.HCl (42.9 mg, 0.635 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (48.3 mg, 0.127 mmol) and 1-hydroxy-7-azabenotriazole (17.3 mg, 0.127 mmol) in N,N-dimethylformamide (0.65 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative reversed phase high pressure liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 0%-100% acetonitrile/water as eluent, 0.1% TFA modifier) gave 1-11 as a buff white solid (m/z (ES) 532 (MH+).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[F:6][C:7]1[CH:8]=[C:9]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:14]=O)[CH:10]=[CH:11][CH:12]=1.[OH-].[K+]>C(OCC)C.C(O)C.C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14][CH2:1][C:2](=[O:5])[CH:3]=[CH:4]2)[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(C)=O
Reactant: O=CC(c1cccc(F)c1)c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C=CC(c2cccc(F)c2)(c2cccc(F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Butenone (50.4 cc) is added to a solution of bis-(3-fluorophenyl)acetaldehyde (144.5 g) in ethyl ether (500 cc) and then, after cooling to 0° C., a solution of potassium hydroxide (13.9 g) in ethanol (89 cc) is added dropwise. The reaction mixture is stirred for 2 h at 0° C. and then for 16 hours at 25° C. and diluted with ethyl acetate (300 cc) and water (500 cc). The aqueous phase is washed with ethyl acetate (300 cc). The combined organic phases are washed with saturated sodium chloride solution (500 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed (in two passes) on silica gel (particle size 0.04-0.063 mm, columns 8.5 cm in diameter and 34 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10). 4,4-bis-(3-Fluorophenyl)-cyclohexenone (90.3 g) is obtained in the form of white crystals. m.p.=95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C@H:25]([CH2:27][OH:28])[CH3:26]>>[OH:28][CH2:27][C@H:25]([NH:24][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH:11]=2)=[CH:20][N:19]=1)=[O:23])[CH3:26]
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Reactant: C[C@H](N)CO
Product: C[C@H](CO)NC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Yield: 47 %

Procedure:
As described for example 17b, 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (80 mg, 0.24 mmol) was converted, using L-alaninol instead of D-alaninol, to the title compound (44 mg, 47%) which was obtained as a white solid. MS: m/e=389.0 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH2:36])=[CH:35][C:30]=2[NH:29][CH:28]=1>>[N:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=5)[N:23]4[N:22]=3)=[CH:35][C:30]=2[NH:29][CH:28]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 3H-benzimidazol-5-ylamine (60 mg, 0.45 mmol) at 105° C. for 120 h to afford the title compound. Yield of TFA salt: 24 mg (16%) of brown powder; LC/MS: 462 (M+H); HPLC: 97% pure, RT=2.65 min; 1H NMR: (DMSO, δ) 9.91 (s, 1H), 9.40 (s, 1H), 9.11 (s, 1H), 8.59 (s, 1H), 8.42 (d, J=8.0, 1H), 8.09 (s, 1H), 8.01 (d, J=8.0, 1H), 7.85 (m, 2H), 7.77 (t, J=7.7, 1H), 7.65 (s, 1H), 7.28 (d, J=4.9, 1H), 7.06 (d, J=4.9, 1H), 1.10 (s, 9H)— benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][O:28][C:29]([O:31][CH2:32]I)=[O:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:27][O:28][C:29]([O:31][CH3:32])=[O:30])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: COC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: COC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.5 %

Procedure:
In the same manner as in Example 81, 148 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 103 mg of methoxycarbonyloxymethyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[H-].[Na+].[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:38]=[CH:37][C:36]=1[S:46](Cl)(=[O:48])=[O:47].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:46]([C:36]1[CH:37]=[CH:38][C:39]([O:41][C:42]([F:43])([F:44])[F:45])=[CH:40][C:35]=1[O:34][CH3:33])(=[O:47])=[O:48])[C:6](=[O:11])[C:5]2([N:20]1[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:21]1[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 512 mg of (4R)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimet hyl-L-prolinamide (levorotatory isomer), which is the compound described in Preparation 3.2 (Isomer B) of Brochure No. WO01/55130 in DMF (5 ml) was added 57.1 mg of NaH under ice cooling, and the solution was stirred for 30 minutes at the same temperature. A solution of 415 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride in DMF (3 ml) was added, then, the solution was stirred for 30 minutes at the same temperature. To the reaction solution was added an aqueous solution of 10% K2CO3, and the resulting mixture was stirred at room temperature for 1 hour. Water and EtOAc were added, liquid separation was performed, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and saturated brine, then, was dried over MgSO4. The drying agent was separated by filtration, solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=1/2 to 1/2.5; v/v), to obtain 561 mg of the title compound (colorless amorphous).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:22]4=[CH:23][C:24]5[O:28][CH2:27][O:26][C:25]=5[CH:29]=[C:21]4[O:20][CH2:19]3)[C:11]2=[O:30])=[CH:5][CH:4]=1.[I-].[Na+].Cl[Si](C)(C)C>O.C(#N)C>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:22]4=[CH:23][C:24]5[O:28][CH2:27][O:26][C:25]=5[CH:29]=[C:21]4[O:20][CH2:19]3)[C:11]2=[O:30])[CH:5]=[CH:4]1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a mixture of 1′-[(6-methoxypyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.23 g, 0.57 mmol), sodium iodide (0.28 g, 1.87 mmol), water (2 drops) in anhydrous acetonitrile (5.00 mL) was added chlorotrimethylsilane (0.19 g, 1.78 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with sodium bisulfite (0.20 g). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (2×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with ether (2×10.0 mL) to give the title compound (0.16 g, 72%) as light yellow solid: mp 247-250° C.; 1H NMR (300 MHz, DMSO-d6,) δ 11.50 (br, 1H), 7.50 (bd, 1H), 7.36-7.24 (m, 2H), 7.17-7.12 (m, 2H), 7.01 (dt, 1H), 6.67 (s, 1H), 6.28 (d, 1H), 6.09 (s, 1H), 5.91-5.88 (m, 2H), 4.78 (d, 1H), 4.67-4.62 (m, 3H); MS (ES+) m/z 389.15 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([C:8](=[N:18][OH:19])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=NO)c1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone (5.0 g, 17.65 mmol) was dissolved in a mixed solvent of chloroform (18 ml) and methanol (70 ml). Hydroxylamine hydrochloride (1.88 g, 27.0 mmol) and pyridine (4.36 ml, 54.1 mmol) were added to the resulting solution, and the mixture was stirred for 6 hours while heating under reflux. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. 2N Hydrochloric acid (13.9 ml) was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was washed with n-hexane and dried to thereby obtain 4.6 g of powdery white 1-(5-bromo-2-cyclopentyloxyphenyl)ethanone oxime (yield: 87%).