Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC.O1CCCC1>CCCCCC>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CCCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 2,3,4,5,6,7-hexahydroazepine (2.8 ml), a 1.6M solution of butyllithium in hexane (15 ml), and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 2,3,4,5,6,7-hexahydro-1-[(2-phenylquinazolin-4-yl)-carbonyl]-azepine (2 g), melting at 140° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[CH:7][C:8]=1[CH3:9])[NH2:6].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)c(C)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C(C)(C)C)c(C)cc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2,5-xylidine (8 g) in pyridine (60 ml) was added pivaloyl chloride (4.7 ml) at room temperature. After 30 minutes, the mixture was poured into dilute hydrochloric acid/ice solution. The precipitate was filtered and washed with water to give the title product.
Reaction SMILES: [O:1]1[C:6]2([CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][S:4][C:3]2[C:13](=[O:22])[C:14](=[O:21])[C:15]3[C:20]([C:2]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:9]1[CH2:10][CH2:11][CH2:12][C:6]2([O:1][C:2]3[C:20]4[C:15]([C:14](=[O:21])[C:13](=[O:22])[C:3]=3[S:4][CH2:5]2)=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:7][CH2:8]1)=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 62 was synthesized using spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=98-100° C., 400 MHz 1H NMR (CDCl3) δ: 8.08-8.06 (m, 1H), 7.76-7.66 (m, 2H), 7.52-7.48 (m, 1H), 7.42-7.21 (m, 4H), 3.87-3.86 (m, 1H), 3.67-3.49 (m, 3H), 3.05-2.92 (m, 2H), 2.39-2.17 (m, 4H), 2.04-1.96 (m, 1H), 1.89-1.76 (m, 1H); LCMS: 454 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]([OH:35])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([C:16]([F:18])([F:19])[F:17])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Cc1cc(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(CC(O)c2ccc(Cl)cc2Cl)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Reaction time: 1 h

Procedure:
To a solution of Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-7-yl ester (340 mg, 1.1 mmol) in dry THF (8 mL0 at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1.2 mL). After 30 minutes 2,4-dichloro-benzaldehyde (130 μL) was added slowly into the reaction mixture and the reaction-mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield trifluoro-methanesulfonic acid 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromen-7-yl ester as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:16]([N+:28]([O-])=O)[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:16]([NH2:28])[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Nc2ccccc2Cl)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(Nc2ccccc2Cl)c(N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
140 mg of (S)-2-[4-(2-Chloro-phenylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester were dissolved in 5 ml ethyl acetate, 342 mg of tin(II)chloride-dihydrate were added and the mixture was stirred at rt for 4 h. Water was added to the reaction. The mixture was filtrated over celite. The pH of the filtrate was adjusted to 7, the layers were separated and the organic layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated to yield 103 mg (79%) of (S)-2-[3-Amino-4-(2-chloro-phenylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:9]1.[N:23]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C:10]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9]2)[CH2:11][CH2:12]1)#[N:23]
Reactant: N#CBr
Reactant: CN1CCC2(CC1)CN(c1ccccc1F)c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)CN(c1ccccc1F)c1ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 0.82 g of 1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 10, 0.92 g of cyanogen bromide and 1.0 of potassium carbonate in 24 ml of methylene dichloride is stirred at ambient temperature for 5 hours and then an additional 0.20 g of cyanogen bromide is added. Stirring is continued for 16 hours before filtering the mixture. The filtrate is boiled with methyl alcohol and the hot solution is evaporated to dryness leaving a brown foam. This product is purified by passing through a silica gel column, ether methylene chloride (1:1) mixture eluant, to provide a tan solid. The solid is recrystallized from an acetone-hexane mixture to provide white needles (slight tan tint), mp 131°-132° C. of 1'-cyano-1-(2-fluorophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)ccc(N)c1[N+](=O)[O-]
Yield: 86.6 %

Procedure:
3-methyl-2-nitroaniline (6.2 g, 41 mmol) was dissolved in 150 mL acetic acid, stirred and treated in portions with N-bromosuccinimide (7.3 g, 41 mmol). After 1 h the mixture was poured into 400 mL water with stirring. The precipitated product was collected by filtration, washed well with water, and then taken up in 200 mL ethyl acetate. This solution was washed with 50 mL water, 50 mL saturated NaHCO3, 50 mL saturated NaCl, dried (Na2SO4) and evaporated under vacuum to give the title compound as a bright orange solid (8.2 g, 87%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.33 (d, J=8.8 Hz, 1H), 6.62-6.49 (d, J=8.8 Hz, 1H), 4.75 (s, 2H), 2.41 (s, 3H); EIMS m/z 230.
Reaction SMILES: Br[C:2]1[C:10]([Br:11])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:11][C:10]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:3][C:4]2[O:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cc2c(cc1Br)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cc3c(cc2Br)OCO3)cc1
Yield: 71.1 %

Procedure:
Under nitrogen, 1.1 g of Pd(PPh3)4 was added to a stirred solution of 10.4 g (37.2 mmol) of 5,6-dibromo-1,3-benzodioxole and 2.6 g (18.6 mmol) of 4-fluorophenylboronic acid in 100 mL of toluene, 60 mL of ethanol, and 40 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried over Na2SO4. Purification by silica gel chromatography (Waters Prep-500A) with hexane as the eluent gave 3.9 g (71%) of 5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole as a colorless solid: mp 86.0-87.5° C.; NMR (CDCl3) δ 6.02 (s, 2H), 6.77 (s, 1H), 7.04-7.13 (m, 3H), 7.28-7.35 (m, 2H)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:38]=3[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: Cn1ccc2cccc(N)c2c1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4ccn(C)c(=O)c34)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (203.1 mg, 0.4793 mmol) and 8-amino-2-methylisoquinolin-1(2H)-one (Compound 131A, 100.0 mg, 0.5740 mmol). The crude product was purified using the Teledyne/ISCO Combiflash system, eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo, yielding the title material as a yellow solid, 225.9 mg (82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 9.88 (s, 1H), 8.87 (br s, 1H), 8.48 (s, 1H), 7.55-7.68 (m, 3H), 7.53 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.1 Hz, 1H), 7.24 (dd, J=8.6, 2.3 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 3.91-4.01 (m, 4H), 3.53 (s, 3H), 3.20 (d, J=21.2 Hz, 2H), 1.18 (t, J=6.9 Hz, 6H). MS (ES+): m/z 562.11 (100) [MH+]. HPLC: tR=3.58 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH3:14][N:15]1[C:19]2=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:24][C:21]1[N:20]=[C:19]2[N:15]([CH3:14])[CH:16]=[CH:17][C:18]2=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: Cn1ccc2ccc(N)nc21
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2ccn(C)c2n1
Temperature: 140 °C
Yield: 17.8 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (195 mg, 0.882 mmol) and 1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamine (156 mg, 1.06 mmol) were dissolved in acetonitrile (2.7 mL), then heated at 140° C. for 2 d. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 5 to 70% ethyl acetate in hexanes) gave 6-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid ethyl ester (52 mg, 18%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.78 (s, 1H) 9.34 (s, 1H) 7.90 (d, J=8.3 Hz, 1H) 7.14 (d, J=3.3 Hz, 1H) 6.74 (d, J=8.3 Hz, 1H) 6.45 (d, J=3.5 Hz, 1H) 4.58 (d, J=7.1 Hz, 2H) 3.90 (s, 3H) 1.52 (t, J=7.2 Hz, 3H); LCMS (EI/CI) m/z: 332 [M+H].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.58 min; [M+H]+=436.28.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[N:9]([Si](C)(C)C)=[N+:10]=[N-:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:9]([CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)=[N+:10]=[N-:11]
Reactant: Cc1nc(CCl)cs1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(CN=[N+]=[N-])cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Dissolve 4-(chloromethyl)-2-methyl-thiazole (350 mg, 2.37 mmol) and azidotrimethylsilane (315 μL, 2.37 mmol) in anhydrous THF (1 mL) under nitrogen. Add a 1M solution of tetrabutylammonium fluoride (3.6 mL, 3.56 mmol) in THF and stir at ambient temperature overnight. Pour the reaction mixture into water (10 mL), extract with ethyl ether (3×2 mL), wash the organic extracts with brine, thy over MgSO4, filter, and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (165 mg, 45%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([S:27]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][CH:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)=[CH:13][CH:14]=2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NS(=O)(=O)c3ccc(F)c(F)c3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 3,4-difluorobenzene sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32]>C(N(CC)CC)C>[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.8 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 200 ml DMF and 1.6 g HOBtxH2O and 15.0 ml triethylamine is stirred at ambient temperature for 0.5 h. Then 6.04 g EDCxHCL are added and the suspension is stirred again for 0.5 h. Finally 1.23 g O-(tetrahydro-2H-pyran-2-yl)hydroxylamine are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate and evaporated. The title product is isolated by flash chromatography. By this method 4.6 g of a yellow foam are obtained.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[N:6]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])CO.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:6]1[C:7](=[O:20])[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]1[CH:2]=[O:1]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H](O)CO)c(OC)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C=O)c(OC)c1
Temperature: 50 °C
Yield: 98.2 %

Procedure:
To a solution of benzyl ((2S,3S)-2-((R)-1,2-dihydroxyethyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (240 g, 0.557 mol) in EtOAc (4.5 L) was added a solution of sodium periodate (132 g, 0.617 mol) in water (1.125 L) and the bilayer was heated to 50° C. for 2 h, whereupon it was cooled to rt and the layers were separated. The aqueous layer was extracted with EtOAc (500 mL) and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (218 g, 98%) as a pale yellow solid. LCMS: m/z=399.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=3.2 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.39-7.23 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.3, 2.4 Hz, 1H), 5.00-4.96 (m, 2H), 4.90 (dd, J=8.5, 5.8 Hz, 1H), 4.38 (d, J=14.5 Hz, 1H), 4.29 (d, J=14.5 Hz, 1H), 4.05 (dd, J=5.9, 3.3 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:32])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:33][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[N:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:32])([CH3:6])[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nn2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nn2)ccc1OC(C)(C)C(=O)O

Procedure:
0.183 g (0.386 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridazin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 8 ml of THF/EtOH=1/1, treated with 1.16 ml (3 eq.) of 1N NaOH and kept at ambient temperature over night. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness to yield, after recrystallisation from hexane/AcOEt, 0.160 g of the title compound as light yellow crystals of mp. 191–192° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.B(O)O.[C:15]([O-:18])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:3]1[CH:8]=[CH:7][C:6]([CH:15]=[O:18])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 177.3 %

Procedure:
To a stirred solution of 2-trifluoromethyl-bromobenzene (0.7 g, 2.75 mmol) and 4-carbaldehyde boronic acid (0.5 g, 3.3 mmol) in dioxane (20 mL) under nitrogen at 80° C. was added Pd(PPh3)4 (0.05 g) followed by the addition of a solution of Na2CO3 (0.7 g) in H2O (5 m). The mixture was stirred at 100° C. for 6 h. The solvent was evaporated and the residue was diluted to 50 ml with EtOAc and washed with H2O. The solvent was evaporated to dryness and the residue was purified by FCC (SiO2) to give the title compound (0.61 g; 88%), as creamy solid. 1H-NMR (CDCl3) 7.49 (d, 1H, J=7.41 Hz); 7.48 (d, 2H, J=8.13 Hz); 7.61-7.53 (m, 2H); 7.76 (d, 1H, J=7.8 Hz); 7.91 (d, 2H, J=8.34 Hz); 10.07 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2([CH3:13])[CH3:12].[CH:14](O)=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:14]=[O:15])[CH2:7][CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)CCNc2ccc(Br)cc21
Reactant: O=CO
Product: CC1(C)CCN(C=O)c2ccc(Br)cc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline, available in accordance with U.S. Pat. No. 5,089,509, the specification of which is incorporated herein by reference (1.8 g, 7.5 mmol) in 10 mL of formic acid was refluxed for 3 h. The reaction mixture was then cooled to ambient temperature and poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 15-25% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow solid (1.8 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[NH:34][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: [NH4+]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2cnccn2)cc1F
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3cnccn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a solution of 5-[3-fluoro-4-(methylsulfanyl)phenyl]-1-(pyrazin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (438 mg) in acetic acid (5 mL) was added ammonium acetate (1.29 g), and the mixture was stirred at 110° C. for 2.5 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (367 mg, yield 88%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 398 (MH+).