Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3CCN2C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round-bottomed flask containing crude 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (25 mg, 104 μmol) and CH2Cl2 (10 mL) was added 1-fluoro-4-isocyanatobenzene (0.03 mL, 264 μmol). The solution was stirred at RT. After 1 h, the reaction was concentrated in vacuo and taken up in DMF and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini™ column (5 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an linear gradient of 10% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 10 min to give crude product, that was lypholized and resubjected to the same purification conditions to give N-(4-fluorophenyl)-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide, as a white solid that contained 0.66 eq of TFA. MS (ESI pos. ion) m/z: 377 (M+1).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH2:36][CH3:37])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:36]([C:13](=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH3:37]
Reactant: CCOP(=O)(CCNCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=CCc1c(O)c2c(c(C)c1CC)COC2=O)CNCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.7 %

Procedure:
(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (24.9 mg, 0.045 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (68.7 mg, 0.449 mmol) was added and the reaction was stirred at room temperature. After 20 hours, the reaction was quenched with MeOH (0.15 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 8.0 mg of the free phosphonic acid [MS: 498 M++1].
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C(OCC)(=O)C>[Fe].O>[CH:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(SC2CCCCC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(SC2CCCCC2)nc1

Procedure:
2-Cyclohexylthio-5-nitropyridine (13.4 grams) was added to a suspension of 50 grams of ammonium chloride and 20 grams of powdered iron in a mixture of 220 ml. of ethyl acetate and 30 ml. of water. The reaction mixture was refluxed for 6 hours. TLC indicated some starting material remained. Additional powdered iron (10 grams) was added and the reaction mixture refluxed for another 2 hours. TLC indicated no starting material remaining. The reaction mixture was filtered, taken up in chloroform, washed with water, dried, and evaporated. The main product residue was crystallized from ethyl acetate-hexanes, 8.4 grams of tan crystals; a second crop was crystalled from chloroform-hexanes with charcoal, 0.8 gram. The second crop was analyzed as follows:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1CCCC1

Procedure:
The 1-(2-hydroxyethyl)-pyrrolidine (Aldrich, 0.14 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:53])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:45]C(OC(C)(C)C)=O)[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36](=[O:44])[C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH:35]=3)=[O:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:53])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH2:45])[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36](=[O:44])[C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH:35]=3)=[O:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Reaction time: 0.75 h

Procedure:
To a solution of ((S)-5-tert-butoxycarbonylamino-6-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (I-1a) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL). After stirring for 45 minutes, the reaction mixture was concentrated in vacuo to afford crude ((S)-5-amino-6-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a dark amber residue.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([N:28](CC3C=CC(OC)=CC=3OC)[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[N:18]([CH3:45])[CH:17]=1>>[CH3:45][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([S:25]([NH:28][C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:26])=[O:27])[CH:20]=2)[C:16]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[CH:17]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cn1cc(-c2ccc(OC(F)(F)F)cc2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (4-(trifluoromethoxy)phenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-N-(1,2,4-thiadiazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 7.41 (m, J=8.13 Hz, 2 H) 7.52-7.58 (m, 1 H) 7.74-7.79 (m, 2 H) 7.88-8.00 (m, 4 H). m/z (ESI) 454.0 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][C:6]1[N:10]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:3][C:2]#[CH:1])[C:34]=2[CH2:33][CH2:32]1
Reactant: C#CCBr
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCn1c2c(c3ccccc31)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 60 h

Procedure:
Propargyl bromide (0.086 ml) was added to a suspension of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl ]-4H-carbazol-4-one (500 mg) and potassium carbonate (265 mg) in acetone (10 ml) and the mixture was stirred under nitrogen for 60 h. More propargyl bromide (0.086 ml) was added and the mixture was stirred at room temperature for 24 h and then at reflux for 6 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a gum (650 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 80:19:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (95 mg) as a foam, t.l.c. on Et3N impregnated SiO2 (ethyl acetate:hexane 4:1) Rf 0.30.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C.O>[Br:1][C:18]1[N:17]=[C:16]([O:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[C:9]([CH3:12])([CH3:10])[CH3:11])[C:21]([NH2:22])=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccccc1Oc1nc(Br)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.3 %

Procedure:
A solution of N-bromosuccinimide (2.32 g, 13.0 mmol) in DMF (20 ml) was added to a cold (−20° C.) solution of 1b (2.76 g, 11.4 mmol) in DMF (25 ml). The reaction rapidly turned dark red. HPLC analysis after 5 min showed that the reaction was complete. The reaction was quenched with a freshly prepared solution of sodium thiosulfate (40 ml, 10% aqueous). A precipitate formed. The mixture was warmed to rt and was diluted with water (60 ml). The solid was filtered, washed with water and dried overnight under reduced pressure to give 123a (3.82 g, 96% yield) as brown solid. [M+H]+=321.14. 1H NMR (500 MHz, CDCl3) δ ppm 1.40 (s, 9H), 3.91 (s, 2H), 6.93 (m, 2H), 7.00 (d, J=8.07 Hz, 1H), 7.12 (t, J=7.73 Hz, 1H), 7.20 (t, J=7.73 Hz, 1H), 7.41 (d, J=8.07 Hz, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+](=[CH2:31])=[N-].CCOCC>CO>[CH3:31][NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: CNS(=O)(=O)c1ccc(C=C2C(C)=C(CC(=O)OC)c3cc(OC)ccc32)cc1
Yield: 29 %

Procedure:
A solution of 4a (100 mg) in methanol (20 ml) was treated with excess diazomethane ether solution to give two products. They are separated via preparative tlc using 1500 μm silica gel plates developed 3 times with 5% ethyl acetate in chloroform to give Z methyl 1-(4-(N-methylaminosulfonyl)phenyl)methylene-5-methoxy-2-methyl-1H-3-indenylacetate (6a) (30 mg, 29% yield): m.p. 167°-169° C.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38]>>[OH:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][OH:38])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[C:11]=1[C:26]([NH2:27])=[O:28]
Reactant: NCCCCN(CCO)CCO
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(CCO)CCO)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.1 minutes. 1H NMR (400 MHz, CD3OD) δ 7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm; MS (APCl, m/z): 502 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16](Br)[N:17]=2)=[O:12])=[C:8]([CH3:19])[C:7]([O:20][CH3:21])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(C)C)(C)C>C(NC(C)C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:17]=2)=[O:12])=[C:8]([CH3:19])[C:7]([O:20][CH3:21])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(Br)cs2)c1C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC(C)OC(C)C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C#C[Si](C)(C)C)cs2)c1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a suspension of compound 207b (10.12 g, 1 eq.) in diisopropylamine (40 mL) were added ethynyltrimethylsilane (5.7 mL, 1.5 eq.), triphenylphosphine (0.283 g, 0.04 eq.), copper iodide (0.206 g, 0.04 eq.), and PdCl2(PPh3)2 (0.38 g, 0.02 eq.). The mixture was stirred under nitrogen and heated to 80° C. (external temperature). After 10 min, the solvent was refluxed, and the mixture solidified and turned brown grey. DIPA (20 mL) was added to solubilize the reaction mixture. After 2.5 hrs, the reaction was complete and the mixture cooled down to room temperature. Diisopropyl ether (20 mL) was added. A grey solid was recovered by filtration, dissolved in dichloromethane, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give black solid. The residue was purified by chromatography on silica gel (dichloromethane) to give compound 208b as a beige solid in 84% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.29 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H), 3.93 (s, 3H), 6.81 (d, J=8.78 Hz, 1H), 7.69 (s, 1H), 7.76 (d, J=8.78 Hz, 1H), 11.05 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15]C)=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO.O>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
A mixture of Bicyclo[2.2.2]octane-1,4-dicarboxylic acid dimethyl ester (III Example 80, 20.4 g, 89.5 mmol), barium hydroxide octahydrate (14 g, 44.7 mmol) in methanol (160 ml) and water (40 ml) is stirred at 20-25° C. for 18 hour. The mixture is diluted with water (600 ml) and extracted with hexane (150 ml×2). The aqueous mixture is acidified (6 N hydrochloric acid) to pH=1-2 and extracted with chloroform (150 ml 2). The combined chloroform extracts are concentrated. The residue is dissolved in toluene, filtered and concentrated to give the title compound, mp 169-173° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:23][C:24]2[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C>[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]([CH2:23][C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)=[CH:25][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2S(=O)(=O)c2ccccc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound obtained in Example 30 (4) (0.1722 g) in ethanol (14 ml), potassium hydroxide (0.047 g) was added and the mixture was stirred at 15 to 30° C. for 30 minutes. To the mixture was added 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=0.1:1) to obtain 0.07.48 g of the desired product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7](OCC)C.C[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[H-]>C(OCC)(=O)C>[CH3:13][CH:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[CH3:7])[OH:15]
Reactant: CCC(=O)c1ccccc1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(C)O

Procedure:
In a dry flask under nitrogen atomosphere was suspended 3.25 g (0.086 mol) lithium aluminum hydride and 250 ml of dry diethyl ether. The suspension was cooled in an ice/water bath, then 24.5 g (0.184 mol) of 2-methylacetophenone was added dropwise. After 12 hours the excess hydride was decomposed with 100 ml of ethyl acetate. The reaction mixture was washed with ammonium chloride solution and water. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 25.0 g of a clear oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:11]1[CH:12]=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CO>[C:3]([N:10]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@H:11]1[CH2:12][OH:13])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 105 %

Procedure:
Sodium borohydride (227 mg, 6 mmol) was added at 0° C. to a stirred solution of (2S,4R)—N—BOC-4-(t-butyldimethylsilyloxy)prolinaldehyde (522 mg, 1.58 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 3 h. The reaction was quenched by adding sat. NaHCO3 (20 mL), and the resulting mixture was extracted with EtOAc (3×50 mL). The EtOAc extracts were washed with brine (2×50 mL), and dried (Na2SO4). The solvent was removed in vacuo to give (2S,4R)—N—BOC-4-(t-butyldimethylsilylhydroxy)prolinol (550 mg).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([C:46](=[O:54])[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[C:19]([CH2:55][CH3:56])[CH:18]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[O:7])(=[O:3])[CH3:2].[CH3:57][C:58]([O:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C@H:69]([NH2:77])[C:70]([O:72]C(C)(C)C)=[O:71])=[CH:64][CH:63]=1)([CH3:60])[CH3:59].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([NH:4][CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([C:46](=[O:54])[C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:31])=[C:19]([CH2:55][CH3:56])[CH:18]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:77][C@@H:69]([CH2:68][C:65]1[CH:64]=[CH:63][C:62]([O:61][C:58]([CH3:57])([CH3:59])[CH3:60])=[CH:67][CH:66]=1)[C:70]([OH:72])=[O:71])=[O:14])=[O:7])(=[O:3])[CH3:2]
Reactant: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A mixture 5-{[2-(acetylamino)-3-(4-{2-[(benzhydryloxy)carbonyl][tert-butoxy(oxo)acetyl]anilino}-3-ethylphenyl)propanoyl]amino}pentanoic acid (30 mg, 0.04 mmol), H-TYR(TBU)-OTBU HCL(26 mg, 0.08 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (16 mg, 0.048 mmol) and diisopropylethylamine (26 μL) in N,N-dimethylformamide (250 μL) was stirred at ambient temperature overnight, concentrated under reduced pressure and the residue purified by reverse-phase HPLC eluting with 5-100% acetonitrile/aqueous 0.1% trifluoroacetic acid to provide the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[C:21]#[N:22])(=[O:25])[CH3:24]
Reactant: N#Cc1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C#N)cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F

Procedure:
5-Amino-4-cyano-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole (6.5 g) in acetic anhydride (30 ml) was heated at reflux for 3.5 hours. The reaction mixture was then evaporated to dryness and the solid residue was dissolved in ethanol (50 ml). Saturated aqueous sodium bicarbonate solution was then added to give a pH of 7-8 and the solution was then evaporated to dryness. The solid residue was triturated with hexane (20 ml) to give an off-white powder which was crystallized from toluene (50 ml) to give 5-acetamido-4-cyano-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole (1.4 g), m.p. 153°-154° C., in the form of colourless crystals.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[NH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>C(#N)C>[C:6]([C:5]([C:8]#[N:9])=[CH:4][NH:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16])#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: NCCNC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CC(C#N)=CNCCNC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
After adding acetonitrile (100 mL) and ethoxymethylenemalononitrile (4.5 g) to N-(2-aminoethyl)(4-fluorophenyl)carboxamide hydrochloride (8.3 g), a solution of triethylamine (4.5 g) in acetonitrile (20 mL) was added thereto. After stirring at room temperature for 15 minutes, the solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was stirred. The precipitated solid was filtered out to obtain the crude title compound (6.5 g) as a brown solid.
Reaction SMILES: C(O[C:5](=[CH:19][C:20](=[O:22])C)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[Br:18])=[O:8])(=O)C.S(=O)(=O)(O)[OH:24]>>[Br:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[C:15]2[C:10]=1[NH:9][C:7](=[O:8])[CH:6]=[C:5]2[CH2:19][C:20]([OH:22])=[O:24]
Reactant: COc1ccc(Br)c(NC(=O)CC(=CC(C)=O)OC(C)=O)c1
Reactant: O=S(=O)(O)O
Product: COc1ccc(Br)c2[nH]c(=O)cc(CC(=O)O)c12
Reaction time: 0.5 h
Yield: 89 %

Procedure:
1-(2-bromo-5-methoxyphenylamino)-1,5-dioxohex-3-en-3-yl acetate (8 g; 21.50 mmol) was added in small portions to concentrated sulfuric acid (30 ml) at room temperature and the mixture was stirred for 30 min. Ice was added to the reaction mixture and the formed precipitate was filtered, washed with water and dried over phosphorus pentoxide under reduced pressure to afford 5.97 g (89%) of 2-(8-bromo-5-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acetic acid as a grey solid.