Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](/[CH:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([O:22]CC)=[O:21])\[CH3:14])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2>CCCCCC.C(OCC)(=O)C>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](/[CH:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([OH:22])=[O:21])\[CH3:14])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2
Reactant: CCOC(=O)C1CCCC1/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)C1CCCC1C(=O)O)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran -5-yl)-2,4-dimethyl-4-hexenoate with ethyl (E)-2-[-3-(4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-methylpropenyl ]-cyclopentane-carboxylate and compounds of Formula I-ZH-A1, prepared e.g, as described in Example ZH-6B, there are obtained (E)-2-[-3-(1,3-dihydro-4-hydroxy -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-methylpropenyl]-cyclopentane-carboxylic acid, mp 157°-158° C. (hexane/ethyl acetate) and the corresponding compounds of Formula I-ZH-A2 as identified in the following table.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][C:11]([Cl:57])=[C:12](/[C:14](=[N:50]/[O:51]C2CCC=C2)/[C:15]([NH:17][C@@H:18]2[C:48](=[O:49])[N:20]3[C:21]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])=[C:22]([S:25][CH2:26][C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>ClCCl>[NH2:8][C:9]1[S:10][C:11]([Cl:57])=[C:12](/[C:14](=[N:50]/[OH:51])/[C:15]([NH:17][C@@H:18]2[C:48](=[O:49])[N:20]3[C:21]([C:32]([OH:34])=[O:33])=[C:22]([S:25][CH2:26][C:27]4[CH:31]=[N:30][NH:29][CH:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: Nc1nc(/C(=N/OC2C=CCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cn[nH]c4)CS[C@H]23)c(Cl)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)c(Cl)s1
Reaction time: 2 h
Yield: 35.5 %

Procedure:
Under nitrogen atmosphere, trifluoroacetic acid (4.0 ml) was added dropwise to a solution of diphenylmethyl 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(2-cyclopenten-1-yloxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (1.71 g) in the mixture of dichloromethane (6.0 ml) and anisole (2.0 ml) at 0° C. Stirring was continued for 2 hours at the same temperature, the mixture was poured into isopropyl ether (200 ml). The resulting precipitate was collected by filtration, and then dissolved in the mixture of ethyl acetate and pH 6.86 buffer. The organic layer was removed, and the aqueous layer was adjusted pH 3.0 with 1N hydrochloric acid, concentrated in vacuo, then chlomatographed on a HP-20 column (eluent: water-methanol) to afford 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (418.3 mg).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[F:21][C:22]1[CH:23]=[C:24]([C:37]2([C:40]([O:42][CH3:43])=[O:41])[CH2:39][CH2:38]2)[CH:25]=[C:26]([F:36])[C:27]=1OS(C(F)(F)F)(=O)=O.[Cl-].[Li+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)CCC.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([F:36])=[CH:25][C:24]([C:37]4([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]4)=[CH:23][C:22]=3[F:21])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]
Reactant: COC(=O)C1(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCCC#N
Product: COC(=O)C1(c2cc(F)c(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(F)c2)CC1
Temperature: 150 °C
Yield: 44.1 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (226 mg, 0.83 mmol), methyl 1-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)cyclopropanecarboxylate (Intermediate 28-2; 300 mg, 0.83 mmol), lithium chloride (70.6 mg, 1.67 mmol) and tripotassium phosphate (265 mg, 1.25 mmol) in butyronitrile (2 mL) was degassed for 10 minutes then put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (137 mg, 0.17 mmol). The reaction mixture was heated in the microwave at 150° C. for 1 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 90% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate (160 mg, 43.9%)
Reaction SMILES: CC(CC(C)C)=O.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Br:25][CH:26]([CH:30]([CH3:32])[CH3:31])[C:27](Cl)=[O:28]>O>[CH3:8][C:9]([NH:17][C:27](=[O:28])[CH:26]([Br:25])[CH:30]([CH3:32])[CH3:31])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C(Br)C(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
Into a 500 ml four-necked flask, there were charged methylisobutylketone (150 ml), α,α-dimethylbenzylamine (27.0 g) and triethylamine (21.2 g), and α-bromo-isovaleryl chloride (40.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, water (200 ml) was added thereto and the reaction mixture was gradually heated to remove methylisobutylketone, followed by cooling at room temperature. The precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-isovaleramide (51.9 g).
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:38]=CC(N)=C[CH:33]=1.C(N1CCC(N)C1)(OC(C)(C)C)=O>>[F:31][C:32]1[CH:38]=[CH:9][C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:11][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: Nc1ccc(F)cc1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Product: O=C(Nc1ccc(F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-fluoroaniline of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 353 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.11 (1H, s) 9.90 (1H, s) 8.01 (1H, d, J=5.42 Hz) 7.88 (1H, d, J=5.42 Hz) 7.64 (2H, dd, J=9.13, 5.08 Hz) 7.49 (1H, d, J=5.42 Hz) 7.30 (1H, dd, J=3.25, 2.66 Hz) 7.16 (2H, t, J=8.93 Hz) 6.82 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.49, 1.93 Hz)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[S:11][CH:12]=2)=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32])(=[O:24])=[O:23].[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][C:12]1[S:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:9][C:8]=1[C:7]1[C:2]([F:1])=[C:3]([NH:21][S:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])(=[O:23])=[O:24])[CH:4]=[CH:5][C:6]=1[F:20]
Reactant: CN1CCN(c2nc(-c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)cs2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1CCN(c2nc(-c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(Br)s2)CC1
Temperature: 25 °C
Yield: 73 %

Procedure:
150 mg (0.31 mmol) of N-{2,4-Difluoro-3-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-phenyl}-2,5-difluoro-benzenesulfonamide were suspended in 15 mL of dry DCM and 103 mg (0.62 mmol) of N-bromosuccinimide were added. The reaction was maintained at r.t. for 1 h then diluted with the same solvent and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with petroleum ether and filtered, to afford 128 mg (73%) of N-{3-[5-bromo-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][C@H:14]([CH:10]=[CH:11]2)[C@@H:3]1[C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC=CC(=O)CCCC
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCC(=O)[C@@H]1[C@@H](C)[C@H]2C=C[C@H]1C2
Yield: 83 %

Procedure:
Prepared according to general procedure A from oct-2-en-4-one (89 μL, 0.60 mmol), cyclopentadiene (74 μL, 0.90 mmol), 70% aqueous perchloric acid (10.3 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32.4 mg, 0.12 mmol) neat for 34 hours at 0° C. Purification by silica gel chromatography (19:1 hexanes:ethyl acetate) provided the title compound as a colorless oil in 83% yield (95.7 mg, 0.50 mmol); 22:1 endo:exo, endo 92% ee. IR (film) 3061, 2958, 2871, 1707,1462, 1409, 1375, 1332, 1267, 1137, 1045, 904.4, 801.4, 715.9 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.19 (dd, J=5.4, 3.0 Hz, 1H, CH═CH), 5.87 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 3.10 (br s, 1H, CHCH═CH), 2.43 (m, 1H, CHCH═CH), 2.39 (in, 3H, CHCO and CH2CO), 1.86 (m, 1H, CHCH3), 1.57-1.20 (m, 6H, COCH2CH2CH2, and CHCH2CH), 1.12 (d, J=6.9 Hz, 3H, CHCH3), 0.87 (dd, J=7.5, 7.5 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 211.3, 138.6, 132.6, 61.2, 49.3, 46.6, 41.7, 35.9, 26.2, 22.8, 21.4, 14.3; HRMS (CI) exact mass calc'd for (C13H20O) requires m/z 192.1514, found m/z 192.1509. [α]D=+89.3 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (150° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=6.1 min, and (1S, 2S, 3R, 4S) endo isomer tr=5.9 min, exo isomers tr=5.5, 5.6 min.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH:10]12[CH2:16][CH:14]([CH2:13][NH:12][CH2:11]1)[CH2:15][NH:8][CH2:9]2
Reactant: c1ccc(CN2CC3CC(C2)CN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C1NCC2CNCC1C2

Procedure:
Obtainable by catalytic hydrogenation of 3,7-dibenzyl-3.7-diazabicyclo[3.3.1]nonane. Hydrogenation is performed by stirring 3,7-dibenzyl-3.7-diazabicyclo[3.3.1]nonane in a mixture of ethanol, concentrated hydrochloric acid and palladium on carbon under an atmosphere of hydrogen.
Reaction SMILES: C1C=CN=CC=1.F.[Si:8]([O:15][C@@H:16]([CH2:42][C@H:43]([O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])/[CH:44]=[CH:45]\[C@H:46]([CH3:70])[C@H:47]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:48]([CH3:61])[CH2:49][C@@H:50]([CH3:60])[CH2:51][O:52][Si](C(C)(C)C)(C)C)[C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>N1C=CC=CC=1.C1COCC1>[Si:63]([O:62][C@@H:47]([C@@H:46]([CH3:70])/[CH:45]=[CH:44]\[C@@H:43]([O:71][Si:72]([C:75]([CH3:78])([CH3:76])[CH3:77])([CH3:74])[CH3:73])[CH2:42][C@H:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:48]([CH3:61])[CH2:49][C@@H:50]([CH3:60])[CH2:51][OH:52])([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C[C@@H](CO)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 21 h
Yield: 66.9 %

Procedure:
HF-pyridine in pyridine (40 mL, prepared by slow addition of 12 mL pyridine to 3 mL HF-pyridine complex followed by dilution with 25 mL THF) was slowly added to a solution of TBS ether 35 (4.27 g, 4.10 mmol) in THF (5 mL) at 0° C. The mixture was stirred for 21 h at 0° C. and quenched with saturated aqueous NaHCO3 (100 mL). The aqueous layer was separated and extracted with Et2O (3×50 mL). The combined organic layers were washed with saturated aqueous CuSO4 (3×50 mL), dried over MgSO4, filtered and concentrated. Flash column chromatography (EtOAc/hexane 1:4) afforded 2.55 g (67%) of the alcohol 36 as a colorless oil: IR (CHCl3) 3350, 2956, 2928, 2856, 1471, 1448, 1254, 1086, 836, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.52 (m, 6H), 7.32 (m, 9H), 5.68 (m, 2H), 5.50 (t, J=10.6 Hz, 1H), 5.35 (dd, J=10.9, 8.5 Hz, 1H), 4.61 (t, J=8.5 Hz, 1H), 4.00 (t, J=8.1 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.58 (dd, J=10.6, 4.3 Hz, 1H), 3.45 (m, 1H), 3.36 (dd, J=9.9, 7.3 Hz, 1H), 2.66 (m, 1H), 2.48 (m, 1H), 1.70 (m, 3H), 1.49 (m, 3H), 1.04 (d, J=6.6 Hz, 6H), 0.97 (s, 18H), 0.93 (m, 6H), 0.87 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H), 0.11 (s, 6H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.3, 134.4, 133.0, 132.1, 128.7, 127.7, 126.8, 86.7, 79.8, 72.3, 67.7, 66.5, 65.1, 42.4, 41.5, 37.3, 35.7, 35.5, 33.3, 26.2, 26.0, 25.9, 19.6, 18.4, 18.14, 18.06, 17.98, 15.7, 13.2, −2.9, −3.6, −3.7, −4.1, −4.2, −4.3; LRMS (ESI) 951.8 [M+Na]+, 771.6, 328.3; HRMS (ESI) calcd for C56H92O5Si3Na 951.6150 [M+Na]+, found 951.6162; [α]20D−12.0 (c 0.71, CHCl3).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][C@@H:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]3[CH:19]=[CH:20][S:21][C:11]=23)[CH2:6][CH2:5][C@@H:4]1[CH2:22][C:23]#[N:24]>[Pd].CO>[NH2:16][C:15]1[C:10]([NH:9][C@H:7]2[CH2:6][CH2:5][C@H:4]([CH2:22][C:23]#[N:24])[C@H:3]([O:2][CH3:1])[CH2:8]2)=[C:11]2[S:21][CH:20]=[CH:19][C:12]2=[N:13][CH:14]=1
Reactant: CO[C@@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Yield: 89.1 %

Procedure:
A mixture of {(1R,2R,4S)-2-methoxy-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (racemic) (380 mg, 1.1 mmol) and 10% palladium on carbon (0.38 g, 0.36 mmol) in methanol (7.3 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated and purified with flash chromatography (eluting with 15% methanol in dichloromethane) to give the desired product (310 mg, 89%). LCMS calculated for C16H21N4OS (M+H)+: m/z=317.1. Found: 317.1.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20]>C(O)(C)(C)C.CO>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:20][CH2:19][C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A suspension of diphenylacetonitrile (38.6 g, 200 mmol) in tert-butanol (200 ml) was warmed to 60° C. for 30 minutes. The resulting solution was cooled to 50° C. and a solution of potassium hydroxide (0.6 g, 10.69 mmol) in methanol (2 mL) was added. tert-Butyl acrylate (30 mL, 200 mmol) was then added dropwise and the mixture was stirred at 50° C. for 2 hours and at room temperature for 18 hours. Further potassium hydroxide (0.6 g, 10.69 mmol) was added and the mixture was re-warmed to 50° C. for 3 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with diethyl ether (300 mL), washed with water (200 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 90% yield, 57.95 g.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl.N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13])[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(Br)cc1)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
60.5 g (4-Bromo-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 270 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 76.0 g (386.4 mmol) p-toluenesulfonylchloride in 100 ml of dichloromethane was added and the solution was stirred at room temperature. After 3 h, the reaction mixture was washed twice with 2 N HCl and saturated sodium hydrogen carbonate-solution. The organic layer was dried over magnesium sulfate and evaporated. Final silica gel chromatography (heptane/ethylacetate 4:1) gave 59.9 g of the title compound. Rt=1.82 min (Method C). Detected mass: 396.1/398.1 (M−OMe−).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:14][CH3:15])=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:15][NH:14][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CNC(=O)CCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCc1c[nH]c2ccccc12

Procedure:
A solution of 60.6 g 3-(3-indolyl)-N-methyl-propionamide in 500 ml anhydrous tetrahydrofuran are added dropwise at 25° for 15 minutes under nitrogen atmosphere to a suspension of 34.2 g lithium aluminium hydride in 800 ml anhydrous tetrahydrofuran and maintained at 66° for 3 hours. N-methyl-3-(3-indolyl)-propylamine (M.pt 81°-82° after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([C:13]([O:15]C)=[O:14])[NH:8]3)=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([C:13]([OH:15])=[O:14])[NH:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc3c(cc2[nH]1)OCO3
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2cc3c(cc2[nH]1)OCO3

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 5,6-methylenedioxyindole-2-carboxylate (PREPARATION 78, 4.77 g), potassium hydroxide (1.47 g), the title compound is obtained, C,H,N analysis calcd. for C10H7NO4C,58.54; H, 3.44; N, 6.83; found: C,58.27; H, 3.18; N, 6.95.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([S:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH3:22][S:21][C:15]1[CH:20]=[CH:19][C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a cold (0° C.) solution of phenylacetyl chloride (92.8 g, 0.6 mol) in CHCl3 (1.2 L) was added AlCl3 (80 g, 0.6 mol) in portions. Thioanisole (62.1 g, 0.5 mol) was then added dropwise. The resulting mixture was stirred at r.t. for 1.5 h. The mixture was poured into 4 L of ice and extracted with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was slurried in 300 mL of 20 % EtOAc/hexane, filtered and washed with hexane to give 78 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: C[C@H](C(=O)N[C@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](C(=O)N[C@H](c1ccc(O)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Yield: 45.4 %

Procedure:
(R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (78 mg, 0.152 mmol) and palladium on carbon (10% wt) (36 mg, 0.034 mmol) in methanol (3.031 mL) was hydrogenated under 60 psi hydrogen gas for 4 h. The mixture was filtered through diatomaceous earth (Celite®) eluting with EtOAc and the filtrate concentrated in vacuo. Obtained (R)-tert-butyl 2-((R)-(4-hydroxyphenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (29.1 mg, 0.069 mmol, 98% yield) as a colorless oil which was carried forward without further purification. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.79 Hz, 1H), 7.25-7.31 (m, 1H), 7.13-7.23 (m, 4H), 6.91 (d, J=8.31 Hz, 2H), 6.52 (d, J=8.56 Hz, 2H), 4.45 (dd, J=10.83, 6.04 Hz, 1H), 3.99-4.14 (m, 1H), 3.27-3.57 (m, 3H), 1.72-2.07 (m, 2H), 1.59 (t, J=11.46 Hz, 2H), 1.51 (s, 9H), 1.42 (d, J=7.30 Hz, 3H); LRMS (ESI) m/e 447.20 [(M+Na)+, calcd for C25H32N2NaO4 447.23].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[Br:33].CC(C)([O-])C.[Na+].O>C1COCC1>[Br:33][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:25]=1[NH:24][C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1
Reactant: N#Cc1ccc(N)c(Br)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cc(Nc2ccc(C#N)cc2Br)nc2c(C=O)cnn12)C1CC1
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (225 mg, 0.67 mmol) and 4-amino-3-bromobenzonitrile (197 mg, 1 mmol) were dissolved in anhydrous THF (4.5 mL). Sodium tert-butoxide (96 mg, 1 mmol) was added in one portion. After 1.5 h, the reaction was poured into H2O (25 mL) and extracted with EtOAc (3×30 mL). The organics were washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The tan solid was purified via flash column chromatography (30% EtOAc/hexanes) to provide tert-butyl 5-(2-bromo-4-cyanophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (106 mg, 32%) as a pale yellow solid. LCMS (ES): >90% pure, m/z 497 [M+1]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2]C.[CH3:19][O:20]C(C1C=NC(Cl)=C(Br)N=1)=O.N1CCCC1.[OH-].[K+]>COCCO>[CH3:19][O:20][CH2:2][CH2:1][O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: COC(=O)c1cnc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Solvent: COCCO
Product: COCCOc1nc(C(=O)O)cnc1N1CCCC1
Yield: 17 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, 2-methoxy-ethanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 17% yield. m/z (ES+): 268.0 (M+H).