Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:30])[N:21]([CH2:26][C:27]([OH:29])=O)[C:22]([CH3:25])=[CH:23][N:24]=1)[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([CH2:44][NH2:45])[CH:42]=2)[NH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O.O>[CH3:12][O:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]1[CH:33]=[CH:32][CH:31]=[C:15]([CH2:16][CH2:17][NH:18][C:19]2[C:20](=[O:30])[N:21]([CH2:26][C:27]([NH:45][CH2:44][C:41]3[CH:42]=[C:43]4[C:38](=[CH:39][CH:40]=3)[NH:37][CH:36]=[C:35]4[CH3:34])=[O:29])[C:22]([CH3:25])=[CH:23][N:24]=2)[CH:14]=1
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2ncc(C)n(CC(=O)O)c2=O)c1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Reaction time: 72 h
Yield: 56.8 %

Procedure:
A mixture of 2-[3-[(3-{(1R/S)-1-[(tert-butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 123) (35 mg, 0.076 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (13 mg, 0.08 mmol), HOBT (11 mg, 0.08 mmol), WSCDl.HCl (16 mg, 0.08 mmol) and N-methylmorpholine (16 ml, 0.15 mmol) in N,N-dimethylformamide (2 ml), was stirred at room temperature for 18 hrs. Additional (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (8 mg, 0.038 mmol), was added, and stirring continued for a further 72 hrs at room temperature. The reaction mixture was poured into water (10 ml), and the resulting precipitate filtered, and dried to give the desired product, (26 mg, 57%).
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].[O:16]([CH2:23][C:24]([NH:26][CH:27]1[C:55](=[O:56])[N:29]2[C:30]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:31](OS(F)(=O)=O)[CH2:32][S:33][C@H:28]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:16]([CH2:23][C:24]([NH:26][CH:27]1[C:55](=[O:56])[N:29]2[C:30]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:31]([CH:1]=[CH2:2])[CH2:32][S:33][C@H:28]12)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)F)CS[C@H]12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.05 h
Yield: 88.8 %

Procedure:
A solution of palladium (II) acetate (3.6 mg, 0.016 mmol, 0.1 eq.) in 1-methyl-2-pyrrolidinone (2 mL) was treated with vinyl tri-n-butylstannane (58.4 mL, 0.2 mmol, 1.2 eq.) under an inert atmosphere and allowed to stir for 3 minutes. The resulting dark suspension was then treated with diphenylmethyl 7-phenoxyacetamido-3-[(fluorosulfonyl)oxy] -3-cephem-4-carboxylate (100.0 mg, 0.16 mmol, 1.0 eq.) in one portion and the reaction mixture was allowed to stir for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with 3×20 mL of water. The organic fraction was dried over magnesium sulfate then concentrated. The crude brown residue was purified by flash filtration through a pad of silica gel (W. R. Grace, 951W) first with dichloromethane (50 mL) to remove the residual stannane and then with 10% ethyl acetate in dichloromethane (75 mL), which upon concentration furnished 74.8 mg (85%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([OH:22])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:37][CH2:38][C:39]([NH:41][C@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44])=[O:40]>>[C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([NH:37][CH2:38][C:39]([NH:41][C@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44])=[O:40])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@@H](CO)C(=O)O
Yield: 60.9 %

Procedure:
Starting from 2-hexadecanoyloxyhexadecanoic acid (128 mg) prepared by the method described in Preparation 7 and N-glycyl-L-serine (162 mg), N-[N-(2-hexadecanoyloxyhexadecanoyl)glycyl]-L-serine (100 mg) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A flame-dried 200 mL round bottomed flask was charged with 3-(2-formyl-4-hydroxyphenyl)acrylic acid tert-butyl ester (10.0 g, 40.3 mmol), tert-butylchlorodiphenylsilane (12.6 mL, 48.3 mmol), and dry CH2Cl2 (150 mL). Triethylamine (11.2 mL, 80 mmol) and N,N-dimethylaminopyridine (1.0 g, 1.0 mmol) were added, and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with additional CH2Cl2, washed with brine (2×), dried (Na2SO4), and concentrated to an oil. The crude product was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to give a pale yellow oil (18.3 g, 93%). 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 1.51 (d, J=15.1 Hz, 9H), 6.15 (d, J=5.1 Hz, 1H), 6.87 (dd, J=8.6, 2.7 Hz, 1H), 7.34-7.47 (m, 7H), 7.68-7.73 (m, 5H), 8.28 (d, J=15.6 Hz, 1H), 10.1 (s, 1H). MS (ES) m/e 487 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][CH:11](OCC)[CH2:12][NH:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15])C>O>[O:10]=[CH:11][CH2:12][NH:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15]
Reactant: CCOC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)s1)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCNC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Add water (21 mL) followed by trifluoroacetic acid (100 g) to a 250 mL three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, and thermocouple. To the stirring TFA solution, add 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide (25 g, 0.07 mol) in one portion. Stir the reaction mixture for 4 h, pour onto ice/water (1200 mL), and stir for 1.25 h. Filter the resulting slurry and rinse the solid with water (500 mL) and heptane (500 mL), and then dry to give 18.65 g (95%) of the title compound as a yellow-white solid. LC-MS/ES m/z (35Cl) 278 (M−H)−. 1H NMR (500 MHz, CDCl3): δ 4.40 (d, J=4.0 Hz, 2H), 6.69 (bs, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.53-7.58 (m, 3H), 9.78 (s, 1H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:50]=[CH:49][C:11]([C:12]([O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:47]=[C:45]([CH3:46])[C:43](=[O:44])[NH:42][C:40]3=[O:41])[CH2:36][C@@H:35]2[OH:48])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].C(N(C(C)C)CC)(C)C.C(CC[O:64][P:65](Cl)[N:66](C(C)C)C(C)C)#N>ClCCl>[P:65]([O:48][C@@H:35]1[C@@H:34]([CH2:33][O:32][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:11]2[CH:49]=[CH:50][C:8]([O:7][CH2:1][CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6])=[CH:9][CH:10]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:17][CH:18]=2)[O:38][C@@H:37]([N:39]2[CH:47]=[C:45]([CH3:46])[C:43](=[O:44])[NH:42][C:40]2=[O:41])[CH2:36]1)([NH2:66])[OH:64]
Reactant: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OP(N)O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Compound 31 (3.0 grams, 4.43 mmol) was dissolved in anhydrous dichloromethane and diisopropylethylamine (2.7 mL; 15.5 mmol) was added. The solution was cooled to 0° C. and 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (2.0 mL, 8.86 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring under argon. After 4 hours the solution was diluted with dichloromethane and washed with a 5% aqueous solution of sodium bicarbonate (2×). The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; EtOAc/hexane, 3/7) to afford 2.8 grams (72%) of compound 32 as a fluffy white solid. 1H NMR (300 MHz, CDCl3) δ1.01-1.20 (m, 12H), 1.41 (s, 3H), 2.25-2.67 (m, 8H), 3.26-4.22 (m, 11H), 4.60-4.65 (m, 1H), 5.02 (dd, J=1.5, 10.4 Hz, 2H), 5.14 (dd, J=1.5, 17.3 Hz, 2H), 5.69-5.84 (m, 2H), 6.11-6.48 (m, 5H), 6.82 (dd, J=3.2, 8.9 Hz, 4H), 7.16-7.43 (m, 9H), 7.62 (d, J=15.2 Hz, 1H), 8.05 (bs, 1H); 31P NMR (300 MHz, DMSO-d6) 152.9, 152.4; Anal. Calcd for C50H61N4O8P1 (877.0276): C, 68.48; H, 7.01; N, 6.39. Found: C, 68.48; H, 7.22; N, 6.33. ##STR18##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:18])[NH:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.I[CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:18][CH2:20][CH3:21])=[N:9][N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ncc12

Procedure:
tert-Butyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (1.19 g, 4.41 mmol), iodoethane (0.715 mL, 8.85 mmol), and cesium carbonate (4.36 g, 13.38 mmol) were stirred in DMF (15 mL) at room temperature for 16 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave tert-butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate. MS ESI calc'd. For C13H16ClN3O3 [M+1]+ 298. found 298.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:24]([O:23][C:22]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([N+:19]([O-:21])=[O:20])[C:2]=1[OH:1])=[O:26])[CH3:25]
Reactant: COC(=O)c1c(-c2noc(C)n2)cc(O)c(O)c1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1cc(-c2noc(C)n2)c(C(=O)OC)c([N+](=O)[O-])c1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), ethyl chlorocarbonate (0.02 mL), potassium carbonate (28 mg) and N,N-dimethylformamide (2 mL) was stirred at 50° C. for 3 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20%-100% ethyl acetate/hexane, gradient elution) to give the title compound (51 mg). The structural formula was illustrated in table 13.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[CH:48]1([CH:51]=O)[CH2:50][CH2:49]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:51]([CH:48]5[CH2:50][CH2:49]5)=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: O=CC1CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2nc(C3CC3)[nH]c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF was combined with 20 μL (0.27 mmol) cyclopropanecarbaldehyde and stirred for 2 days at RT. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][CH:17]([O:30][CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][NH:21]C(C1CCCCC1)=O)[CH3:15]>>[CH2:31]([O:30][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][NH:21][C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:12])[CH3:32]
Reactant: O=C(Cl)N1CCc2ccccc2C1
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Product: CCOC(CCCNC(=O)N1CCc2ccccc2C1)OCC

Procedure:
3,4-Dihydro-1H-isoquinoline-2-carboxylic acid (4,4-diethoxy-butyl)-amide (24B) is prepared from 24A as described for 20A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH2:23][CH3:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH:36][CH2:37][C:38]#[CH:39]>>[CH2:23]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:39]#[C:38][CH2:37][NH:36][CH3:35])=[CH:3][CH:4]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH2:25][CH2:26][OH:27])[CH3:24]
Reactant: C#CCNC
Reactant: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C#CCNC)cc3)nsc2c1

Procedure:
In analogy to example 36.1, {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amine and N-Methylpropargylamine were converted to yield 2-[Ethyl-(4-{3-[4-(3-methylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-amino]-ethanol as brown oil, MS: 438 (MH+).
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Using General Procedure I; a solution of ethyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:11]=1)=[O:4].Br.C(S[C:28](=[NH:30])[NH2:29])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:28]([N:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[N:11]=[C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[S:8][CH:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)(=[NH:29])[NH2:30]
Reactant: COC(=O)CCc1nc(-c2ccc(C3CCNCC3)cc2)cs1
Reactant: CCSC(=N)N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(-c2ccc(C3CCN(C(=N)N)CC3)cc2)cs1

Procedure:
Prepared from 2-(2-methoxycarbonyl-ethyl)-4-[4-(4-piperidinyl)-phenyl]-thiazole and S-ethylisothiourea-hydrobromide by heating to 100° C. for 4 hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].C(=O)([O-])[O-:14].[K+].[K+].Cl[CH2:20][C:21]#[N:22].[OH-].[Na+]>>[NH2:22][C:21](=[O:14])[CH2:20][O:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: N#CCCl
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)COc1ccc(Cl)cc1C(=O)O

Procedure:
Commercially available, methyl 5-chloro-2-hydroxybenzoate (Maybridge), potassium carbonate, 2-chloroacetonitrile (Aldrich) and sodium hydroxide were processed according to the method described for Example 130A to obtain the title compound. MS (ESI+) m/z 248 (M+H2O)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:19]
Reactant: NCC(=O)CCC(=O)O
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1cccc([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
From 3-nitrobenzyl alcohol (5.0 g; 33 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 20 h at 100° C. The yield was 1.00 g (55%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)O)[CH:17]=[CH:18][C:19]=1[F:20].FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)c1ccc(F)c(Cl)c1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(F)c(Cl)c3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.15 g (4.23 mmol) of the compound from Example 177A in analogy to the synthesis of the compound from Example 278. 483 mg (26% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH:29]([CH3:31])[CH3:28])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 40 h
Yield: 43.2 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.27 g, 0.739 mmole), acetone (0.09 g, 1.48 mmol), and acetic acid (0.04 g, 0.739 mmol) in 10 mL of dry dichloromethane was added sodium triacetoxyborohydride (0.31 g, 1.48 mmol) under nitrogen. The mixture was stirred for 40 hours, and then aqueous 1 N NaOH (20 mL) solution was added. After 1 h of stirring, the layers were separated, and the aqueous layer was extracted twice with dichloromethane (15 mL). The organic extracts were combined, washed twice with 1 N NaOH (20 mL), dried (Na2SO4), and concentrated to give a brown-black glass. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 0.13 g (43%) of N,N-diethyl-4-[benzyl(1-isopropylpiperidin-4-yl)amino]benzamide as a colorless oil. MS (ES), m/z 408 (MH+). 300 MHz 1H NMR (CDCl3) δ1.06 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.0 Hz, 6H), 1.68-1.92 (m, 4H), 2.29 (br t, 2H), 2.69-2.85 (br m, 1H), 2.97 (br d, J=10.3 Hz, 2H), 3.32-3.52 (m, 4H), 3.74-3.89 (br m, 1H), 4.53 (s, 2H), 6.65 (d, J=8.8 Hz, 2H), 7.18-7.42 (m, 7H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:14][C:15]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([S:14]([C:15]1[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=1)=[O:9])[CH3:13]
Reactant: CCOC(=O)c1ccc(SCC)nc1C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)CC)nc1C(F)(F)F

Procedure:
Under an atmosphere of nitrogen and with stirring and cooling, a solution of 2.5 g of m-chloroperbenzoic acid in 40 ml of methylene chloride is added dropwise at a temperature of −20° C. to a solution of 2.8 g of ethyl 6-ethylthio-2-trifluoromethylpyridin-3-ylcarboxylate, which had been charged initially, and the mixture is stirred at a temperature of +5° C. for 20 hours. The mixture is then evaporated gently and purified over silica gel (hexanelethyl acetate 7:3). This gives 2.48 g (84%) of 6-ethylsulfinyl-2-trifluoromethylpyridin-3-yl-ethyl ester. 1H NMR (CDCl3, ppm): 8.38 (d, 1H); 8.30 (d, 1H); 4.45 (q, 2H); 3.26-3.00 (m, 2H); 1.43 (t, 3H); 1.26 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[OH:8])[NH:1][C:17](=[O:18])[O:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(O)c(Cl)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-amino-2-chlorophenol (21.45 grams, 0.15 mole) in dry DMF (150 ml.) and pyridine (11.8 grams) is added at 0°C. slowly dropwise with stirring isopropyl chloroformate (16.5 grams, 0.016 mole). After 4 hours at 0° C. to 5°C., a further one gram of isopropyl chloroformate is added. The mixture is stirred at 25°C. for 16 hours, then poured into ice-dilute hydrochloric acid. After 4 hours stirring and scratching, a solid separates out and is filtered off. Crystallization from methanol gives 14.5 grams, 42%, melting point 89°C. to 90°C.