Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)=[CH:30][C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3ccc(C(F)(F)F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 21 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 4-trifluoromethylbenzyl bromide in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 21% yield: mp 278-280° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.65-8.62 (m, 1H), 7.78-7.64 (m, 4H), 7.30-7.29 (m, 5H), 6.44-6.41 (m, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.30 (s, 2H), 4.38 (d, J=6.0 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.3, 161.9, 161.6, 153.9, 150.4, 140.7, 139.9, 132.3, 128.8, 128.7, 127.7, 127.2, 126.4, 126.0, 125.9, 123.8, 104.3, 97.7, 69.8, 43.1, 17.5; MS (ES+) m/z 500.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[CH3:17][N:18]([CH2:22][CH2:23]Cl)[CH2:19][CH2:20]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[CH3:17][N:18]1[CH2:22][CH2:23][N:16]([C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:20][CH2:19]1
Reactant: Nc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2ccc(N3CCCCC3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of 512 mg g (2.31 mmol) of 3-nitro-4-piperidin-1-yl-phenylamine (as prepared in the previous step) and 404 mg (2.10 mmol) of mechlorethamine hydrochloride in 15 mL of EtOH was added 1.45 g (10.5 mmol) of anh K2CO3 and the mixture heated to reflux under Ar for 48 h. The mixture was cooled to RT, concentrated in vacuo, extracted with EtOAc (3×20 mL) and the combined extracts filtered (Celite), and concentrated to a dark oil. Chromatography of the resulting residue on a 70-g silica SPE column with a gradient of 0-3% MeOH-dichloromethane afforded 456 mg (71%) of the title compound as a dark red solid: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 305.2 (M+H), found 305.1.
Reaction SMILES: [C:1]1([C:7]([CH3:12])([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(NCC(O)=O)C=CC=CC=1.ClC1C=CC=CC=1C(O)C(O)=O>>[C:1]1([C@:7]([CH3:12])([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(C(=O)O)c1ccccc1
Agent: O=C(O)C(O)c1ccccc1Cl
Agent: O=C(O)CNc1ccccc1
Product: C[C@@](O)(C(=O)O)c1ccccc1
Reaction time: 0.03 h

Procedure:
The analysis of phenyllactic acid was initially plagued with the same problems discussed for phenylglycine and 2-chloromandelic acid. However, in this case, adjustment of the solvent concentration in the nonchiral HPLC method led to a shift in the retention time of the acid, so that it no longer coeluted with the cell lysate peak. Following this, no problems were encountered with either the nonchiral or chiral methods. Representative nonchiral chromatograms of the product (1.9 min) and cyanohydrin substrate (3.7 min) are shown in FIG. 8A, while the chiral analysis of the acid is shown in FIG. 8B, with the L-enantiomer eluting at 2 min and the opposite enantiomer at 6 min.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[O:23])[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl.[CH2:67]([O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73])[CH3:68]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:67]([O:69][C:70](=[O:74])[CH2:71][CH2:72][NH:73][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:11]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=2)=[O:23])[C@H:8]2[CH2:9][CH2:10][C@@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)[CH3:68]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)[C@H]2CC[C@@H](C(C)(C)C)CC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid (0.3 g, 0.6 mmol), 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.13 g, 0.7 mmol) were dissolved in DMF (10 mL). Diisopropylethylamine (0.1 g, 0.7 mmol) and 3-aminopropionic acid ethyl ester, hydrochloride (0.07 g, 0.7 mmol) in DMF was added and the reaction mixture was stirred for 16 hours at 20° C. Ethyl acetate (80 mL) and water (50 mL) were added and the organic phase isolated. The aqueous phase was extracted with ethyl acetate (50 mL) and the organic phases combined, dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptane and ethyl acetate (4:1) to give 3-{4-[1-(cis-4-tert-butylcyclohexyl)-3-(4-trifluoromethoxy-phenyl)ureidomethyl]benzoylamino}propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:29]([CH:32]([CH3:34])C)=[C:30]=[O:31]>C(N(CC)CC)C>[C:30]([N:29]1[CH2:32][CH2:34][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:31])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1c(F)cccc1C(F)(F)F
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3c(F)cccc3C(F)(F)F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-fluoro-6-trifluoromethyl-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyric chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 8.71 (m, 1H), 8.26 (m, 2H), 8.13 (m, 1H), 7.98 (d, 1H), 7.79 (m, 6H), 4.01 (d, 1H), 3.60 (d, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.15 (t, 2H), 1.45 (m, 2H), 1.43 (q, 2H), 1.17 (m, 2H), 0.81 (t, 3H). LC/MS m/z 514 (M−H)−, 516 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].O>CS(C)=O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(Cn1ccc2ccccc21)OCC
Reaction time: 1 h

Procedure:
To a solution of 12 g of indole in 100 ml of dimethyl sulfoxide was added 6.5 g of sodium hydride at room temperature. The mixture was stirred at the same temperature for 1 hour, and 20 ml of bromoacetaldehyde diethyl acetal was added thereto, followed by further stirring at 50° C. for 1 hour. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 23 g of the title compound.
Reaction SMILES: [OH-].[K+:2].[NH:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[N:6][N:5]=[N:4]1>C(O)C>[NH:6]1[C:7]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([O-:15])=[O:14])=[N:3][N:4]=[N:5]1.[K+:2]
Reactant: O=C(O)C(=O)Nc1cccc(-c2nnn[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C(=O)Nc1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
Potassium hydroxide (1.27 g) was dissolved in 100 ml of ethanol and 5 g of 3-(1H-tetrazol-5-yl)oxanilic acid was added to the solution, followed by stirring at room temperature for 4 hours. Crystals separated out from the reaction solution were filtered off, washed with 50% aqueous solution of ethanol and dried under reduced pressure at 40° C. in the presence of phosphorous pentoxide to obtain 4.65 g of the objective potassium 3-(1H-tetrazol-5-yl)oxanilate (yield 85%). Decomposition point: not less than 300° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([NH:44][C:45](=[N:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])SC)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CCN(C(C)C)C(C)C>>[C:49]([NH:48][C:45](=[N:44][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])=[O:18])[NH:11][C:9](=[O:10])[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 78.4 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-(1-phenylethyl)ornithine amide (0.50 g; 1.0 mmol; from step (c) above), N,N'-bis(Cbz)-S-methylisothiourea (0.40 g; 1.1 mmol) and DiPEA (0.3 mL; 1.6 mmol) yielding 0.58 g (73%) of the sub-title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4]C)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C2CNC2)[CH:13]=[CH:14][C:15]=1[Cl:16].C=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]2[CH2:4][N:3]([CH3:1])[CH2:6]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: Clc1ccc(C(Oc2ccccc2)C2CNC2)cc1Cl
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC(C(Oc2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.2 mL, 1.313 mmol) was added to 20 mL of 3-((3,4-dichlorophenyl)(phenoxy)methyl)azetidine hydrochloride (300 mg, 0.870 mmol) dissolved in a methanol solution, and the mixture was stirred at room temperature for 1 hour. 37% formaldehyde aqueous solution (0.3 ml, 3.50 mmol) and acetic acid (0.2 ml, 3.50 mmol) were added to the reaction mixture, and NaBH(OAc)3 (742 mg, 3.50 mmol) was added thereto, followed by stirring for one day. Thereafter, 1 mL of 1 N NaOH was added thereto, and the mixture was stirred for 30 minutes. The organic layer was washed with distilled water, and the organic layer was adjusted to pH 7 using a 1 N NaOH aqueous solution, and extracted with methylene chloride (3*30 mL) and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain a colorless liquid, which was purified by flash chromatography (methylene chloride:methanol (9:1, v/v)). The product was identified as a single compound by TLC (methylene chloride:methanol (9:1, v/v)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][CH:32]([F:41])[C:33]1[CH:34]=[CH:35][C:36]([F:40])=[C:37]([CH:39]=1)[NH2:38].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[C:33]([CH:32]([F:31])[F:41])[CH:34]=[CH:35][C:36]=3[F:40])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cc(C(F)F)ccc1F
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)F)ccc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 5.8 %

Procedure:
The title compound was prepared by following the same procedure as described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 5-(difluoromethyl)-2-fluoroaniline (Intermediate-46, 0.097 g, 0.600 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.13 (s, 2H), 7.07 (t, J=55.5 Hz, 1H), 7.33-7.52 (m, 6H), 8.76 (d, J=6.9 Hz, 1H), 10.24 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 519.20.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][C:7]1[C:12]([CH:13]=O)=[C:11]([CH3:15])[CH:10]=[CH:9][N:8]=1>O.C(O)C>[CH3:6][C:7]1[C:12]([CH:13]=[N:2][OH:3])=[C:11]([CH3:15])[CH:10]=[CH:9][N:8]=1
Reactant: NO
Reactant: Cc1ccnc(C)c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccnc(C)c1C=NO
Temperature: 65 °C
Yield: 88.4 %

Procedure:
A solution of hydroxylamine hydrochloride (0.21 g, 3.0 mmol) and sodium hydroxide (0.12 g, 3.0 mmol) in water (1.9 mL) was added to a solution of 2,4-dimethyl-3-pyridinecarbaldehyde (0.35 g, 2.6 mmol) in ethanol (3.8 mL). The solution was heated in a 65° C. oil bath for 2 hours. The mixture was concentrated and the residue diluted with water and filtered. The resulting white solid was dried in a 45° C. vacuum oven with P2O5 to yield 2,4-dimethyl-3-pyridinecarbaldehyde oxime (345 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=5 Hz, 1H), 7.08 (d, J=5 Hz, 1H), 2.48 (s, overlapping DMSO), 2.33 (s, 3H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[C@H:24]1[C@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:27]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:25]1)(=O)=O.[C:63]([CH2:67]O[Na])([F:66])([F:65])[F:64]>C(CO)(F)(F)F>[CH2:47]([O:46][C@H:27]1[C@H:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)[C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5][CH2:67][C:63]([F:66])([F:65])[F:64])[O:25][C@@H:26]1[CH2:54][O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCOS(C)(=O)=O)cc2Cl)cc1
Reactant: FC(F)(F)CO[Na]
Solvent: OCC(F)(F)F
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCOCC(F)(F)F)cc2Cl)cc1
Reaction time: 9 h

Procedure:
The solution of 5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenethyl methanesulfonate (58 mg, 0.066 mmol) in 0.8 mL of 1.5 M CF3CH2ONa in CF3CH2OH was stirred at 60° C. under argon. After it was stirred for about 9 h, an additional 0.6 mL of 1.5 M of CF3CH2ONa in CF3CH2OH was added and the mixture was stirred for another 15 h at 60° C. After removal of the volatiles with a rotary evaporator under vacuum, the residue was partitioned between water and EtOAC. The organic layer was separated, washed with brine and dried over Na2SO4. Concentration gave the crude product, which was purified by preparative TLC to yield 30 mg of title compound. MS ESI (m/z) 896 (M+NH4)+, calc. 878.
Reaction SMILES: C(C1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1)#N.[C:36]([C:40]1[CH:72]=[CH:71][C:43]([C:44]([NH:46][C:47]2[N:52]=[CH:51][C:50]([C:53]3[CH:61]=[C:60]4[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:70])[CH3:69])[C:64]([O:66]C)=[O:65])[C:59]4=[O:62])=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)=[O:45])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:72]=[CH:71][C:43]([C:44]([NH:46][C:47]2[N:52]=[CH:51][C:50]([C:53]3[CH:61]=[C:60]4[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:69])[CH3:70])[C:64]([OH:66])=[O:65])[C:59]4=[O:62])=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)=[O:45])=[CH:42][CH:41]=1)([CH3:38])([CH3:37])[CH3:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)nc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)nc3)cc2C1=O
Yield: 88 %

Procedure:
The compound of example 492 was prepared analogous to the compound of example 40 by hydrolysis of the compound of example 491.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: COc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: COc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 74 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methoxy-2-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methoxy-2-thienyl)oxazole. The yield was 74%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 96-97° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:28])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:28][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 107 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.27 g, 0.47 mmol) prepared in Example 29b, triethylsilane (0.38 mL, 2.36 mmol), trifluoroacetic acid (0.47 g, 0.44 mmol) and dichloromethane (5.0 mL), to yield the title compound (0.21 g, 22%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[Cl:20])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2ccc(Cl)cc2)n1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(Cl)cc2)n1

Procedure:
A mixture of 2.58 g (7.1 mmol) 2-(4-Chloro-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 1.87 g (10.7 mmol) 2-Chlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate and to yield after evaporation of the product fractions 2.21 g (74%) of the title compound. MS (m/e): 421.0 (MH+, 100%)
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]([NH:25][NH:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=1)=[O:24])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:8]([CH2:22][C:23]1[O:24][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)=[N:26][N:25]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)NNC(=O)CN(Cc2ccccc2)S(=O)(=O)c2ccccc2C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1cccc(-c2nnc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3C(F)(F)F)o2)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
A mixture of N-benzyl-N-{2-[N′-(3-methanesulfonyl-benzoyl)-hydrazino]-2-oxo-ethyl}-2-trifluoromethyl-benzenesulfonamide (111 mg) and phosphorus oxychloride (1.5 g) was stirred for 18 h at 110° C. and then was concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:1 to ethyl acetate) to give N-benzyl-N-[5-(3-methanesulfonyl-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (74 mg) as a colorless foam. MS: 552.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[CH2:11]([N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)=[N:3]1)[CH3:12]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCn1nc(Br)c2ncccc21
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: O
Solvent: COCCOC
Product: CCn1nc(-c2ccc(O)cc2)c2ncccc21
Yield: 36.9 %

Procedure:
A mixture of 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (904 mg), (4-hydroxyphenyl)boronic acid (690 mg), Pd(PPh3)4 (139 mg), Na2CO3 (1.48 g), DME (17.5 mL), and H2O (3.5 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue purified by basic silica gel column chromatography (AcOEt) and crystallized from hexane/AcOEt to give the title compound (353 mg).