Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:6].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:28]([NH:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)=[O:6])=[O:29])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: NCC(=O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
To a solution of 2-amino-1-(4-morpholin-4-ylphenyl)ethan-1-one dihydrochloride (3.71 g), (2S)-(tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid (5.73 g) and diphenylphosphoryl azide (3.48 g) in N,N-dimethylformamide (70 ml) was added dropwise N,N-diisopropylethylamine (4.41 ml) at 0° C. and the mixture was stirred for 20 minutes. The mixture was heated to ambient temperature and stirred for 8 hours. The resulting mixture was diluted with ethyl acetate (200 ml) and washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual solid was triturated with ethyl acetate-diisopropyl ether (1: 2) to give (2S)-(tert-butoxycarbonylamino)-N-[2-(4-morpholin-4-ylphenyl)-2-oxoethyl]-3-(2-pyridyl)-propanamide (2.06 g) as off-white crystals.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)(Cl)Cl.[CH3:18][S:19][C:20]#N.[OH2:22]>C1(C)C=CC=CC=1>[CH3:18][S:19][C:20](=[O:22])[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O
Reactant: CSC#N
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: CSC(=O)c1ccccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 1.69 g of diphenylamine in 10 ml of toluene was added 5.5 ml of a solution of 2.02M boron trichloride--toluene under ice-cooling, and the mixture was refluxed with heating on an oil bath for 1 hr. After ice-cooling, the reaction mixture was mixed with 1 ml of methyl thiocyanate and stirred at room temperature for 16 hr. The reaction mixture was mixed with 20 ml of water and refluxed with heating on an oil bath for 30 min. The insoluble materials were filtered off and the toluene layer was dried over anhydrous magnesium sulfate, chromatographed on a column of silica gel and eluted with toluene. The solvent was concentrated to give 1.03 g of N-phenylthioanthranilic acid S-methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.NN>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ncoc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncoc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a solution of 2-{6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (0.3 g, 0.69 mmol) dissolved in tetrahydrofuran (7 mL) was added hydrazine hydrate (171 mg, 3.4 mmol). After stirring for 24 hours at room temperature the precipitate formed was filtered. The filtrate was evaporated and purified on silica affording 6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (0.19 g, 85%).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)(=O)(O)O.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[C:7]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[OH:22])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(c1ccccc1)c1ccccc1O

Procedure:
A stock solution containing 6 wt% DCP, 15 wt% cumene, 1 wt% water and 50 ppm sulfuric acid with the balance composed of equimolar phenol and acetone was distributed among several melting point capillary tubes which were subsequently sealed and heated for various lengths of time in a stirred oil bath. The tubes were then quickly cooled by immersion in an ice bath and the contents were analyzed by gas chromatography. The amount of AMS formed increased with time up to a maximum yield and then declined as increased amounts of AMS dimers and cumylphenol were formed. Table IV records the maximum AMS yield obtained at each temperature as well as the heating time required to reach that yield. It is clear from the data of Table IV that best yields of AMS are obtained at temperatures over 100° C., e.g., 120° to 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:16])([CH3:15])[CH2:10][O:11][CH2:12]OC)[CH:4]=1.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH2:12][O:11][CH2:10][C:9]2([CH3:16])[CH3:15]
Reactant: COCOCC(C)(C)c1cccc(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C)(C)COC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 136.1 %

Procedure:
1-methoxy-3-[2-(methoxymethoxy)-1,1-dimethyl-ethyl]benzene (Intermediate 40, 300 mg, 1.3375 mmol) was dissolved in DCM (8 mL), the solution was cooled to −78° C. and titanium tetrachloride (37.928 mg, 0.2000 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. water (15 mL) was added and the mixture extracted with EtOAc (25 mL). Organics were dried over Na2SO4, filtered and evaporated to afford a crude that was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 90:10 as eluent affording the title compound (350 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)(O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)C.[OH-].[Na+]>I.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1ccccc1)(c1cccc(Cl)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Clc1cccc(C(=Cc2ccccc2)c2c[nH]cn2)c1
Temperature: 160 °C

Procedure:
A mixture of 1-(3 Chlorophenyl)-2-phenyl-l-(1-trityl-1H-imidazol-4-yl)ethanol, (Intermediate 15) mg; 0.9 mmol) in 57% aqueous HI (10 mL) and iPrOH (2 mL) was added red phosphorus (280 mg, 9.0 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH:.CH2Cl2 to give 4-(1-(3-chlorophenyl)-2-phenylvinyl)-1H-imidazole, as a solid, (86 rug), AGN-216677. 1HNMR (CD3OD, 300 MHz) δ 7.71 (s, 1H), 7.37-6.96 (m, 9H), 6.55 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(=O)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 3α-hydroxy-17β-methoxy-5β-androstane (250 mg, 0.82 mmol) in dry pyridine (2 mL) was treated with isobutyryl chloride (0.12 mL, 1.15 mmol), and N,N-dimethylaminopyridine (5 mg) at 5° C. After stirring the mixture at 5-10° C. for 1 hr the mixture was quenched with HCl solution (0.5 N, 25 mL). The mixture was extracted with EtOAc. The organic layer was washed with dil. HCl, water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:acetone mixture (9:1) gave 3α-isobutyryloxy-17β-methoxy-5β-androstane (266 mg); mp 82-87° C.; TLC Rf (hexane:acetone 9:1)=0.6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21]>>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared by the general method of Example 1 using 198 g (0.79 mole) of t-butoxycarbonyl-D-methionine (Boc-D-Met) and 99.5 g (0.79 mole) glycine methyl ester (Gly-OMe) hydrochloride. The title compound was isolated as an analytically pure solid without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)C(O)=O.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH:26]([O:28][CH2:29][CH3:30])[CH3:27])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=COCC
Reactant: CSc1ccc(-c2[nH]cnc2-c2ccccc2)cc1
Agent: O=C(O)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(C)n1cnc(-c2ccccc2)c1-c1ccc(SC)cc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A mixture of 12.0 g (0.045 mole) of 4-phenyl-5-(4-methylthiophenyl)-1H-imidazole, 6.7 g (0.052 mole) of dichloroacetic acid and 24.6 g (0.34 mole) of ethyl vinyl ether in 485 ml of toluene was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and was then stirred overnight with 130 ml of 25% aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with ether (2X). The organic fractions were combined, washed with brine and dried over anhydrous potassium carbonate. Removal of the solvent under vacuum afforded 15.3 g of an oil. The product was used in the subsequent reaction without purification.
Reaction SMILES: [N+](C1C=C(C=CC=1)C=O)([O-])=O.N[C@H]1CCNC1.[Cl:18]C1C(F)=C(F)C=C2C=1N(C1CC1)C=C(C(O)=O)C2=O.[Cl:38][C:39]1[C:40]([N:57]2[CH2:61][CH2:60][C@H:59]([N:62]=CC3C=CC=C([N+]([O-])=O)C=3)[CH2:58]2)=[C:41]([F:56])[CH:42]=[C:43]2[C:48]=1[N:47]([CH:49]1[CH2:51][CH2:50]1)[CH:46]=[C:45]([C:52]([OH:54])=[O:53])[C:44]2=[O:55]>>[ClH:18].[NH2:62][C@H:59]1[CH2:60][CH2:61][N:57]([C:40]2[C:39]([Cl:38])=[C:48]3[C:43]([C:44](=[O:55])[C:45]([C:52]([OH:54])=[O:53])=[CH:46][N:47]3[CH:49]3[CH2:50][CH2:51]3)=[CH:42][C:41]=2[F:56])[CH2:58]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC[C@H](N=Cc4cccc([N+](=O)[O-])c4)C3)c(F)cc2c1=O
Agent: N[C@H]1CCNC1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Product: Cl
Product: N[C@H]1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1

Procedure:
If, for example, the reaction mixture of 3-nitrobenzaldehyde and (S)-3-aminopyrrolidine is reacted with 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a one-pot reaction, the course of the reaction via the intermediately formed 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[(S)-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid to give 7-[(S)-3-amino-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride can be represented by the following equation: ##STR19##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1.O=CCCCNC(=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCCO)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: COc1ccccc1N1CCN(CCCC=O)CC1

Procedure:
4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butyraldehyde (30B) is prepared from 30A as described for 1E.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(CCl)NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1NCC(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (17.8 g), DIPEA (19.5 mL) and 4-fluoro-2-methyl-aniline (10.6 mL) in anhydrous DMF (174 mL) was stirred at 100° C. for 40 hours under a Nitrogen atmosphere. After cooling to r.t., the dark solution was partitioned between AcOEt (200 mL) and water (200 mL). The separated aqueous phase was extracted with further AcOEt (3×200 mL). The combined organic extracts were washed with water (200 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 2:8) to give a dark solid, which was triturated with CH to give the title compound as a beige solid (16.2 g).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](O[K])([CH3:29])([CH3:28])C.C1(C)C=CC(S(O[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:59]([O:25][CH2:24][CH:22]([CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:23][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]/[CH:48]=[CH:47]\[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:28][CH2:26][CH3:29])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]/[CH:51]=[CH:50]\[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH3:42]
Reactant: OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O[K]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
In 120 ml of xylene was dissolved 3.22 g (10 mmol) of 1-O-tritylglycerol, followed by addition of 3.36 g (30 mmol) of t-butoxypotassium under argon. After 5 minutes of stirring, 30 ml of a solution of 12.8 g (30 mmol) oleyl p-toluenesulfonate in xylene was added dropwise and the mixture was stirred under reduced pressure (20-30 mmHg) at ambient temperature for 30 minutes and, then, at 50 for 1 hour. The reaction mixture was then poured in ice-water and extracted with ether, and the extract was washed with water, dried, and concentrated. The residue was purified by column chromatography (silica gel/n-hexane-ethyl acetate) to provide 6.10 g (73%) of 1,2-O-dioleyl-3-O-tritylglycerol.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.C(Cl)(=O)CC.Cl.[CH3:14][O:15][C:16](=[O:21])[CH2:17][C:18](C)=[O:19]>O1CCCC1>[CH3:14][O:15][C:16](=[O:21])[CH2:17][C:18](=[O:19])[CH2:6][CH3:7]
Reactant: COC(=O)CC(C)=O
Reactant: CCN(CC)CC
Agent: CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
51.7 g (0.2 mol) of acetoacetic acid methyl ester magnesium enolate in 750 ml of tetrahydrofuran was suspended under nitrogen, 24.3 g (0.24 mol) of triethylamine was added and 38.9 g (0.408 mol) of propionyl chloride was instilled in 15 minutes. The reaction mixture was refluxed for 2 hours, cooled with ice water and hydrolyzed with 285 ml of 1 N HCl. The phases were separated and the water phase was extracted with tert-butyl methyl ether. The organic phases were combined and 140 ml of 10 percent ammonia solution was added with vigorous stirring within 15 minutes. After 1 hour, the phases were separated, dried with sodium sulfate and concentrated by evaporation. The residue was distilled with a Spaltrohr column (split-tube column) at 100 mbars. There was a yield of 23.9 g of 3-oxovaleric acid methyl ester with a purity of 96.0 percent, corresponding to 44 percent of theory. The acetoacetic acid methyl ester separated as the first runnings was able to be used again. The yield thus increased, relative to reacted acetoacetic acid methyl ester, to 69 percent. The boiling point of the product was 109° to 111 C./100 mbars.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH3:23])[CH:19]=[C:18]2[Cl:24]>>[ClH:24].[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH3:23])[CH:19]=[C:18]2[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Product: Cc1ccc2[nH]c(C)c(-c3cc(C)nc4c(Br)cccc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a, using 2,5-dimethylindole and 8-bromo-4-chloro-2-methylquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:2].CO.O.[BH4-].[Na+]>O1CCCC1.[Co](Cl)Cl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cc(F)cc(C#N)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(F)cc(CN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a mixed solution of tert-butyl 3-cyano-5-fluorobenzoate (3.00 g) in tetrahydrofuran (60.0 mL)-methanol (30.0 mL) was added a mixture of cobalt (II) chloride (4.40 g) and water (60.0 mL) under ice-cooling, and then sodium borohydride (1.54 g) was added under an argon flow, followed by stirring at room temperature for 30 minutes. The insoluble material was filtered through Celite and then washed with a mixed solvent of tetrahydrofuran-methanol-water (2:1:2, and then the filtrate was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium chloride solution, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform-methanol) to obtain tert-butyl 3-(aminomethyl)-5-fluorobenzoate (1.46 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29](/[C:43](/[NH:46]O)=[N:44]/[H])[CH:30]=[C:31]2[C:35]=1[NH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:44]=[C:43]([C:29]3[CH:30]=[C:31]4[C:35](=[C:27]([F:26])[CH:28]=3)[NH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]4)[N:46]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (150 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (280 mg) and HOBT (223 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (214 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (763 mg) was added. The reaction mixture was sealed and heated in Biotage Initiator using initial high to 120° C. for 2 hrs. After cooling the reaction, the solvent was removed. The residue was diluted with EtOAc (30 mL). The organic phase was washed with water (25 mL×4) and dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D165) (180 mg) as a white solid. MS (ES): C25H23FN4O4 requires 462; found 463.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5].[C:16]([O:20][C:21](=[O:33])[NH:22][C@H:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:2][O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][N:10]([CH2:31][C:28]3[CH:27]=[CH:26][C:25]([C@@H:23]([NH:22][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:33])[CH3:24])=[CH:30][CH:29]=3)[CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: COC(=O)c1cccc2c1CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 600 mg (2.64 mmol) 1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester hydrochloride and 657 mg (2.64 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 5 mL THF are added 452 μL (7.91 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C., 838 mg (3.95 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of 500 μl water and purified by HPLC (ACN/H2O/NH3).