Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.C([Si](C(C)C)(C(C)C)[O:21][CH2:22][C:23](=O)[CH2:24]O[Si](C(C)C)(C(C)C)C(C)C)(C)C.Cl>O1CCCC1.C(OC(=O)C)C>[OH:21][CH2:22][C:23]1[C:10]2[O:9][CH:13]=[CH:12][C:11]=2[C:14](=[O:16])[O:15][CH:24]=1
Reactant: O=C(O)c1ccoc1
Reactant: CC(C)[Si](OCC(=O)CO[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=c1occ(CO)c2occc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Add lithium diisopropylamine (0.454 mole) as a solution in tetrahydrofuran (100) mL to a solution of 3-furoic acid (23.36 g, 0.208 mole) at −78° C. over 30 minutes and stir for 1 hour at −78° C. To the resulting di-anion add 1,3-Bis-triisopropylsilanyloxy-propan-2-one as a solution in tetrahydrofuran (250 mL)over 30 minutes and stir at −78° C. for 1 hour and allow to warm to room temperature overnight. Quench the reaction with saturated aqueous ammonium chloride, pour into ethylacetate (1 L), add 1N HCL (1L) and separate the two layers. Wash the organic layer with 1N HCl, water, and brine, dry over magnesium sulfate, filter and concentrate to an oil. Dissolve the crude oil in 50% tetrahydrofuran and 50% 3N HCl (1L) and heat a reflux over night. Distill off tetrahydrofuran, concentrate under reduced pressure and, add acetonitrile remove it under reduced pressure to azeotrope off the remaining water. Dissolve the resulting crude oil in acetonitrile (250 mL) and add the solution to a solution of toluene containing a catalytic amount of p-toluenesulfonic acid at reflux that is fitted with a Dean Stark trap over 30 minutes. Toluene was added to replace the acetonitrile and water removed by distillation and azetroping (500 mL). Heat the solution at reflux until it appears no futher water is being removed. The hot solution was poured into an erlenmeyer flask and allowed to cool. Triturate the brown remaining residue with ethylacetate and methanol and combine it with the toluene solution and concentrate. Dilute with ethylacetate and wash with saturated aqueous sodium bicarbonate and brine, dry over magnesium sulfate and concentrate to an off white solid. Purification by flash chromatography eluting with hexane:ethylacetate gives 13.27 g (42%) of the tide compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1cccc(F)c1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3)nc2n(CCC)c1=O
Yield: 74.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using. 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.19 g (19.2 mmol) of 3-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 4.67 g (yield 75%) of Compound 37 as a pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)=[N:5][CH:4]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CO>[OH:23][B:14]1[C:13]2[CH:24]=[C:9]([O:8][C:6]3[S:7][C:3]([C:1](=[NH:2])[NH:27][OH:28])=[CH:4][N:5]=3)[CH:10]=[C:11]([CH3:25])[C:12]=2[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C#N)s3)cc(C)c21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)NO)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanothiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2.5 g, 7 mmol, 1 eq.) and hydroxylamine hydrochloride (1.21 g, 17.4 mmol, 2.5 eq.) in methanol was added triethylamine (3.41 ml, 24.5 mmol, 3.5 eq.). After stirring at room temperature overnight, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and then washed with water. The organic layers were collected, dried with Na2SO4 and evaporated to give the crude product as a yellow solid. The crude was used in subsequent steps without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].Cl>O>[C:13]([O:16][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1CCl
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)OCc1ccccc1S(N)(=O)=O

Procedure:
A mixture of 2-(chloromethyl)benzenesulfonamide (2.00 g), potassium acetate (6.0 g) and water (75 ml) was heated to reflux for 1.5 hour. The pH was adjusted to ca. 5.0 by addition of hydrochloric acid and the chilled mixture was filtered to give 1.05 of of shiny white solid, m.p. 131°-133°. 'H NMR δ(CD3)2CO 8.00-7.83 (M), 7.60-7.25 (M), 6.55 (brd s), 5.47 (s), 2.97 (brd s), 2.10 (s), consistent with the assigned structure.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:22])[NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=1)[CH3:14])([CH3:9])([CH3:8])[CH3:7].[Cl-].[NH4+]>C1COCC1.[Zn+2].[Br-].[Br-].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>[C:6]([O:10][C:11](=[O:22])[NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:1]2[CH2:3][CH2:2]2)=[CH:17][N:16]=1)[CH3:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: Br[Mg]C1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CC2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a stirred solution of ZnBr2 (7.85 g, 34.9 mmol) in THF (40 ml) was added cyclopropylmagnesium bromide (54.8 ml, 27.4 mmol) in THF dropwise at −78° C. After stirring at −78° C. for 30 minutes, the resulting solution was warmed to 0° C. and stirred at 0° C. for 30 minutes. (S)-tert-Butyl-1-(5-bromopyridin-2-yl)ethylcarbamate (Method 27; 3.00 g, 9.96 mmol) and Pd(PPh3)4 (0.576 g, 0.498 mmol) were added successively. The resulting mixture was stirred at 60° C. for 3 hours. After cooled to room temperature, 100 ml of saturated ammonium chloride was added, extracted with EtOAc and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc=4:1) to give the title compound as a white solid (2.04 g, 78%). 1H NMR (400 MHz) δ 8.30 (d, J=2.0 Hz, 1H), 7.37 (dd, J=1.6 and 8.0 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 4.61 (m, 1H), 1.92 (m, 1H), 1.37 (s, 9H), 1.29 (d, J=7.2 Hz, 3H), 0.96 (m, 2H), 0.69 (m, 2H). MS: Calcd.: 262. Found: [M+H]+263.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:22])([F:24])[F:23])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1
Reactant: NCc1ccc(F)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(F)cn3)c2CC1)C(F)(F)F
Yield: 62.6 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 2-aminomethyl-5-fluoro-pyridine (230 mg, 1.8 mmol) and a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.2 mmol) in toluene (4 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography to give 7-chloro-6-[(5-fluoro-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (302 mg, 64%). GC-MS m/z: 402 (M+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:21][OH:22])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]1[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](CO)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C)[C@H](CO)C1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
(S)-2-hydroxymethyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (5.66 g, 17.9 mmol) was dissolved in THF (10 mL) and cooled to 0° C. 2M LiAlH4 in THF (28.5 mL, 57.0 mmol) was added. The reaction mixture was stirred at reflux for 4 hours and then cooled to 0° C. and quenched with the drop-wise addition of 1M sodium hydroxide solution (20 mL). The reaction mixture was diluted with THF (50 mL), filtered and the filtrate was concentrated in vacuo to give 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (1.44 g, 56%) as a colourless oil which was used without further purification.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:37][CH:38]([CH3:40])[CH3:39])[C:14]([N:16]2[CH:25]([C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])=[CH:8][CH:7]=1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:37][CH:38]([CH3:40])[CH3:39])[C:14]([N:16]2[CH:25]([C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:30]=3)[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])=[CH:8][CH:7]=1
Reactant: CC(C)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(Cc1ccc(O)cc1)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1

Procedure:
3-(4-tert-Butoxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one (0.086 g, 0.16 mmol) was added to ice cooled trifluoroacetic acid (3 mL). After 1.5 hour the reaction was concentrated under reduced pressure to give a clear oil. This material was purified via a Gilson preparative HPLC resulting in the isolation of desired product 3-(4-hydroxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl- 1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one as a white solid after lyophilization, which proved 100% pure by HPLC at 254 and 214 nm, (LC/IMS; Measured MW (MH+): 481).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 79.5 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 79.5% of theory, C28H29N5O4 (499.6); Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=500.0; (M+H+Na)++=261.7.
Reaction SMILES: [C:1](Cl)(=[O:19])[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][CH2:16][CH2:17][CH3:18].[NH2:21][CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([O-:25])=[O:24].[K+]>>[C:1]([O:24][C:23](=[O:25])[CH:22]([NH2:21])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:19])[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][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)CC(N)C(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCC(=O)OC(=O)C(N)CC(C)C
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27 g (70 mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 13.03 g (77 mmol) of potassium 2-amino-4-methylpentanoate. The round bottomed flask is placed in an ice bath and the stearoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-4-methylpentanoic stearic anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=O)[C:17](=O)N2>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:16]([C:17]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:6]=1)[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:14]=1)[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-chloro-1H-indole-2,3-dione to replace 4-chloro-1H-indole-2,3-dione, 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (38%) as an orange solid: mp 172-173° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.60 (m, 2H), 7.36-7.27 (m, 11H), 7.22-7.17 (m, 1H).
Reaction SMILES: COC([N:5]1[CH2:12][C@@H:11]2[C@@H:7]([N:8]([CH2:13][CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:24]5[CH:28]=[N:27][N:26]=[CH:25]5)[CH:22]=4)[NH:17][CH:16]=3)[CH2:9][CH2:10]2)[CH2:6]1)=O.O.NN.[OH-].[K+]>C(O)CO>[N:26]1[N:27]=[CH:28][N:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:14][CH2:13][N:8]2[CH2:9][CH2:10][C@@H:11]3[CH2:12][NH:5][CH2:6][C@H:7]23)[CH:25]=1
Reactant: COC(=O)N1C[C@H]2CCN(CCc3c[nH]c4ccc(-n5cnnc5)cc34)[C@H]2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: c1cc2[nH]cc(CCN3CC[C@@H]4CNC[C@@H]43)c2cc1-n1cnnc1
Temperature: 100 °C
Yield: 62 %

Procedure:
A mixture of cis-1-[2-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid methyl ester (enantiomer B) (1.9 g, 5.0 mmol), hydrazine hydrate (1.2 ml, 25 mmol) and powdered potassium hydroxide (3.4 g, 61 mmol) in dry ethylene glycol (25 ml) was stirred and heated at 100° C. under nitrogen for 16 hours. Upon cooling the mixture was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane ) and n-butanol (×2). The combined extracts were evaporated and the residue was purified by chromatography on neutral alumina (grade III) (dry loaded), eluting with CH2Cl2 /MeOH/NH3 (95:5:0.5) to give the title amine (1.0 g, 62%) as a pale yellow foam; δ (250 MHz, d6 -DMSO) 1.33-1.48 (1H, m), 1.90-2.04 (1H, m), 2.14-2.26 (1H, m), 2.40 (1H, dd, J=11.8, 4.9 Hz), 2.56-2.96 (11H, m), 3.07 (1H, t, J=7.4 Hz), 7.30 (1H, dd, J=8.6, 2.1 Hz, Ar--H), 7.34 (1H, d, J=2.2 Hz, Ar--H), 7.48 (1H, d, J=8.6 Hz, Ar--H), 7.79 (1H, d, J=2.0 Hz, Ar--H), 9.03 (2H, s, Triazole-H), 11.11 (1H, br s, NH).
Reaction SMILES: C1C=CC(CC(NC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=O)=CC=1.[CH3:23][C:24]1([CH3:45])[S:28][C@@H:27]2[C@H:29]([NH:32]C(CC3C=CC=CC=3)=O)[C:30](=[O:31])[N:26]2[C@H:25]1[C:42]([O-:44])=[O:43].[K+]>O>[CH3:23][C:24]1([CH3:45])[S:28][C@@H:27]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:26]2[C@H:25]1[C:42]([OH:44])=[O:43]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [K+]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 38 °C
Reaction time: 9 h

Procedure:
120 g of carrier-bound penicillinacylase (moist weight) according to Example 4, with an activity of 1,160 U (NIPAB test) and 120 g of potassium penicillin G, are introduced into 1,300 ml of water and stirred for 9 hours at 38°C. and pH 7.8, as described in Example 14. The mixture is worked up as described in Example 14. The carrier-bound penicillinacylase is employed 5 times in succession for the enzymatic splitting reaction. The yields of 6-APS achieved are listed below:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)C=Cc1cccc(N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-(3-nitro-phenyl)-acrylic acid methyl ester (22) (10.0 g, 48 mmol) and SnCl2.2H2O (54 g, 240 mmol) in anhydrous ethanol (200 ml) was heated at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, then the solvent was partially evaporated by vacuum rotary evaporator (up to ca. ½ volume). The residue was poured in ice water, neutralised (pH˜7) with saturated Na2CO3 and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with saturated NaCl and dried (Na2SO4). The extract was filtrated through a small amount of silicagel and evaporated to give pure title compound in a form of white crystals (8.5 g, 99%). 1H NMR (CDCl3. HMDSO), δ: 3.69 (2H, br s); 3.79 (3H, s); 6.39 (1H, d, J=16.0 Hz); 6.61-7.03 (3H, m); 7.18 (1H, t, J=7.6 Hz); 7.62 (1H, d, J=16.0 Hz).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.CCCCCC.C([Li])CCC.[CH3:35][C:36]1[N:41]=[C:40]([CH:42]=[O:43])[CH:39]=[CH:38][CH:37]=1.O>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([CH:42]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[N:41]=2)[OH:43])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: Cc1cccc(C=O)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3cccc(C)n3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
4-(2-Iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxyquinoline (compound 116) (100 mg) was dissolved in tetrahydrofuran (7 ml) to prepare a solution which was then brought to −78° C. n-Butyllithium hexane solution (0.22 ml) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for 20 min. 6-Methyl-2-pyridine-carbaldehyde (57 mg) was dissolved in tetrahydrofuran (7 ml) to prepare a solution which was then added dropwise to the reaction solution, followed by stirring at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give [3-(6,7-dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol (73 mg, yield 73%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([C:17](=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:18](OCCCC)=[O:19])CCC[CH2:13][CH2:12]1.Cl>C(Cl)Cl>[CH:11]1([C:17](=[C:25]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:18][OH:19])[CH2:13][CH2:12]1
Reactant: CCCCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Reaction time: 2 h
Yield: 63.5 %

Procedure:
Diisobutylaluminum hydride (6.6 mL of 1M solution, 6.6 mmol) was added to a solution of butyl 2-cyclohexyl-3,3-bis(4-fluorophenyl)propenoate (0.8 g, 2.2 mmol) in 10 mL of methylene chloride at -70° C. After stirring for 2.0 hours the mixture was hydrolyzed by adding 2N hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 0.4 g of the title compound; m.p. =88°-90° C.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C#N)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 22 (0.200 g, 1.19 mmol) in tetrahydrofuran (5.0 mL), methanol (1.0 mL) and water (5.0 mL) at 0° C. was added lithium hydroxide (0.073 g, 1.79 mmol). The reaction was warmed to room temperature and stirred overnight whereupon the mixture was carefully acidified to pH 5.0 with 2 N hydrochloric acid and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried and concentrated to give the title compound (0.15 g, 82%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>CCO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)OC)c1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CCOC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 78 %

Procedure:
A mixture of methyl [3-[[(4,5-diphenyl-2-oxazolyl) methyl](ethoxycarbonyl)amino]phenoxy]acetate (0.90 g, 1.9 mmol), LiOH.H2O (82 mg, 2 mmol) and 95% EtOH (25 mL) was stirred at room temperature for about 25 hours. The EtOH was evaporated, the residue diluted with H2O and acidified with 2N HCl solution. Extraction with CH2Cl2 afforded an oil which was chromatographed first on a column of silica gel using CH2Cl2 /MeOH (9:1) as eluent and subsequently on a column of silica gel using hexanes/EtOAc/AcOH (12:7:1) as eluent to give [3-[[(4,5-diphenyl-2-oxazolyl) methyl](ethoxycarbonyl)amino]phenoxy]acetic acid (0.70 g, 80%). IR (film) 3000, 1710 cm-1 ; 1H NMR (CDCl3) δ1.22 (3H, t, J=8 Hz, OCH2CH3), 4.21 (2H, q, J=8 Hz, OCH2CH 3), 4.55 (2H, s, OCH2CO2CH3), 5.03 (2H, s, CH2 -oxazole), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.00 (2H, m, aromatic H), 7.20 to 7.40 (7H, m, aromatic H), 7.50 to 7.70 (4H, m, aromatic H), 10.49 (1H, bs, CO2H); MS m/z 473 (MH+).