Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22](#[N:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO.[NH4+].[Cl-]>CN(C=O)C.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:24][CH2:23][C:22]#[N:25])[C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2scc(Cn3c(=O)n(CCC#N)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in dry DMF (1.0 mL) are added acrylonitrile (0.012 mL, 0.19 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.008 mL, 0.017 mmol). The resulting mixture is stirred at room temperature for 2 hr and then Sat. NH4Cl (2 mL) is added along with water (30 mL). Then the mixture is extracted with EtOAc (3×30 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography affords 58 mg (98%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionitrile.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH:58](S(C3C(C)=CC=CC=3)(=O)=O)O)[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:70][O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.[OH-].[Na+].O>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH3:58])[C@@H:47]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:70][O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](C(O)S(=O)(=O)c3ccccc3C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
The compound (32.6 g, 30.3 mol) synthesized in Example 2 (2d) was dissolved in diethyl ether (600 mL) and lithium aluminium hydride (1.72 g, 45.4 mol) was added thereto, followed by heating of the mixture under reflux for 1 hour. After the reaction mixture was diluted with diethyl ether (200 mL), 1N aqueous NaOH solution (2.0 mL) and water (2.0 mL) were added thereto, followed by stirring of the mixture for 30 minutes. After celite filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 7:1-6:1, V/V) to obtain the desired title compound (15.0 g, yield 55%) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21][O:22][C:23]2[C:24]([F:33])=[C:25]([C:29]([F:32])=[CH:30][CH:31]=2)[C:26]([NH2:28])=[O:27])[S:18][N:17]=1)C1C=CC=CC=1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]2[N:20]=[C:19]([CH2:21][O:22][C:23]3[C:24]([F:33])=[C:25]([C:29]([F:32])=[CH:30][CH:31]=3)[C:26]([NH2:28])=[O:27])[S:18][N:17]=2)=[C:9]([OH:8])[CH:14]=1
Reactant: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3OCc3ccccc3)ns2)c1F
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3O)ns2)c1F
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
To a solution of 3-((3-(2-(benzyloxy)-4-chlorophenyl)-1,2,4-thiadiazol-5-yl)methoxy)-2,6-difluorobenzamide (0.05 g, 0.10 mmol) in dichloromethane (5 ml) was added methanesulfonic acid (0.50 ml, excess) at room temperature under nitrogen atmosphere and allowed to stir at same temperature for 90 min. After the completion of the reaction (TLC monitoring), the solution was cooled to 0° C. and basified with saturated NaHCO3 solution (aqueous) followed by extraction with EtOAc (3×25 ml). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated. The residue was washed with ether to get the desired product (0.012 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]O>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid(2.07 g, 11.2 mmol) and cH2SO4(0.5 ml) in MeOH(10 ml) was refluxed for 8 h. The solvent was evapolated. The residue was dissolved in AcOEt and washed with saturated NaHCO3 aqueous solution, water, brine, dried (Na2SO4), and concentrated to give 2.14 g(96%) of ivory solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1C1C=CC=CC=1.O1C=CC=C1C1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=CC([I:59])=C(O)C=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[I:59])[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: NCc1ccc(I)c(O)c1
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(I)c(O)c1
Yield: 80 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-Furan-2-yl-4-methoxymethylene-4H-isoquinoline-1,3-dione (60 mg, 0.22 mmol) and 5-Aminomethyl-2-iodo-phenol (58 mg, 0.23 mmol) in 80% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:16])[NH:14][CH3:15])=[O:11].[C:17](#N)C>CN(C=O)C.CC(N(C)C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH:15]=[N:14][C:13]([NH:16][CH3:17])=[N:12][C:10]1=[O:11]
Reactant: CC#N
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 105 °C

Procedure:
About 200 mg. of 1-(2',6'-dimethylphenyl)-3-methylamidinourea is introduced into a gas chromatograph hypo vial and dissolved in 1 ml. of acetonitrile. To the solution is added 0.2 ml. of DMF DMA reagent. The vial is sealed with crimper and heated at 105° C. for 15 minutes in an oven. Seven vials are made. The contents of the vials are then put into a long-neck round bottom flask and evaporated to dryness by a flask evaporator. The solid mass is dissolved in a mixture of 30 ml. of CH CL3 and 20 ml. of water and shaken vigorously in a 60 ml. separatory funnel. The aqueous layer is discarded and 20 ml. of water is added and shaken. The CH Cl3 layer is then taken off and about 10 g. of anhydrous Na2SO4 is added, the CH Cl3 solution is decanted into a flask and evaporated to dryness. The solid material is dissolved in pentanone-2 (about 80 ml.) at 70° C. The solution is concentrated and crystallizes upon cooling. The crystals are collected and dried in a desiccator with P2O5 with vacuum for one hour.
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([NH:11][C:12]3[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(N2CCCC2)n1
Reactant: C1CNCCN1
Product: c1c(NC23CC4CC(CC(C4)C2)C3)nc(N2CCCC2)nc1N1CCNCC1
Yield: 49.7 %

Procedure:
4-(1-Adamantylamino)-6-chloro-2-pyrrolidinopyrimidine is reacted with piperazine as described in Example 4 to give the title compound in a yield of 49.7%, m.p.: 152°-156° C.
Reaction SMILES: [OH-].[K+].C([O:10][C:11]([C@@H:13]1[N:18]2[C:19](=[O:32])[C@@H:20]([NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:17]2[S:16][CH:15]=[C:14]1[O:33][CH3:34])=[O:12])C1C=CC=CC=1.C(OC(C1N2C(=O)[C@@H](NC(=O)COC3C=CC=CC=3)[C@H]2SCC=1OC)=O)C1C=CC=CC=1.[Cl-].[Na+]>O1CCCC1.C(Cl)Cl>[O:24]([CH2:23][C:22]([NH:21][C@@H:20]1[C:19](=[O:32])[N:18]2[C@@H:13]([C:11]([OH:12])=[O:10])[C:14]([O:33][CH3:34])=[CH:15][S:16][C@H:17]12)=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccccc1
Agent: COC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C

Procedure:
15 ml of pre-cooled 0.1 N potassium hydroxide solution are added, whilst stirring, to a solution prepared at 0° C., of 454 mg (1 mmol) of an approx. 3:1 mixture of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid benzyl ester and 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid benzyl ester in 30 ml of tetrahydrofurane. The mixture is stirred for a further 5 minutes at 0° C., 100 ml of ice water and 100 ml of pre-cooled methylene chloride are then added and the whole is stirred vigorously. Addition of a little saturated aqueous sodium chloride solution causes the mixture to separate into two phases. The methylene chloride phase is separated off and the aqueous phase is washed with a further 30 ml of methylene chloride. The aqueous phase is covered with 50 ml of methylene chloride, 10 ml of 2 N hydrochloric acid are added and the mixture is thoroughly shaken. After separating off the organic phase, the aqueous phase is extracted twice more with 30 ml of methylene chloride at a time. The combined methylene chloride extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. The resulting white foam crystallises on addition of chlorofrom and diethyl ether and gives 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of melting point 142° C. (decomposition). IR spectrum (KBr): characteristic bands at 5.65, 5.75 and 5.95μ.
Reaction SMILES: C([O:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=O)C(C)(C)C.C[O-].[Na+]>CO>[OH:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC(C)(C)C(=O)OCn1ccc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCn1ccc2ccccc21
Yield: 30 %

Procedure:
1-(hydroxymethyl)indole is prepared by reaction of 1-(pivaloyloxy-methyl)indole with sodium methylate in methanol at ambient temperature (yield: 30%) according to the procedure described in the following publication: D. Dhanak, C. B. Reese J. Chem. Soc., Perkin Trans. 1 1986, 2181-2186. It was characterized by mass spectrometry and by 1H and 13C NMR.
Reaction SMILES: Cl[C:2]1(C#N)[CH2:7][CH:6]2[CH2:8][CH2:9][C:3]1([O:10][CH3:11])[CH:4]=[CH:5]2.[OH2:14]>C(O)C>[CH3:11][O:10][C:3]12[CH2:9][CH2:8][CH:6]([CH:5]=[CH:4]1)[CH2:7][C:2]2=[O:14]
Reactant: COC12C=CC(CC1)CC2(Cl)C#N
Reactant: O
Solvent: CCO
Product: COC12C=CC(CC1)CC2=O
Yield: 57 %

Procedure:
A solution of 2-chloro-1-methoxybicyclo[2.2.2]oct-5-ene-2-carbonitrile (14.0 g, 71 mmol) and Na2S.9H2O (34.0 g, 142 mmol) in ethanol (175 mL) was heated under reflux for 14 h. The solution was poured into H2O and extracted three times with ether. The combined extracts were washed with saturated aqueous NH4Cl solution, H2O, and brine. The organic layer was dried over Na2SO4, concentrated to the residue. The crude product was purified by column chromatography to afford 1-methoxybicyclo[2.2.2]oct-5-en-2-one (5.7 g, 57%). 1H NMR (CDCl3, 400 MHz) δ 6.46 (dd, 1H), 6.22 (d, 1H), 3.50 (s, 3H), 2.94 (m, 1H), 2.11 (m, 2H), 1.53-1.92 (m, 4H).
Reaction SMILES: Br[CH:2]=[CH:3][O:4][Si](C)(C)C.C([Li])(C)(C)C.[CH3:14][CH:15]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17][CH2:18][C:19](=O)[CH3:20].Cl>C(OCC)C.CCCCC>[CH3:20][C:19]([CH2:18][CH2:17][CH2:16][CH:15]([CH3:14])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:2][CH:3]=[O:4]
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: C[Si](C)(C)OC=CBr
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(=CC=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
1-Bromo-2-trimethylsilyloxyethylene (1 g, 5.3 mmol) in anhydrous ethyl ether (10 cc) is introduced under an argon atmosphere into a 50-cc round-bottomed flask. The mixture is cooled to -70° C. and a 1.2M solution (8 cc) of tert-butyllitium in pentane is then added. Stirring is performed for 90 minutes at -70° C. and then 6,10,14-trimethyl-2-pentadecanone (1.19 g) is added in solution in anhydrous ethyl ether (3 cc). The temperature is allowed to rise to about -15° C. and stirring is continued for 1 hour. The solution is cooled to -60° C. and 3N hydrochloric acid (7 cc) is then added over 15 minutes. Stirring is performed for 30 minutes at 10° C. After extracting with ether, washing the ether phases until neutral, drying the ether phases over magnesium sulphate, filtering and evaporating off the solvents, a product is obtained and is purified by flash chromatography. 3,7,11,15-Tetramethyl-2-hexadecenal (1.05 g) is thus obtained and is characterized by its infrared spectrum and its proton nuclear magnetic resonance spectrum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][CH2:18][O:19][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]>[Pd].O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(C#CCOC)c2c1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(CCCOC)c2c1C
Reaction time: 20 h

Procedure:
A mixture of 4-(3-methoxy-prop-1-ynyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.6566 g, 0.00977 mol, Example 22, Step 1) and 10% palladium on activated carbon (705 mg) and tetrahydrofuran (60 mL) was stirred under a hydrogen atmosphere (balloon) for 20 hours. After filtering the mixture through a celite pad the resulting solution was reduced to dryness furnishing 2.46 g (91%) of of 4-(3-methoxy-propyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a clear oil. MS (ES) m/z: 277.1 (M+H)+, 553.3 (2M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][C@H:10]([CH3:43])[O:11][C:12]1[CH:13]=[C:14]([C:29]2[NH:33][C:32]([C:34]3[O:35][CH:36]([C:39](OC)=[O:40])[CH2:37][N:38]=3)=[CH:31][CH:30]=2)[CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:17]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][C@H:10]([CH3:43])[O:11][C:12]1[CH:13]=[C:14]([C:29]2[NH:33][C:32]([C:34]3[O:35][CH:36]([CH2:39][OH:40])[CH2:37][N:38]=3)=[CH:31][CH:30]=2)[CH:15]=[C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:17]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)OC)O3)[nH]2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(CO)O3)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Lithium aluminum hydride (17.0 mg, 0.448 mmol) was suspended in tetrahydrofuran (2 mL). Methyl 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylate (77.0 mg, 0.146 mmol) synthesized in Example (27b) was dissolved in tetrahydrofuran (2 mL), followed by dropwise addition at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 30 minutes, water (17 μL) and an aqueous sodium hydroxide solution (5M, 68 μL) were added dropwise slowly and sequentially. After filtration through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired compound (54.1 mg, yield 74%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[C:11]([OH:14])(=[O:13])[CH3:12].ON1C(=O)N(O)C(=O)N(O)C1=O.O=O>[Ti].C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[C:8]([OH:10])(=[O:9])[C:5]1[CH:6]=[CH:7][C:12]([C:11]([OH:14])=[O:13])=[CH:3][CH:4]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Mn+2]
Agent: [Ti]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a 500-ml titanium autoclave equipped with a stirrer and a pressure gauge, 15.36 g of p-toluic acid, 104.0 g of acetic acid, 0.066 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (1,3,5-trihydroxyisocyanuric acid) (0.33% by mole relative to p-toluic acid), 0.112 g of cobalt(II) acetate.4H2O and 0.277 g of manganese(II) acetate.4H2O were placed. The autoclave was charged with 2 MPa of oxygen gas and 2 MPa of nitrogen gas and placed in a heated oil bath. The mixture was stirred at 150° C. for 1 hour. After the completion of the reaction, the autoclave was placed on cold water to cool down the reaction mixture quickly. The resulting mixture was analyzed by high performance liquid chromatography and was found to yield terephthalic acid in 63% yield at 68% conversion of p-toluic acid.
Reaction SMILES: C([O:8][C:9](=[O:36])[CH:10]([NH:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:26])=[CH:20][CH:19]=1)[CH2:11]C(C)C)C1C=CC=CC=1.[CH2:37]1[CH2:41]OC[CH2:38]1>CO.[OH-].[OH-].[Pd+2]>[CH3:11][C:10]([NH:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:26])=[CH:20][CH:19]=1)([CH2:38][CH2:37][CH3:41])[C:9]([OH:8])=[O:36]
Reactant: C1CCOC1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC(C)(NC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)cc1)C(=O)O

Procedure:
A mixture of 4-methyl-2-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-pentanoic acid benzyl ester (4.0 g) and palladium hydroxide on carbon (1.0 g) in 200 ml of MeOH and 200 ml of THF was shaken on a Parr apparatus under 30 p.s.i. of H2. After 2 h the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 3.6 g of the title compound as a white solid. MS [M+1]+398.3; 1H nmr (400 MHz, DMSO-d6) δ0.79 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.4 Hz, 3H), 1.44-1.63 (m, 3H), 2.21 (s, 3H), 3.36-3.40 (m, 2H), 4.15-4.20 (m, 1H), 6.91 (t, 1H), 7.09-7.14 (m, 4H), 7.33 (d, 2H), 7.81 (d, 1H), 7.89 (s, 1H), 8.26 (d, 1H), 8.97 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=O)[N:18]([CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[S:40])[N:18]([CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.700 g, 1.66 mmol) in toluene (15 mL) and DME (15 mL) was added Lawesson's reagent (1.058 g, 2.66 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.540 g, 74%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, J=8.8 Hz, 1H), 6.67 (br, 1H), 6.39 (m, 1H), 6.36 (m, 1H), 4.88 (d, J=15.2 Hz, 2H), 4.74 (m, 1H), 4.27 (m, 2H), 4.19 (m, 2H), 3.97 (m, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.14 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]1.[NH2:20][C@@H:21]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23]>>[CH2:41]([O:40][CH2:39][C@H:21]([NH:20][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH2:15][CH2:14]1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccccc1N1CCN(CC(=O)O)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COc1ccccc1N1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 38.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-methoxyphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 217, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-methoxyphenyl)piperazin-1-yl)acetamido)propanamide (19 mg, 38.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (1H), 5.02 (d, 1H), 7.61 (d, 2H), 7.25-4.30 (m, 4H), 7.20-7.23 (m, 3H), 4.00-7.04 (m, 3H), 6.85-6.98 (m, 5H), 4.71 (m, 1H), 4.53 (s. 2H), 3.80 (m, 1H), 3.77 (s, 3H), 3.72 (m, 1H), 3.05 (d, 2H), 2.99 (m, 4H), 2.62 (m, 4H). MS (EI) for C35H37FN4O5. found 613.6 (MH+).