Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1>CCO.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=5)=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1
Reactant: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1

Procedure:
A solution of (E)-3-(4-{6-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethylphenyl)-acrylic acid methyl ester (1.0 g) in 40 mL EtOH/THF (1:1) was hydrogenated over 5% Pd/C (300 mg) at one atm for 3 h. The catalyst was filtered through Celite and was washed with EtOH and THF. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (heptane/EtOAc=1:2) to give the title compound. MS: m/z 483 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(COC)OC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][CH:24]=[C:15]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:16]=3)[CH:21]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2cc(-c3ccccc3)ccc2c1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: Brc1ccc(-c2ccc3cc(-c4ccccc4)ccc3c2)cc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 73.2 %

Procedure:
Under an argon gas atmosphere, 20.0 g (70.7 mmol) of 4-bromoiodobenzene, 17.5 g (70.7 mmol) of 6-phenylnaphthalene-2-boronic acid, 1.63 g (1.41 mmol) of tetrakis(triphenylphosphine) palladium(0), 200 mL of toluene, 50 mL of dimethoxyethane and 107 mL of 2M sodium carbonate solution were mixed, and stirred for 10 hours at 90 degrees C. Subsequently, the reaction mixture was cooled down to room temperature, added with water and stirred for one hour. After the solid precipitated during the reaction was separated by filtration, the obtained solid was cleansed with water, methanol, dimethoxyethane and toluene in this order. By dissolving the obtained solid in toluene and refining the solution by silica-gel column chromatography, 18.6 g of 2-(4-bromophenyl)-6-phenylnaphthalene was obtained at an yield of 73%.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)#[CH:25]>>[C:26]1([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1cccc2ccccc12
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3cccc4ccccc34)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-ethynylnaphthalene. MS (+ESI) m/z: 423.2.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[B:34](OCC)([O:38]CC)[O:35]CC.OS(O)(=O)=O>C1COCC1>[B:34]([C:10]1[CH:9]=[C:8]([F:11])[C:4]([C:5]([OH:7])=[O:6])=[C:3]([O:12][CH3:13])[C:2]=1[F:1])([OH:38])[OH:35]
Reactant: CCOB(OCC)OCC
Reactant: COc1c(F)ccc(F)c1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1c(F)c(B(O)O)cc(F)c1C(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of 3,6-difluoro-2-methoxybenzoic acid (i-6b) (0.94 g, 5 mmol) in THF (5 mL) at −70° C. was added a solution of LDA [freshly prepared from diisopropylamine (1.51 g, 15 mmol) and n-BuLi (10M solution in hexane, 1.5 mL, 15 mol) in THF (15 mL). The resultant solution was stirred for 15 mins, followed by the addition of B(OEt)3 (1.46 g, 10 mmol). The mixture was stirred for 15 mins and then hydrolyzed with dilute aq. H2SO4. The organic phase was separated and the aqueous layer was extracted with Et2O. The combined organics were concentrated and the residue solid was washed with H2O and hexane, dried to give the title compound as white crystals. LCMS (ESI) calc'd for C8H7BF2O5 [M+H]+: 233. found: 233.
Reaction SMILES: [NH2:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].P(Cl)(Cl)(Cl)=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH3:36])[C:31](O)=[O:32])[N:29]=1.C[Si](CC(N)=O)(C)C>O.CC(C)=O.C(OCC)(=O)C.CN(C)C=O>[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH3:36])[C:31]([NH:1][CH:2]2[C:12](=[O:13])[N:4]3[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:32])[N:29]=1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
7-Amino-3-cephem-4-carboxylic acid (1.7 g.) and sodium bicarbonate (2.84 g.) were dissolved in a mixture of water (35 ml.) and acetone (35 ml.). On the other hand, phosphorus oxychloride (1.95 ml.) was added dropwise to a suspension of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer: 3.42 g.) in dry ethyl acetate (34 ml.) over 10 minutes at 0° to 6° C., and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a solution of trimethylsilylacetamide (2.39 g.) in ethyl acetate (5 ml.) at 0° to 6° C. over 20 minutes, and the mixture was stirred for 20 minutes. After phosphorus oxychloride (1.95 ml.) was added dropwise to the mixture at the above temperature over 10 minutes, the mixture obtained thus was stirred for 30 minutes. And further, dimethylformamide (1.29 ml.) was added dropwise to the mixture over 10 minutes at the same temperature and stirred for one hour to give a clear solution. The solution was added dropwise to the solution of 7-amino-3-cephem-4-carboxylic acid at -5° to 5° C., over 30 minutes, at pH 6.5 to 7.5, and the reaction mixture was stirred for one hour at the same temperature. Ethyl acetate (200 ml.) was added to the resultant solution, and the aqueous layer was separated, washed with methylene chloride, bubbled with nitrogen gas and adjusted to pH 4 with acetic acid. The solution was subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade mark: manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous solution of isopropyl alcohol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 2.0 g.). The product was identified with the authentic sample by IR and NMR spectrum.
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.C(O)C>[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)CCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Lithium hydroxide monohydrate (134 mg) was added to a solution of ethyl E-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoate (545 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoic acid (465 mg, yield 90%) as colorless crystals. m.p. 88-89° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]([F:34])([F:33])[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[F:34][C:24]([F:23])([F:33])[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O=C(N1CCNCC1)C(F)(F)F
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(C(=O)C(F)(F)F)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2,2,2-trifluoro-1-(piperazin-1-yl)ethanone to give 229. MS: (ESI+)=478.1
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[CH:4][CH:3]=1.C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([NH:41][CH2:36][C:35]#[N:34])=[O:10])=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)C[C@H](Nc1ccc(Br)cc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](Nc1ccc(Br)cc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2S)-2-(4-bromoanilino)-4-methylpentanoic acid (5.80 g, 20.28 mmol), PyBOP (11.08 g, 21.29 mmol), and aminoacetonitrile hydrochloride (3.75 g, 40.56 mmol) in dry DMF (150 mL) under dry nitrogen at 0° C. was added triethylamine (8.8 mL, 62.87 mmol) dropwise and the reaction was warmed to rt and stirred overnight. Aqueous sat. NaHCO3 was added and the product was extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 35/65 then 4/6) to afford (2S)-2-(4-bromoanilino)-N-(cyanomethyl)-4-methylpentanamide.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)CCCC(=O)O
Product: CC(=O)CCCC(=O)Cl

Procedure:
As shown in Table B, 5-ketohexanoic acid IX was reacted with thionyl chloride. The reaction mixture yielded 5-ketohexanoylchloride X which was recovered after distillation. The 5-ketohexanoyl chloride X intermediate was reacted with acetylene and aluminum chloride and converted into the chloro-diketone compound XI. The diketone compound was converted into the corresponding iodovinyl diol XIII by adding to the reaction mixture sodium iodide in a solvent such as acetone, and reducing the intermediate compound XII to the diol by adding sodium borohydride.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:56][C:57]1[N:62]=[C:61]([CH:63]=O)[CH:60]=[CH:59][CH:58]=1>>[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[CH2:63][C:61]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:56])[N:62]=1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: Cc1cccc(C=O)n1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1Cc1cccc(C)n1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (30 mg) was reacted with 6-methyl-pyridine-2-carbaldehyde according to General Procedure D. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH up to 1:1 hexanes EtOAc+5% MeOH) to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(6-methyl-pyridin-2-ylmethyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 845.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:33][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:23])=[CH:19][CH:20]=2)[N:4]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccc(F)cc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)OCc3ccc(F)cc3)cc2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
To a mixture of methyl {4-(dimethylamino)-2-[4-({[(4-fluorobenzyl)oxy]carbonyl}amino)benzyl]-pyrimidin-5-yl}acetate (45 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added 1N NaOH aq. (0.2 mL). The reaction mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure. The residue was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. This residue was dissolved with chloroform/methanol (10:1) and the insoluble was removed by filtration. The filtrate was concentrated under reduced pressure to give {4-(dimethylamino)-2-[4-({[(4-fluoro-benzyl)oxy]carbonyl}amino)benzyl]pyrimidin-5-yl}acetic acid (35 mg, 80%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[S:19])[C@@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si](C)(C)[Si](C)(C)C.II>C(Cl)Cl>[CH2:13]([C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:2])=[S:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC[C@H](CCCCCC)C(=S)OC
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Solvent: ClCCl
Product: CCCCCCCC[C@H](CCCCCC)C(O)=S
Temperature: 55 °C
Yield: 96.1 %

Procedure:
Alternatively, (S)-Methyl-2-hexylthiodecanoate (5.092 g, 16.8 mmol) was dissolved in methylene chloride (51 mL). To this solution was added hexamethyldisilane (5.4 mL, 26.4 mmol) and iodine (8.97 g, 35.3 mmol). The reaction was heated to 55° C. slowly and allowed to reflux for 2 hours. The reaction was cooled to rt and extracted with ethyl acetate (200 mL). The organic phase was washed with H2O (100 mL) followed by 0.1 N sodium bisulfite solution (2×200 mL) and brine. The organic phase was dried (MgSO4) and concentrated to yield (S)-2-hexylthiodecanoic acid (4.66 g, 16.15 mmol, 96%). [α]D =-49.7° (c=1.0, MeOH).
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O.[OH:26][C@H:27]([C@H:32]([NH:36][C:37](=[O:101])[C@H:38]([NH:60][C:61](=[O:100])[C@H:62]([CH2:70][C:71](=[O:99])[NH:72][C@H:73]([OH:98])/[CH:74]=[CH:75]/[CH2:76][CH2:77][S:78][C:79]([C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH2:39][S:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:63]([C@@H:62]1[C:61](=[O:100])[NH:60][C@H:38]([CH2:39][S:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:37](=[O:101])[NH:36][C@H:32]([CH:33]([CH3:35])[CH3:34])[C@@H:27]([OH:26])[CH2:28][C:29](=[O:31])[O:30][O:98][C@H:73](/[CH:74]=[CH:75]/[CH2:76][CH2:77][S:78][C:79]([C:92]2[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=2)([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[NH:72][C:71](=[O:99])[CH2:70]1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: CC(C)[C@@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](CC(=O)N[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1)[C@@H](O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)CC(=O)N[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OOC(=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of MNBA (54 mg, 0.16 mmol) and DMAP (38 mg, 0.31 mmol) in CH2Cl2 (29 mL) was added dropwise a solution of the acid 5A (137 mg, 0.13 mmol) in CH2Cl2 (117 mL) over 4.5 h, this was then stirred overnight at room temperature. The reaction mixture was washed sequentially with HCl (1M, 40 mL), sodium hydrogen carbonate (40 ml) and sat. brine (40 mL) before being dried (MgSO4), filtered and concentrated in vacuo to give a brown solid. Purification by column chromatography on silica gel (eluent 4:6-1:1 EtOAc/Hexane increased to 1:9 MeOH/CHCl3) gave 6A (79.4 mg, 0.08 mmol, 58%) as a white/brown solid: Rf 0.14 EtOAc/Hexane (4:6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[CH:21][C:20]([CH2:34]O)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:34][C:20]3[CH:21]=[C:22]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:27][CH:28]=4)[N:18]([CH3:17])[N:19]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(CO)cc1-c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)n(C)n3)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless solid.
Reaction SMILES: OC1C(C)=C(O)C=CC=1C=O.C(OCCl)C.C(N(CC)C(C)C)(C)C.C(OC[O:30][C:31]1[C:38]([CH3:39])=[C:37]([O:40][CH2:41][O:42][CH2:43][CH3:44])[CH:36]=[CH:35][C:32]=1[CH:33]=[O:34])C>>[CH2:43]([O:42][CH2:41][O:40][C:37]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[C:31]([OH:30])[C:38]=1[CH3:39])[CH3:44]
Reactant: CCOCOc1ccc(C=O)c(OCOCC)c1C
Agent: CCOCCl
Agent: Cc1c(O)ccc(C=O)c1O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOc1ccc(C=O)c(O)c1C

Procedure:
By following Example 2 procedure, 25.0 g of 2,4-dihydroxy-3-methylbenzaldehyde was reacted with 40.0 g of ethoxymethyl chloride (prepared from 23 g of diethoxymethane and 17.3 g of acetyl chloride) and 31.8 g of N,N-diisopropylethylamine to get 36.0 g of crude title product containing 11.5% of 2,4-bis(ethoxymethoxy)-3-methylbenzaldehyde by GC. Crude product was purified by column chromatography to get the title compound (25.0 g) as white solid. DSC: 43.1° C. (peak). IR (KBr): 3283, 3095, 3038, 2972, 2952, 2909, 2876, 2807, 2765, 2734, 1641, 1621, 1584, 1492, 1453, 1434, 1396, 1320, 1298, 1242, 1176, 1128, 1094, 1071, 1017, 978, 882, 849, 807, 777, 736, 691, 642, and 617 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 11.48 (s, 1H, exch. with D2O, OH), 9.73 (s, 1H, CHO), 7.35 (d, J=8.8 Hz, 1H, H-6), 6.78 (d, J=8.8 Hz, 1H, H-5), 5.33 (s, 2H, OCH2O), 3.74 (q, J=6.8 Hz, 2H, OCH2CH3), 2.12 (s, 3H, ArCH3), 1.23 (t, J=6.8 Hz, 3H, OCH2CH3) 13C NMR (CDCl3, 100 MHz): δ 194.91 (CHO), 162.11 (C-4), 161.30 (C-2), 132.72 (C-6), 115.72 (C-1), 114.26 (C-3), 105.82 (C-5), 92.81 (OCH2O), 64.76 (OCH2CH3), 15.06 (OCH2CH3), 7.47 (ArCH3). Mass (EIMS): 210.17 (M), 209.10 (M−1).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1OC1CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Yield: 86 %

Procedure:
A solution of 3-(7-isopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 13) Rt=2.104 min, 0.042 g, 0.098 mmol) in DCM (2 mL) and TFA (0.5 mL) was stirred at 25° C. for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-yloxy)-7-isopropyl-4(R)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (SFC (Table 1, Method 14), Rt=1.610 min, 0.036 g, 86%) as a pale yellow solid. LC/MS (Table 1, Method 5) Rt=2.077 min.; MS m/z: 331 [M+H]+.