Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14]
Reactant: C#CCCCO
Reactant: Fc1ccccc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: OCCCC#Cc1ccccc1F

Procedure:
1-Bromo-2-fluorobenzene [1072-85-1](3.0 g, 17 mmol, 1.0 equiv) and pent-4-yn-1-ol [5390-04-5](2.3 mL, 25 mmol, 1.5 equiv) were dissolved in acetonitrile (40 mL). CuI (0.13 g, 0.68 mmol, 0.04 equiv) and TEA (3.4 mL, 25 mmol, 1.5 equiv) was added to the stirred solution followed by tetrakis(triphenylphosphine)palladium(O) (0.39 g, 0.34 mmol, 0.02 equiv). The solution was heated at reflux for 16 hours. The solution was cooled, filtered through Celite, the Celite pad rinsed with EtOAc and the solvent removed by rotoevaporation. Column chromatography (9:1 hexanes:ethyl acetate) of the residue afforded pure 5-(2-fluorophenyl)pent-4-yn-1-ol Intermediate 60 (1.3 g, 43%). 1H NMR (600 MHz, DMSO-d6) δ: 7.42 (t, J=7.48 Hz, 1H), 7.38-7.32 (m, 1H), 7.22 (t, J=9.10 Hz, 1H), 7.14 (t, J=7.56 Hz, 1H), 4.50 (t, J=5.21 Hz, 1H), 3.49 (q, J=5.92 Hz, 2H), 2.47 (t, J=7.12 Hz, 2H), 1.66 (quin, J=6.68 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[S:5][CH:6]=1.N[C@@H](CC1C=CC([Cl:48])=CC=1Cl)CN1C(=O)C2C(=CC=CC=2)C1=O.C1C(=O)N(Cl)C(=O)C1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[S:5][C:6]=1[Cl:48]
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1cc(Br)cs1
Reactant: N[C@@H](Cc1ccc(Cl)cc1Cl)CN1C(=O)c2ccccc2C1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1cc(Br)c(Cl)s1
Temperature: 50 °C
Yield: 65 %

Procedure:
A solution of 1,1-dimethylethyl ((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (prepared according to Preparation 22), except substituting 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione for 2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.455 mmol) and NCS (61 mg, 0.455 mmol) in DMF (3 ml) was heated at 50° C. in a sealed tube for 2 hours. The solvent was removed and the residue was purified by biotage (30% Hex/EtOAc) to give the title product (140 mg, 65%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH:33]2[CH2:35][CH2:34]2)=O)=[CH:27][CH:26]=1>O1CCCC1.CCCCCC>[CH:33]1([C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:36])[F:37])=[CH:26][CH:27]=2)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:35][CH2:34]1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(C(F)(F)F)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
A stirred solution of 4.1 grams (0.04 mole) of diisopropylamine in 100 ml of tetrahydrofuran was cooled to -78° C., and 17.4 ml (0.04 mole) of 2.3 M n-butyllithium in hexane was added during a 15 minute period. Upon completion of addition, the reaction mixture was stirred at -78° C. for 15 minutes. After this time, 6.4 grams (0.04 mole) of ethyl (trimethylsilyl)acetate was added during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at -78° C. for 30 minutes, and 8.5 grams (0.04 mole) of cyclopropyl (4-trifluoromethylphenyl) ketone was added during a 5 minute period. After this time the reaction mixture was stirred at -78° C. for one hour, at -25° C. for one hour, and finally at ambient temperature for two hours. The reaction was then quenched with aqueous 5% hydrochloric acid. The mixture was then extracted with diethyl ether, and the combined extracts were dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 6.0 grams of ethyl 3-cyclopropyl-3-(4-trifluoromethylphenyl)propenoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>>[Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)c1
Reactant: CN(C)CCCl
Product: Cc1cccc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2Br)c1

Procedure:
The title compound was prepared essentially as described in Example 117 except that the compound of Example 126 was reacted with 2-(N,N-dimethylamino)ethyl chloride. mp 71° C., NMR, IR, MS 464, 466.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([N:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44]CC)=[O:43])[CH2:38][CH2:37]4)[S:33][C:34]=3[CH3:35])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([N:36]4[CH2:37][CH2:38][CH:39]([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]4)[S:33][C:34]=3[CH3:35])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(N3CCC(C(=O)O)CC3)sc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a mixture of ethyl 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylate (0.28 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylic acid as colorless crystals (0.23 g, yield 85%). Recrystallized from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH:9]([N:16]1C(=O)C2C(=CC=CC=2)C1=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH:9]([NH2:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Temperature: 65 °C

Procedure:
To a solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (23 g, 63 mmol) in THF (180 mL) and MeOH (180 mL) was added 85% hydrazine hydrate (37 mL, 630 mmol) slowly. The resulting mixture was heated to 65° C. for 15 hours. The reaction mixture was cooled to room temperature, then concentrated to dryness. The residue was purified by column chromatography on silica gel (dichloromethane:MeOH, 100:1, 1% NH3 H2O) to give (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester as a white solid. (Yield 7.4 g, 50%). 1H NMR (300 MHz, CDCl3): δ 7.35-7.24 (m, 5H), 4.81 (brs, 1H), 4.08-4.03 (m, 1H), 3.38-3.21 (m, 2H), 1.44 (s, 9H). LC-MS: [M+H]+ 237.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[C:19]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[C:24](N(OC)C)=[O:25])#[N:20].Cl>C1COCC1.O>[Cl:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([C:24](=[O:25])[C:23]2[CH:30]=[CH:31][CH:32]=[C:21]([C:19]#[N:20])[CH:22]=2)[CH:10]=1
Reactant: CON(C)C(=O)c1cccc(C#N)c1
Reactant: COc1cc(C(=O)O)c(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c(C(=O)c2cccc(C#N)c2)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A −78° C. solution of 2-bromo-4-chloro-5-methoxybenzoic acid (0.5 g, 1.88 mmol) in THF (15 mL) was treated with n-BuLi (1.6M in hexane) (1.7 ml, 2.82 mmol) and stirred for 1 h at −78° C. 3-Cyano-N-methoxy-N-methylbenzamide (0.35 g, 1.88 mmol) in THF (15 mL) was added dropwise and the reaction stirred for 1 h at −78° C., then overnight at rt. It was diluted with water (30 mL), acidified with 5N HCl (15 mL), and extracted with EtOAc (2×100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain 4-chloro-2-(3-cyanobenzoyl)-5-methoxybenzoic acid (0.5 g, 84%) (316.33 [M−H]).
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=[N:7]O)[C:4](=[O:6])[CH3:5].[Cl:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=1.O.C>C(#N)C>[Cl:10][C:11]1[C:16]([C:17]2[NH:18][C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:5])[N:7]=2)=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=1
Reactant: Cc1ccc(CN)c(Cl)n1
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccc(C)nc2Cl)[nH]c1C
Temperature: 5 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
A mixture of 0.7 g of 2,3,4-pentanetrione 3-oxime and 0.9 g of 2-chloro-6-methyl-3-pyridylmethylamine in 50 ml of acetonitrile was stirred at the reflux temperature for 4 hours. The reaction mixture was evaporated in vacuo to give an oil. The oil was boiled in 50 ml. of water, treated with activated charcoal and filtered. The filtrate was cooled at 5° C. to yield a precipitate. The precipitate was collected, washed with cold water and dried to give 0.25 g of the product of the Example as a white solid, mp 156°-158° C.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[C:25]#[CH:26]>CN(C=O)C>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:2][CH2:3]1)[C:25]#[CH:24]
Reactant: C#CCBr
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1CCN(c2cccc3c2CCC(=O)N3)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
To a mixture of 1 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 30 ml of DMF and 900 mg of sodium carbonate was added 491 mg of propargyl bromide and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Then, chloroform was distilled off and the residue was purified through silica gel column chromatography and recrystallized from chloroform to give 0.1 g of 5-[4-(2-propynyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 225°-226° C., pale yellow powders.
Reaction SMILES: [Na+].[Cl-:2].[CH:3]1[CH:4]=[CH:5][C:6]2[O:12][C@@H:11]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[S:28](=[O:30])(=[O:29])[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:20]3=[O:21])[CH2:10][CH2:9][C:7]=2[CH:8]=1>>[CH2:10]1[C@H:11]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[S:28](=[O:30])(=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:21])[O:12][C:6]2[C:7](=[CH:8][CH:3]=[CH:4][CH:5]=2)[CH2:9]1.[ClH:2]
Reactant: [Cl-]
Agent: O=C1c2ccccc2S(=O)(=O)N1CCCCNC[C@H]1CCc2ccccc2O1
Agent: [Na+]
Product: Cl

Procedure:
A ready-to-use infusion solution is prepared from the freeze-dried product according to Example 1 by reconstituting the lyophilizate with the aid of a 0.9% by weight NaCl solution and then diluting with this solution to a total volume of 500 ml. The ready-to-use solution is chemically stable on storage for at least 30 h at room temperature, i.e. the solution then still contains at least 90% unchanged repinotan.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1/[C:9](=[N:11]/[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH3:10].Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:17][C:14]([CH3:15])([S@:12]([NH:11][C@@:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:10])[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-5-bromo-phenyl)-(E)-ethylidene]-amide and ethyl 2-bromo-2,2-difluoroacetate, the product (3R)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluoro-5-bromo-phenyl)butanoate was obtained as an orange oil. MS: m/z=446.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](Br)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(NC(C)C)(C)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2c(OCc3ccccc3)cccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.580 g (0.825 mmol) of Pd(PPh3)2Cl2, 0.230 g (1.19 mmol) of Cul, and 5.09 mL (36.3 mmol) of diisopropylamine in 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 m/z (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:15][OH:16])[CH3:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:17][O:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28]Br)=[CH:22][C:21]=1[OH:30]>O1CCCC1>[CH3:17][O:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:16][N:15]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:8][CH:9]=2)[CH3:14])=[CH:22][C:21]=1[OH:30]
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCON=C(C)c2ccc(C(C)(C)C)cc2)cc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 38.9 %

Procedure:
To a slurry of sodium hydride (95%) (0.487 g, 20.3 mmol) in tetrahydrofuran (6 mL) was added 1-(4-tert-butyl-phenyl)-ethanone oxime (0.7021 g, 3.67 mmol) as a solution in tetrahydrofuran (18 mL) and the solution was allowed to stir at room temperature for 40 minutes. 4-(2-Bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester (0.908 g, 3.64 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred at room temperature 1 hour and then heated at reflux 3 days. The reaction was cooled, quenched with brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (5/95 to 10/90) afford 4-{2-[1-(4-tert-butyl-phenyl)-ethylideneaminooxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester (0.546 g, 39%) as a yellow oil which solidified on standing. mp=65.4-66.8° C.; mass spectrum (+ESI, M+H) m/z 386. 1H NMR (400 MHz, DMSO-d6); δ 10.63 (s, 1H), 7.69 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 6.55 (m, 2H), 4.42 (t, 2H), 4.31 (t, 2H), 3.75 (s, 3H), 2.14 (s, 3H), 1.28 (s, 9H). Elemental analysis: Calcd. for C22H27NO5: C, 68.55; H, 7.06; N, 3.63, Found: C, 68.91; H, 7.10; N, 3.60.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][NH2:38]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:38][CH3:37])=[O:34])=[CH:35][CH:36]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CN
Product: CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 40 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:23][CH2:22][C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[O:11])[S:8][C:4]=2[CH2:3]1.O.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:24])[CH2:23][CH2:22][C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]([OH:14])=[O:13])=[O:11])[S:8][C:4]=2[CH2:3]1
Reactant: CC1(C)CCc2nc(NC(=O)C(=O)OCc3ccccc3)sc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC1(C)CCc2nc(NC(=O)C(=O)O)sc2C1

Procedure:
The acids of Examples 26 to 37 are also prepared by hydrogenolysis of the corresponding benzyl esters, by adaptation of the following specific exemplary method. Benzyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzthiazol-2-ylcarbamoylcarboxylate (1 g.) in 25 ml. of 50:50 water:ethanol in the presence of 5% palladium on carbon (300 mg.) is hydrogenated at atmospheric pressure and room temperature until uptake of hydrogen is complete (in small excess of one equivalent to account for reduction of the catalyst). The catalyst is removed by filtration and the filtrate evaporated to dryness to yield 6,6-dimethyl-4,5,6,7-tetrahydrobenzthiazol-2-ylcarbamoylcarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH:48]([CH3:49])[CH3:50])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (262 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as a light brown oil (320 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([C:23](OCC)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([CH2:23][OH:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(CO)cc(-c2ccc(F)cc2)n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
Ethyl 5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (2.70 g) was dissolved in tetrahydrofuran (30 mL), and the mixture was cooled to −78° C. A 1.5 mol/L toluene solution (13.1 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was further stirred at −78° C. for 2 hr. 1 mol/L Hydrochloric acid (15 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate. The insoluble material was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3) to give the title compound as an oil (yield 1.09 g, 45%).
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.COCC(O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.S(=O)(=O)(O)O.OC=CC1C=CC=CC=1>C(OCC)(=O)C>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OC=Cc1ccccc1
Solvent: COCC(C)O
Solvent: C=Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(O)cc1

Procedure:
A solution was prepared by dissolving 100 parts by weight, as the total amount, of p-t-butoxystyrene and styrene (molar ratio was p-t-butoxystyrene:styrene=80:20) in 150 parts by weight of propylene glycol monomethyl ether. This solution was kept under a nitrogen atmosphere at 70° C. for 10 hr with 4 parts by weight of azobisisobutyronitrile supplied to proceed polymerization. Then, sulfuric acid was added to the reaction solution, and the resultant solution was kept at 90° C. for 10 hr to covert the p-t-butoxystyrene unit into a hydroxystyrene unit through deprotection. Ethyl acetate was added to the obtained copolymer, the resultant solution was washed with water 5 times, the ethyl acetate phase was collected, and the solvent was removed to obtain p-hydroxystyrene/styrene copolymer (hereinafter, referred as “alkali soluble resin (A-1)”).