Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[OH:14][C:15]1[C:10]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:11]=2)[N:9]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCOc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCCOc1ccc2ncc(C(=O)OCC)c(O)c2c1

Procedure:
Prepared as in Example 1c from 4-propoxyaniline and diethyl 2-(ethoxymethylene)malonate as a white solid (65%). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.72-1.77 (m; 2H), 3.98 (t, J=6.0 Hz, 2H), 4.16-4.21 (m, 2H), 6.97-6.99 (m, 1H), 7.53-7.56 (m, 2H), 8.47 (d, J=5.2 Hz, 1H), 12.27 (s, 1H). MS 276 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[CH3:16][NH:17][C:18]([CH3:23])([C:20]([OH:22])=[O:21])[CH3:19].C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:17]([CH3:16])[C:18]([CH3:23])([C:20]([OH:22])=[O:21])[CH3:19])=[O:14]
Reactant: CNC(C)(C)C(=O)O
Reactant: O=C(Cl)CCCCCN1C(=O)C=CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCCCCN1C(=O)C=CC1=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of #248 (600 mg, 2.61 mM) in 10 mL of dichloromethane, N,2-dimethylalanine (306 mg, 2.61 mM) was added followed by triethylamine (1.09 mL, 7.84 mM). The reaction was allowed to stir at room temperature for three hours. Dichloromethane was added to the reaction and the organic layer was washed three times with water and two times with brine. The organic layer was separated and then dried over sodium sulfate before being concentrated in vacuo. The crude residue was purified by silica chromatography (0-30% methanol in dichloromethane) on silica which had been previously neutralized with triethylamine yielding a white solid #249 (127 mg, 16%). LC-MS (Protocol Q): m/z 309.0 [M−H−], retention time=0.96 minutes.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[CH2:4][N:5]([CH3:16])[S:6](=[O:15])(=[O:14])[C:7]3=[CH:8][S:9]2.[Cu][C:18]#[N:19].N1C=CC=CC=1.N>CCOCC.O>[CH3:16][N:5]1[CH2:4][C:3]2=[C:13]3[C:7](=[CH:8][S:9][C:10]3=[CH:11][CH:12]=[C:2]2[C:18]#[N:19])[S:6]1(=[O:15])=[O:14]
Reactant: N#C[Cu]
Reactant: CN1Cc2c(Br)ccc3scc(c23)S1(=O)=O
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CN1Cc2c(C#N)ccc3scc(c23)S1(=O)=O
Temperature: 190 °C

Procedure:
1 g of 6-bromo-4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene-3,3-dioxide is added to 0.32 g of copper (I) cyanide and 10 ml of pyridine. The reaction mixture is heated to 190° C. for 7 h, then poured onto 10 ml of ammonia solution and combined with water and ether (30 ml of each). The aqueous phase is extracted with ether. The combined organic phases are washed with 10 ml of dilute hydrochloric acid and then dried over Na2SO4. After the solution has been evaporated down in vacuo it is purified by chromatography. Yield: 0.06 g. M.p. 238° C.
Reaction SMILES: CC1[N+]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[NH2:14])=CSC=1CCO.N1C=C2C(N=CN2)=NC=1.C(OP(O)(O)=O)[C@H]1[O:33][C@@H](/N=C(\N)/CNC=O)[C@H](O)[C@@H]1O.C1N=CN([C@@H]2O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]2O)C=1N>>[NH2:14][C:13]1[C:8]([CH2:7][OH:33])=[CH:9][N:10]=[C:11]([CH3:15])[N:12]=1
Reactant: N/C(CNC=O)=N\[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: Nc1cncn1[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: c1ncc2[nH]cnc2n1
Product: Cc1ncc(CO)c(N)n1

Procedure:
The following reactions comprise the biosynthesis of thiamine: Thiamine biosynthesis begins with purine metabolism. From here AIR synthetase, the fifth step in the pathway catalyzes the conversion of 5′-phosphoribosyl-N-formylglycinamidine (FGAM) to 5′-phosphoribosyl-5-aminoimidazole (AIR). 4-Amino-5-hydroxymethyl-2-methylpyrimidine is then formed in a series of reactions.
Reaction SMILES: CC1[C@@H:8]2[C:9](C)([CH3:10])[C@@H:6]([CH2:7]2)[C:4](=[O:5])[CH:3]=1.C(#N)C.O.CC[O:18][C:19]([CH3:21])=[O:20]>C(Cl)(Cl)(Cl)Cl>[C:4]([C@@H:6]1[CH2:7][C@H:21]([C:19]([OH:18])=[O:20])[C:9]1([CH3:10])[CH3:8])(=[O:5])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC1=CC(=O)[C@@H]2C[C@H]1C2(C)C
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A stirred solution of verbenone (about 10 g, 66.57 mmol) in CCl4: ACN: H2O (140 ml) NaIO4 (56.9 g, 266.3 mmol) followed by RuCl3.H2O (catalytic) were added at 0° C. and allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was diluted with EtOAc (about 200 ml), filtered through celite bed and the organic layer was separated, the aqueous layer extracted with EtOAc (100 ml×2) combined the organic layers dried with Na2SO4 and concentrated under reduced pressure. The resulting crude was stirred in hexane. Solid was filtered and dried under vacuum (8.56 g). 1H NMR (300 MHZ, CDCl3): δ 2.91-2.77 (m, 2H), 2.63 (q, 1H, J=9 Hz), 2.07 (s, 3H), 1.86-1.95 (m, 1H), 1.40 (s, 3H), 0.97 (s, 3H). Mass: [M+1]+ 171 (10%), [M+Na]+ 193 (72%). IR (KBr, cm−1): 3218, 1737, 1694, 1467, 1368, 1283, 1174, 1080, 836, 703. M.R: 109.5° C.-120.7° C.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(C1C=CC=C(O)C=1O)(C)(C)C>COCCOCCOC>[C:15]1([CH:14]2[CH2:13][CH:2]([C:1]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][CH:5]2[C:6]([O:8][CH3:9])=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1ccccc1
Reactant: COC(=O)/C=C/C=C/C(=O)OC
Agent: CC(C)(C)c1cccc(O)c1O
Solvent: COCCOCCOC
Product: COC(=O)C1CCC(C(=O)OC)C(c2ccccc2)C1
Temperature: 150 °C

Procedure:
In a 75 ml sealed tube, a stirred suspension of trans,trans dimethyl muconate (10.0 g, 58.8 mmol), two equivalents of styrene (13.5 ml, 117.6 mmol), neutral Al2O3 (300 mg of Aldrich 199974, 3 mass percent), and tert-butyl catechol (25 mg, 0.2 mol percent) in diglyme (20 ml, 2.9 M) is heated to 150° C. for 24 hours. After cooling to room temperature, the reaction mixture is filtered, transferred to a flask, and concentrated. The residue is redissolved in triglyme (0.5 M). Pd/Al2O3 catalyst is added (636 mg (0.5 mol percent) of Johnson-Matthey 5 percent Pd/Al2O3 #12) at room temperature. The flask is equipped with a reflux condenser, fritted gas dispersion tube, and internal Temperature probe. Under N2 flow (190 ml/min) and stirring (190 rpm) the mixture is heated to reflux for 63 hours whereby dimethyl phenyl-terephthalate is formed. Some dimethyl 2-phenyl-cyclohexane-1,4-dicarboxylate is also produced.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1)=[O:2].[CH:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:16](O)=[O:17])([CH3:11])[CH3:10]>>[CH:1]([C:3]1[S:7][C:6]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=[C:13]([O:12][CH:9]([CH3:10])[CH3:11])[CH:14]=2)=[N:5][CH:4]=1)=[O:2]
Reactant: Nc1ncc(C=O)s1
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Product: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(C=O)s2)c1
Yield: 40.8 %

Procedure:
N-(5-Formylthiazol-2-yl)-3-isopropoxy-5-phenoxybenzamide (460 mg) was prepared in 41% yield from 5-formyl-2-aminothiazole (600 mg, 4.7 mmol) and 3-isopropyloxy-5-phenoxybenzoic acid (800 mg, 2.95 mmol) following general synthetic description A.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]([C:28]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][C:31]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29]1)[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)(=O)C>CO.O>[C:38]1([C:28]2([CH:11]([OH:10])[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=3)[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH2:29]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)OC(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.5 %

Procedure:
Potassium carbonate (1.75 g, 12.7 mmol) was added to a solution of (RS)-1-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)-3-[3,5-bis(trifluoromethyl)phenyl]propan-1-yl ethanoate (Example 23, 410 mg, 0.773 mmol) in methanol (15 mL) and water (2 mL) and the mixture was stirred at room temperature for 48 hours, then at 50° C. for 24 hours. The mixture was cooled and the methanol was evaporated under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (334 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.68 (1H, s), 7.53 (2H, s), 7.4-7.3 (4H, m), 7.3-7.2 (1H, m), 3.95-3.8 (4H, m), 3.36 (1H, br d, J 9 Hz), 2.91 (1H, ddd, J 14, 10, 5 Hz), 2.64 (1H, ddd, J 16, 9, 7.5 Hz), 2.5-2.4 (1H, m), 2.3-2.2 (1H, m), 1.9-1.7 (3H, m) and 1.65-1.20 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([SH:9])[N:3]=1.CC(C)([O-])C.[K+].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CS(C)=O>[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:9][C:4]1[N:5]=[C:6]([NH2:8])[CH:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1cc(N)nc(S)n1
Reactant: Fc1cccc(CBr)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
4,6-diamino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100 ml) at room temperature under an atmosphere of nitrogen. Potassium tert-butoxide (1M in THF, 48.3 ml) was added followed by 2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and ammonium chloride. The organic phase was washed with ammonium chloride (3×) and brine, then dried over magnesium sulphate and evaporated to give the subtitled product as a white solid (12.2 g)
Reaction SMILES: [C:1]([O:6]CCN1CCNC1=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]([O:20]C)(=[O:19])C(C)=C>>[C:1]([OH:6])(=[O:5])[C:2]([CH2:4][C:15]([OH:20])=[O:19])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: C=C(C)C(=O)OCCN1CCNC1=O
Product: C=C(CC(=O)O)C(=O)O

Procedure:
28.50 g of a 25% strength by weight solution of N-(methacryloxyethyl) imidazolidin-2-one in methyl methacrylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:8])([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1cccc(C(=O)Nc2ccc(-c3c[nH]c(=O)cn3)cc2)c1
Yield: 60 %

Procedure:
5-[4-(3-Nitrobenzamido)phenyl]-2(1H)-pyrazinone was reduced with cyclohexene and palladium on charcoal in ethanol in a manner similar to that described in Example 6 to give the title compound (60%) m.p.>250° C.; δ(DMSO-d6) 8.01 and 8.10 (2H, ABq, pyrazinone ring protons), ##STR15## ν(Nujol mull) 1525 (--NHCO), 1660 (C=0) cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Cl.[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][Mg]Br)[CH3:10]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:11]([CH2:9][CH3:10])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:10]
Reactant: CCCCC(CC)C[Mg]Br
Reactant: Clc1ccccc1Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCCCC(CC)Cc1ccccc1CC(CC)CCCC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A dry 2 L 3-neck flask with attached reflux condenser and addition funnel, flushed with dry nitrogen, was charged with 1,2-dichlorobenzene (79.4 g, 540 mmol), Ni(dppp)Cl2 (3 g, 6 mmol), and 200 mL of dry Et2O. The addition funnel was charged with 2-ethylhexylmagnesium bromide (3M, 400 mL). The solution was cooled to 5° C. and the Grignard reagent was added dropwise to the reaction. After complete addition, the reaction was stirred at 5° C. for 30 min and then warmed to room temperature (RT). The reaction was then heated to reflux for 12 h. After cooling to RT, the reaction mixture was poured onto an ice/HCl (10%) solution and extracted with MTBE. The organic fractions were dried over anhydrous MgSO4 and then concentrated. The product was purified first by distillation followed by column chromatography with hexanes, and isolated as colorless oil (101 g, 62%).
Reaction SMILES: C12CC3CC(CC(C3)C1)C2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.[CH3:45][O:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([CH2:55][C:56]([OH:58])=[O:57])=[C:49]([CH2:59][N:60](C2C=CC=CC=2)[C:61]([CH3:63])=[O:62])[CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([CH2:55][C:56]([OH:58])=[O:57])=[C:49]([CH2:59][NH:60][C:61](=[O:62])[CH2:63][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:48]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1cc(CC(=O)O)c(CN(C(C)=O)c2ccccc2)cc1OC
Agent: C1C2CC3CC1CC(C2)C3
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)Cc2ccccc2)c(CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
2-[1-(3-Hydroxy)phenyl)-1-methoxymethylene]tricyclo[3.3.1.13,7]decane 3a (520 mg), triethylamine (800 μl) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (950 mg) were added to a solution of 4,5-dimethoxy-2-[(phenylacetamino)methyl]phenylacetic acid 7 (656 mg, 1.91 mmol) in anhydrous DMF (10 ml). The reaction mixture was stirred at ambient temperature for 6 hours. The mixture was concentrated under vacuum. Chromatography on silica gel using cyclohexane/EtOAc (v/v:40/60) as eluent gave the ether of 3-(adamantan-2-ylidene-methoxymethyl)phenyl enol ester of [4,5-dimethoxy-2-(phenylacetylaminomethyl)phenyl]-acetic acid 2 (606 mg, 53%) in the form of a white powder. M.p. 95° C. 1H NMR (CDCl3, 300 MHz) δ 7.21 (t, J=7.9 Hz, 1H), 7.15-7.00 (m, 6H), 6.91 (t, J=2.3 Hz, 1H), 6.84 (ddd, J=7.9 Hz, 2.3 Hz, 0.8 Hz, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 4.44 (d, J=5.3 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 2H), 3.81 (s, 3H), 3.53 (s, 2H), 3.30 (s, 3H), 3.25 (br s, 1H), 2.66 (br s, 1H), 1.90-1.55 (m, 12H). 13C NMR (CDCl3, 75 MHz) δ 150.6, 148.6, 148.5, 142.6, 137.3, 134.9, 132.9, 129.4, 129.1, 128.9, 127.3, 127.1, 124.1, 122.1, 120.4, 113.5, 112.9, 58.0, 56.1, 56.0, 43.9, 41.4, 39.3, 39.1, 38.3, 37.2, 32.2, 30.3, 28.3. M.S. (Maldi-T of, positive mode) m/z 634.27 [M+K]+, 618.30 [M+Na]+. Analysis calculated for C37H41NO6: C=74.60, H=6.94 and N=2.35. Analysis measured: C=74.25, H=7.09 and N=2.41.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCCC[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 19 h
Yield: 73.8 %

Procedure:
To a stirred solution of 30.1 (0.054 g, 0.11 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 19 hours. The reaction was then concentrated in vacuo, and 1 N HCl was added to bring the pH to 1. The resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The resulting product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 30 (40 mg, 76% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (2M−H)+, 491.2 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2nc(-c3ccccc3)ccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2nc(-c3ccccc3)ccc2Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 4-(3-chloro-6-phenyl-2-pyridyl)benzoate (1.00 g), 1M aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (20 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (5 ml) was added. The crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give 4-(3-chloro-6-phenyl-2-pyridyl)benzoic acid (0.83 g, yield 91%) as colorless crystals. melting point: 254–255° C.
Reaction SMILES: [C:1]([O-])(C)(C)C.[K+].C(OCC)(=O)CC(OCC)=O.Cl[C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([NH2:25])[CH:24]=1.[OH-].[K+].Cl>CS(C)=O.O>[CH3:1][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([NH2:25])[CH:24]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
Under argon atmosphere, a suspension of potassium tert-butanolate (71.6 g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with a mechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was added drop wise at 20-30° C. under ice bath cooling. To the thick white suspension was the added solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO (100 mL) and the red solution warmed up to 60° C. and stirred for 20 h at 60° C. The mixture was cooled to 23° C. and a solution of potassium hydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise. The mixture was then heated to 100° C. and stirred for further 4 h. The mixture was cooled to 23° C., diluted with water (ca. 1000 mL), acidified with 37% HCl 3 to pH 3, and extracted three times with tert-butyl methyl ether (TBME) The organic layers were washed with brine, dried over MgSO4 and evaporated to give a brown solid, which was triturated with hot heptane, filtered off and washed with heptane to give the title compound as a brown solid (50.0 g, 91%), which was used without further purification. MS (ISN) 218.9 [M−H].
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].OO>C(O)C.S(=O)(=O)(O)O>[CH2:6]([PH:2](=[O:4])[OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=[PH2][O-]
Reactant: C=CCCCCCC
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCC[PH](=O)O
Yield: 84.8 %

Procedure:
To a mixture of 95.1 g (0.897 mol) of sodium hypophosphite hydrate in 600 mL 95% ethanol, 23.8 mL of concentrated sulfuric acid was added. 1-Octene (33.6 g, 0.299 mol) was added to the stirred mixture followed by 1.69 g (0.0149 mol) of 30% hydrogen peroxide. The resulting mixture was refluxed for 8 hs, and then another 1.15 g (0.010 mol) of hydrogen peroxide was added and the reaction mixture was continued to reflux for another 8 hs. The resulting mixture was cooled, filtered, and then the ethanol was removed using a rotary evaporator. To the resulting residue, 200 mL water was added and then 50% sodium hydroxide solution was added until the solution became alkaline. The mixture was extracted twice with 200 mL diethyl ether, and the aqueous phase was then acidified with concentrated sulfuric acid. The aqueous layer was extracted with 200 mL ethyl acetate, and the organic layer was washed with saturated sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was decanted and the drying agent was washed with another 50 mL ethyl acetate. The combined organic layers were evaporated on a rotary evaporator. 45.2 g of n-octylphosphinic acid (84.8% yield) was obtained.
Reaction SMILES: C=O.[C:3](O)(=O)C.[BH4-].[C:8]([Na])#[N:9].N[C:12]1[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([OH:40])[C:31]=2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:24][CH:23]=1>C(#N)C.O>[C:44]([O:43][C:41]([C:31]1[C:32]([OH:40])=[C:33]([C:36]([F:39])([F:37])[F:38])[CH:34]=[CH:35][C:30]=1[CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:13]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH:17][C:12]=2[N:9]([CH3:8])[CH3:3])=[CH:27][CH:26]=1)=[O:42])([CH3:46])([CH3:45])[CH3:47]
Reactant: CC(=O)O
Reactant: N#C[Na]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3N)cc2)ccc(C(F)(F)F)c1O
Agent: C=O
Agent: [BH4-]
Solvent: O
Solvent: CC#N
Product: CN(C)c1cc(CC(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
36% aqueous formaline solution (0.5 ml), acetic acid (100 μl) and cyano sodium borohydride (36 mg, 0.59 mmol) were successively added to a solution of (2-amino-4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetic acid (50 mg, 0.096 mmol) obtained in Example 38 in acetonitrile (4 ml), and the mixture was stirred at room temperature overnight. After the reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride/methanol=20/1) to give the title compound as a yellow oil (48 mg, yield: 92%.)