Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24][OH:25].[CH3:26][Si]([CH:30]=[N+:31]=[N-])(C)C>C(Cl)Cl>[CH3:24][O:25][C:12]1[C:11]([C:30]#[N:31])=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1.[CH3:24][O:25][C:12]1[C:11]([C:15]([O:17][CH3:26])=[O:16])=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OC
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C#N

Procedure:
To a solution of 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (50 mg, 0.15 mmol) from Example 1, Step C (containing a trace of the 3-nitrile starting material) in methylene chloride (3 mL) and methanol (1 mL) was added 2M trimethylsilyldiazomethane in hexanes until the yellow color persisted. The volatiles were removed under a stream of nitrogen and the residue was separated by preparative TLC on silica gel (eluted with 30% ethyl acetate in hexanes) to obtain 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-nitrile (A) and methyl 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxylate (B) as minor products (along with some of the N-alkylation by-products). The main product was the expected methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (same product as obtained in Example 1, Step D).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.Cl.[NH2:14][C@@H:15]([C:20]([OH:22])=[O:21])[C:16]([SH:19])([CH3:18])[CH3:17].[OH-].[K+]>O>[CH3:17][C:16]1([CH3:18])[S:19][CH:9]([C:6]2[C:5]([CH2:11][OH:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=2[OH:8])[NH:14][C@H:15]1[C:20]([OH:22])=[O:21]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ncc(CO)c(C2N[C@@H](C(=O)O)C(C)(C)S2)c1O
Reaction time: 16 h

Procedure:
2.03 g (10 mmoles) of pyridoxal hydrochloride are added to a solution containing 1.50 g (10 mmoles) of D-penicillamine and 0.56 g of potassium hydroxide in 10 ml of water. After stirring for 16 hours, the precipitate is filtered out to give the title acid in a yield of 2.26 g (75.7%) which can be purified by boiling with ethanol, m.p.: 201°-202° C., [α]D25 =+68.1°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[Cl:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)(Cl)Cl>[ClH:22].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(N3CCN(CCN)CC3)c2c1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCN1CCN(c2cccc3ccc(OC)cc23)CC1
Product: Cl

Procedure:
This compound was prepared as indicated in the preceding example, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine and ethyl chloroformate in chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)C(C)C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.O>ClCCl>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:38](=[O:39])[C:37]([C:29]1[CH:28]=[C:27]([C:26]([F:25])([F:43])[F:44])[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=1)([CH3:42])[CH3:41])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1cnccc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1cnccc1C(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
A solution of 397 mg (2 mmol) 3-amino-4-benzoylpyridine and 517 mg (4 mmol) N-ethyldiisopropylamine in 8 ml dichloromethane was cooled in an ice bath and a solution of 765 mg (2.4 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 8 ml dichloromethane was added dropwise. The reaction mixture was warmed to room temperature and was stirred overnight. Water (5 ml) was added and the organic layer was separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 235 mg (24%) of the title compound as orange oil.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16](Cl)Cl>[Ir]>[C:10]1([CH2:9][CH:8]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClCCl
Reactant: Cc1ccccc1C=Cc1ccccc1
Agent: [Ir]
Product: CC(Cc1ccccc1)c1ccccc1
Yield: 94 %

Procedure:
According to the general procedure, a solution of methyl stilbene (57 mg, 0.29 mmol) and iridium catalyst (S)-32 (9.4 mg, 0.0060 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was hydrogenated. Removal of the solvent in vacuo and standard purification gave 33 (54 mg, 94%) as a colorless oil; [α]20D −55.2 (c 1.00, CHCl3); Chiral GC analysis (Chirasil DEX-CB; program: 100° C. for 5 min, the 0.5° C./min to 140° C. for 5 min, then 2° C./min to 180° C. for 10 min) determined a 86:14 er (72% ee) [tR(minor) 66.26 min, tR(major) 66.66 min]; 1H NMR (300 MHz, CDCl3) 7.37-7.30 (m, 3H), 7.24-7.20 (m, 2H), 7.14 (d, 2H, J=7.2 Hz), 3.13-2.98 (m, 2H), 2.82 (q, 1H, J=7.8 Hz), 1.31 (d, 3H, J=6.6 Hz) ppm; 13C NMR (75 MHz, CDCl3) 147.0, 140.8, 129.1, 128.3, 128.1, 127.0, 126.0, 125.8, 45.0, 41.8, 21.1 ppm.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[CH:6]1([C@@H:9]2[C:16]3[CH:15]=[N:14][NH:13][C:12]=3[CH2:11][N:10]2[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:8][CH2:7]1>CC#N.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH:6]1([C@@H:9]2[C:16]3[CH:15]=[N:14][NH:13][C:12]=3[C:11](=[O:2])[N:10]2[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:7][CH2:8]1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1Cc2[nH]ncc2[C@H]1C1CC1
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+3]
Agent: [O-2]
Solvent: CC#N
Product: O=C1c2[nH]ncc2[C@@H](C2CC2)N1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To periodic acid (176 mg, 0.770 mmol) in CH3CN (2 mL) was added chromium(III) oxide (2.1 mg, 0.021 mmol). The reaction was stirred several minutes until it turned fluorescent orange and all solids were dissolved. The reaction was cooled to 0° C. and a solution of (R)-4-cyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (12) (50 mg, 0.14 mmol) in CH3CN (1 mL) was added. The reaction was stirred for 1 hr until TLC monitoring showed the disappearance of starting material. The reaction was filtered through a plug of Celite and concentrated in vacuo. The residue was taken up in EtOAc (2 mL) and washed with water (2 mL), 5% NaHSO3 (2 mL), brine (2 mL), dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified via column chromatography using EtOAc/hexane gradients to yield (R)-4-cyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (23) (15 mg, 28%) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:14][N:15]=2)=[O:10])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:14][N:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc(I)cc1)c1nnc(Nc2ccccc2F)o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(-c2ccccc2)cc1)c1nnc(Nc2ccccc2F)o1
Yield: 19 %

Procedure:
N-(4-Iodophenyl)-5-[(2-fluorophenyl)amino]-1,3,4-oxadiazole-2-carboxamide (Intermediate 35), 150 mg, 0.36 mmol), phenyl boronic acid (35 mg, 0.29 mmol), potassium phosphate (230 mg, 1.44 mmol), and tetrakis(triphenyl phosphine)palladium(0) (22 mg, 0.02 mmol) were stirred in DME (1.2 mL) and water (0.6 mL), in a microwave tube, and heated at 110° C. for 3 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL), and extracted with ethyl acetate (2×10 mL). The organics were combined, and dried by passing through a Varian Chem elut column. The filtrate was concentrated in vacuo and purified by preparative HPLC to afford the title compound as a cream solid (25 mg, 19%):
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:17]([O:24][CH3:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([CH:16]=1)[C:13]([NH2:15])=O>O1CCCC1>[ClH:7].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:17]([O:24][CH3:25])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([CH:16]=1)[CH2:13][NH2:15]
Reactant: COC(c1ccccc1)c1ccc(Cl)cc1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(c1ccccc1)c1ccc(Cl)cc1CN
Product: Cl
Yield: 133.1 %

Procedure:
To a suspension of LiAlH4 (280 mg, 7.37 mmol) in dry tetrahydrofuran (20 mL) under nitrogen atmosphere, a solution of 75 (1.0 g, 3.83 mmol) in THF (10 mL) was added and the mixture was refluxed for 3 h. After cooling, the excess of LiAlH4 was destroyed with a saturated solution of sodium sulfate. The mixture was filtered on MgSO4 and the filtrate concentrated in vacuo. The residue was partitioned between water (30 mL) and CH2Cl2 (30 mL). The aqueous-phase was separated and extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was dissolved in Et2O (5 mL) and treated with HCl/Et2O. The precipitated hydrochloride salt was filtered and triturated with dry Et2O (3×2 mL), obtaining 760 mg of product (yield 70%). 1H NMR (CD3OD, 300 MHz) δ 7.50-7.33 (m, 7H), 7.15 (d, J=9 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H). MS (m/e) (API-ES) 248 (M−Cl)+. m.p 119-121° C.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C>[Cl:21][C:20]1[C:15]([NH:14][CH2:13][C:12]2[CH:24]=[CH:25][C:9]([OH:8])=[C:10]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:11]=2)=[N:16][C:17]([CH3:23])=[N:18][C:19]=1[CH3:22]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OCC3CC3)c2)n1
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C)c(Cl)c(NCc2ccc(O)c(OCC3CC3)c2)n1

Procedure:
A solution of 2.0 g (4.7 mmol) of (4-benzyloxy-3-cyclopropylmethoxybenzyl)(5-chloro-2,6-dimethyl-pyrimidin-4-yl)amine (from example A5) in 50 ml of methanol and 20 ml of glacial acetic acid is admixed with 250 mg of Pd-on-carbon catalyst (type 38H, Johnson Matthey) and hydrogenated by circulation with hydrogen until about 1 equivalent of hydrogen (about 190 ml) has been taken up. After filtration to remove the catalyst, the solution is concentrated and the residue is chromatographed on silica gel (mobile phase: toluene/dioxane/ammonia=2:1:0.05). The fractions with Rf=0.35 are collected and concentrated. After crystallization from diisopropyl ether, 550 mg (35%) of the title compound are isolated as a beige powder. m.p.: 123-125° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([NH:19][C:2]([NH:3][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([Cl:5])=[CH:7][CH:8]=1)=[S:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#C[S-]
Reactant: CC(C)(C)N
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)NC(=S)NC(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a suspension of potassium thiocyanate (KNCS) (611 mg, 6.29 mmol) in dichloromethane (30 mL) was added 200 μL of PEG-400 followed by 4-chlorobenzoyl chloride (1.00 g, 5.71 mmol). The suspension was heated to 40° C. for 2 h, then cooled to room temperature and filtered into an addition funnel. The solution was added dropwise into an ice cold solution of t-butylamine (418 mg, 5.71 mmol) in dichloromethane (30 mL). The reaction was stirred for 20 minutes following the complete addition, and then it was concentrated in vacuo delivering N-(tert-butylcarbamothioyl)-4-chlorobenzamide as a yellow solid (1.49 g, 96% yield). 1HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 11.02 (s, 1H), 7.87 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=8.4 Hz), 1.51 (s, 9H).
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[C:12]([O:16][C:17](=[O:35])[NH:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:15])([CH3:14])[CH3:13]>C(COC)OC>[C:12]([O:16][C:17](=[O:35])[NH:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH2:24])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)NC2CCCC2NC(=O)OC(C)(C)C)cc1
Agent: [Li]
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)NC1CCCC1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of lithium granules (1.52 g, 226.6 mmol) and naphthalene (10.9 g, 85.0 mmol) in dry dimethoxyethane (350 mL) were stirred at room temperature for 2 h. The deep blue solution was then cooled to 0° C., a solution of 4 (10.0 g, 28.33 mmol) in dry dimethoxyethane (40 mL) was added dropwise over 20 min. The mixture was stirred at 0° C. for 5 h. The undissolved lithium was filtered off, and 1 N HCl solution (60 mL) was added to the filtrate. The organic layer was separated and extracted with 1 N HCl (50 mL×2). The aqueous layers were combined, extracted with diethyl ether (50 mL×3), and then basified with 2 N NaOH solution to pH 12-14. The aqueous solution was extracted with ethyl acetate (50 mL×5). Organic layers were combined, dried over Na2SO4, solvent was removed under vacuum to afford rac-1 as a colorless oil, which solidified under vacuum to a white solid (4.08 g, 72%). Rf=0.31 (hexanes/EtOAc 2:1). Mp 60-62° C. IR (film) 3301, 2967, 1689, 1526, 1453, 1390, 1365, 1250, 1170, 1045, 1020, 870, 781 cm−1. 1H NMR (300 MHz, CDCl3) δ 4.48 (s, hr, 1H), 3.48 (m, 1H), 2.99 (m, 1H), 2.14 (m, 1H), 1.98 (m, 1H), 1.70 (m, 2H), 1.45 (s, 9H), 1.38 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 156.1, 78.9, 60.5, 59.4, 33.0, 30.9, 28.4, 20.7. HRMS (EI) m/z calcd for C10H21N2O2 [M+1]+ 201.1603, found 201.1632.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:11]=[N:10]1.Br[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.[F-].[K+]>C1(C)C=CC=CC=1.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.CO>[CH3:8][N:9]1[C:13]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[CH:12][N:11]=[N:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnnn2C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 115.1 %

Procedure:
Triethylamine (0.28 ml, 2.00 mmol) was added to a mixture of 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole (781 mg, 2.1 mmol), methyl 4-bromobenzoate (430 mg, 2.0 mmol), and BIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) CHLORIDE (70.2 mg, 0.10 mmol) in toluene (10 ml) to give a yellow suspension. The reaction mixture was purged with N2, sealed and stirred at 100° C. for 3 hr. Potassium fluoride (465 mg, 8.00 mmol) and MeOH (2 mL) were added. The mixture was stirred at RT for 2 h, filtered on celite, and rinsed with EtOAc. The combined filtrates were concentrated and the residue was purified on a 25M biotage column to give 0.5 g of methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)benzoate as a tan solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][C:19]=1[CH:32]=O.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][C:19]=1[CH:32]1[O:4][CH2:1][CH2:2][O:3]1
Reactant: COC(=O)c1cc(C=O)c(Cl)nc1C(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(C2OCCO2)c(Cl)nc1C(=O)OC
Temperature: 25 °C

Procedure:
Ethylene glycol (14.3 mL, 0.255 mol), and a catalytic amount of p-toluenesulfonic acid monohydrate is added to a solution of 6-chloro-5-formyl-2,3-pyridinedicarboxylic acid, dimethyl ester, 5-(dimethyl acetal) (15.46 g, 0.051 mol) and toluene. The reaction mixture is heated at reflux temperature for 3 hours, cooled to room temperature, treated with ether, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as an orange oil (14.27 g, 93% identified by IR and NMR spectral analyses.
Reaction SMILES: [Na].[Cl-].C(C1C=CC(C[P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CC=1)(C)C.[PH5].CC(=CCCC(CC=[O:43])C)C>C(O)C>[C:24]1([P:11](=[O:43])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na]
Agent: [PH5]
Solvent: CCO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered!) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. nD25 =1.5172.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:154][CH2:155][O:156][Si](C(C)(C)C)(C)C)[S:12]([C:15]1[CH:20]=[C:19]([S:21](=[O:44])(=[O:43])[N:22]([CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][C:16]=1[Bi:45]([C:100]1[CH:105]=[CH:104][C:103]([S:106](=[O:129])(=[O:128])[N:107]([CH2:118][CH2:119][O:120][Si](C(C)(C)C)(C)C)[CH2:108][CH2:109][O:110][Si](C(C)(C)C)(C)C)=[CH:102][C:101]=1[S:130](=[O:153])(=[O:152])[N:131]([CH2:142][CH2:143][O:144][Si](C(C)(C)C)(C)C)[CH2:132][CH2:133][O:134][Si](C(C)(C)C)(C)C)[C:46]1[CH:51]=[CH:50][C:49]([S:52](=[O:75])(=[O:74])[N:53]([CH2:64][CH2:65][O:66][Si](C(C)(C)C)(C)C)[CH2:54][CH2:55][O:56][Si](C(C)(C)C)(C)C)=[CH:48][C:47]=1[S:76](=[O:99])(=[O:98])[N:77]([CH2:88][CH2:89][O:90][Si](C(C)(C)C)(C)C)[CH2:78][CH2:79][O:80][Si](C(C)(C)C)(C)C)(=[O:14])=[O:13])(C(C)(C)C)(C)C.C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:80][CH2:79][CH2:78][N:77]([CH2:88][CH2:89][OH:90])[S:76]([C:47]1[CH:48]=[C:49]([S:52](=[O:75])(=[O:74])[N:53]([CH2:64][CH2:65][OH:66])[CH2:54][CH2:55][OH:56])[CH:50]=[CH:51][C:46]=1[Bi:45]([C:100]1[CH:105]=[CH:104][C:103]([S:106](=[O:129])(=[O:128])[N:107]([CH2:118][CH2:119][OH:120])[CH2:108][CH2:109][OH:110])=[CH:102][C:101]=1[S:130](=[O:153])(=[O:152])[N:131]([CH2:142][CH2:143][OH:144])[CH2:132][CH2:133][OH:134])[C:16]1[CH:17]=[CH:18][C:19]([S:21](=[O:43])(=[O:44])[N:22]([CH2:33][CH2:34][OH:35])[CH2:23][CH2:24][OH:25])=[CH:20][C:15]=1[S:12](=[O:13])(=[O:14])[N:11]([CH2:10][CH2:9][OH:8])[CH2:154][CH2:155][OH:156])(=[O:98])=[O:99]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc([Bi](c2ccc(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c2ccc(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccc([Bi](c2ccc(S(=O)(=O)N(CCO)CCO)cc2S(=O)(=O)N(CCO)CCO)c2ccc(S(=O)(=O)N(CCO)CCO)cc2S(=O)(=O)N(CCO)CCO)c(S(=O)(=O)N(CCO)CCO)c1)N(CCO)CCO
Temperature: 50 °C
Yield: 79.5 %

Procedure:
13.59 g of the tris(2,4-bis(N,N-bis(2-t-butyldimethylsilyloxyethyl)sulfamoyl)phenyl)bismuthine preparation prepared in Example 5 was dissolved in a mixed solvent containing 13.6 ml of ethanol and 27 ml of dichloromethane, and 0.272 g of p-toluenesulfonic acid monohydrate was added thereto. The mixture was refluxed under heating at 50° C. for 6 hours, and then cooled to room temperature. The crystals were collected by filtration, washed with 29.5 ml of dichloromethane and dried. As a result, 5.54 g of the title compound was obtained as crystals with a melting point of 110°-113° C.
Reaction SMILES: [C:1]([N:3]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4](=[O:15])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O)[CH3:6])#[N:2].Cl[C:21]1[O:22][C:23]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=2[N:25]=1.C(=O)([O-])[O-:32].[K+].[K+]>C(#N)C>[C:1]([N:3]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4](=[O:15])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:32][C:21]2[O:22][C:23]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)=[CH:10][CH:9]=1)[CH3:6])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: CCCCN(C#N)C(=O)C(C)Oc1ccccc1O
Agent: [K+]
Solvent: CC#N
Product: CCCCN(C#N)C(=O)C(C)Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1

Procedure:
4.4 g (0.017 mole) of 2-(hydroxyphenoxy)propionic acid N-cyano-N-butylamide, 3.8 g (0.02 mole) of 2,6-dichlorobenzoxazole and 3.5 g (0.025 mole) of potassium carbonate are stirred in 50 ml of acetonitrile for 10 hours at room temperature. The salts are then removed by filtration and the filtrate is concentrated by evaporation. The residue is chromatographed through silica gel eluted with ethyl acetate/hexane (1:3), affording 2-[4-(6-chlorobenzoxazol-2-yloxy)phenoxy]propionic acid N-cyano-N-butylamide with a melting point of 91°-92° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:33](O)(=[O:37])[CH2:34][CH2:35][CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:32]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH:30][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:27]=[CH:26][C:25]=4[CH3:31])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CCCC(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCCC(=O)Nc1ccc(C)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Reaction time: 18 h

Procedure:
A mixture of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (54 mg), butyric acid (11 mg), EDAC (24 mg), HOBT (16 mg) and N-methylmorpholine (24 mg) in dry DMF (1 ml) was stirred at 20 C for 18 h. The mixture was then diluted with water (6 ml) and the resulting colourless solid collected by filtration and dried (42 mg).