Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([O:9][CH3:10])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([I:20])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-methoxy-aniline (20 g, 99 mmol) was dissolved in water (695 mL) and concentrated sulphuric acid (113 mL). The solution was cooled to 0° C. and sodium nitrite (7.5 g, 109 mmol) dissolved in water (32 mL) was added and stirred for 1 hour at 5-10° C. Potassium iodide (21.4 g, 129 mmol) dissolved in water (100 mL) was added slowly whilst the mixture was vigorously stirred. After addition, the mixture was allowed to warm to room temperature. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted with ethyl acetetate (3×). The combined organic phases were then washed with 1M NaOH, 1M Na2S2O3, 1M HCl, 1M saturated NaHCO3 and brine. The separated organic phase was dried (MgSO4), filtered and concentrated in vacuo. The product was purified by flash chromatography using silica gel and eluting with heptane/ethyl acetate 1:1. The product was identified from relevant fractions which were combined and concentrated in vacuo.
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>C1C=CC=CC=1>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:27](=[O:28])[CH:26]=[CH:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccccn1
Solvent: c1ccccc1
Product: COC(=O)C=CC(=O)c1ccccn1

Procedure:
A solution of 33.4 g of carbomethoxymethylene triphenylphosphine [Helv. Chim. Acta. 40, 1242 (1957)] in 500 ml of dry benzene under nitrogen is treated with 10 g of 2-(bromoacetyl)pyridine and heated at reflux temperature for 2 hours. The reaction mixture is cooled and filtered to remove carbomethoxymethyl triphenylphosphonium bromide. The filtrate, containing triphenylphosphine, is treated with methyl bromoacetate and heated at reflux temperature for 2 hours. Cooling and filtration removes additional phosphonium salt. The filtrate is concentrated in vacuo yielding the title compound.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH:23]3[CH2:28][CH2:27][CH:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:18]=2)[CH:13]=1)(C)(C)C>Cl.O1CCOCC1>[C:29]([CH:26]1[CH2:25][CH2:24][CH:23]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:33])=[O:5])[CH:21]=[CH:20]3)[CH2:28][CH2:27]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)CCNCCc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CCNCCC(=O)O)ccc3c2)CC1
Yield: 62.9 %

Procedure:
A solution of 3-{2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-ethylamino}-propionic acid tert-butyl ester (13 mg, 0.028 mmol) in 4 M of HCl in 1,4-dioxane (0.50 mL) was stirred at room temperature overnight. After the solvent was concentrated, the crude was purified via HPLC to give white solid (7 mg, yield: 49%). ESI-MS: 398.30 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.73 (d, 1H), 7.70 (d, 1H), 7.65 (s, 1H), 7.33 (dd, 1H), 7.21 (d, 1H), 7.09 (dd, 1H), 4.31 (m, 1H), 3.41-3.31 (m, 4H), 3.14 (t, 2H), 2.74 (t, 2H), 2.25 (d, 2H), 1.89 (d, 2H), 1.40 (m, 2H), 1.24 (m, 2H), 1.10 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:26][CH2:25][CH2:24][S:23]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:6]2([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=3)[S:26][CH2:25][CH2:24][S:23]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCC2)c1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C2(C3CCCC3)SCCS2)c1

Procedure:
Compound 10 was prepared from Compound 6 using the same procedure as described above for Compound 9. Yield 2.92 g (87%) as an oil. Rf=0.52 (hexane:ethyl acetate 92:8); IR (neat) 2955, 1206, 1066, 694 cm−1; 1H NMR δ 6.98 (d, J=2.19 Hz, 2H), 6.34 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.35–3.09 (m, 4H), 2.82–2.71 (m, 1H), 1.80–1.43 (m, 8H). 13C NMR δ 160.03, 149.37, 106.37, 98.35, 79.474, 55.35, 52.14, 38.79, 31.17, 25.73; MS: (ESI, Pos.) m/z 333 ([M+23]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:12]N)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].O.Cl.C(O[CH:19](OCC)[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29])C>C(O)C>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[NH:12][CH:19]=[C:20]2[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29]
Reactant: CCOC(CCCN1CCCCC1=O)OCC
Reactant: COc1ccc(NN)cc1OC
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc2[nH]cc(CCN3CCCCC3=O)c2cc1OC
Yield: 21.7 %

Procedure:
One dissolves 54 g of 3,4-dimethoxy phenylhydrazine hydrochloride in a mixture of 750 mls of ethanol, 750 mls of water and 350 mls of 5% hydrochloric acid. It is heated under a reflux, and then one adds over a period of 5 minutes a solution of 63 g of 1-(4,4-diethoxybutyl)-2-piperidone in 250 mls of ethanol. After heating under a reflux for 2 hours and then cooling, one eliminates the ethanol by distillation under reduced pressure (20 mm of mercury) and then extracts successively with 500 mls, 300 mls and 200 mls of methylene chloride. The combined organic phases are washed with 500 mls of water and then 500 mls of a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 mm of mercury). The residue (58 g) is chromatographed over 1 kg of silica gel contained in a column with a diameter of 6 cm, collecting fractions of 500 mls and eluting with ethyl acetate containing 1.5% of methanol. Fractions 31 to 43 are combined and evaporated to dryness. In this way one obtains 17 g of 1-[2(5,6-dimethoxy-3-indolyl) ethyl]-2-piperidone in the form of a thick yellow oil which slowly crystallises.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=4[F:52])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:46]1[CH:47]=[CH:48][C:49]([F:51])=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:53]=[CH:54][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cc(F)ccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1cc(F)ccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 44.8 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,5-difluorobenzyl)-1-piperidinecarboxamide (0.238 g, 0.29 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.075 g, 0.13 mmol).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][CH2:69]1>C(OCC)(=O)C.O.CN(C)C=O>[C:77]([O:76][C:74]([N:71]1[CH2:72][CH2:73][CH:68]([NH:67][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([O:31][CH3:32])[C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[CH:23][C:24]=2[F:33])[CH2:69][CH2:70]1)=[O:75])([CH3:80])([CH3:78])[CH3:79]
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To a mixture of 0.075 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.09 g (0.24 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.08 mL (0.48 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.10 g (0.48 mmole) of 4-amino-1-Boc-piperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 0.071 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoyl-amino]-piperidin-1-carboxylic acid tert-butyl ester (I-177).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:18][O:19][CH:20]([O:25][CH3:26])[C:21](OC)=[O:22]>C1COCC1>[CH3:18][O:19][CH:20]([O:25][CH3:26])[C:21]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])=[O:22]
Reactant: O=C1CCCCC1
Reactant: COC(=O)C(OC)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(=O)C1CCCCC1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclohexanone Compound 2a (1.37 g, 14.0 mMol) in THF (5 mL) was added dropwise to a solution of LHMDS (16.0 mL, 16.0 mMol) in anhydrous THF (25 mL) at −78° C. under a N2 atmosphere. The solution was stirred at −78° C. for about 1 hr. Methyl dimethoxyacetate Compound 11a (1.88 g, 14.0 mMol) in anhydrous THF (5 mL) was then added dropwise. The reaction mixture was stirred while warming to r.t. over a period of about 15 hrs, then the reaction was quenched with water (5 mL). The organic layer was diluted with EtOAc (100 mL) and washed with water and brine. The organic layer was separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude product as an oil. The oil was purified by flash chromatography (eluted with 10% EtOAc in hexane) to afford 2-(2,2-dimethoxy-acetyl)-cyclohexanone Compound 11b (1.82 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH:28](=[O:30])[CH3:29].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:28]([OH:30])[CH3:29])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.25 h

Procedure:
A solution of 6.0 g (16.3 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 250 ml diethyl ether was cooled to −100 deg C. and treated with 11.9 ml (17.9 mmol) tert-butyllithium (1.5 M in n-pentane). After 15 min, 1.0 ml (0.79 g, 17.9 mmol) acetaldehyde was added and the reaction was stirred for 40 min at the same temperature. After warming to −75 deg C. the reaction mixture was poured onto 10% aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (2:3) as eluant to afford a first batch of compound. The remaining product-containing fractions were pooled and chromatographed again to yield a second batch of compound (56.9% total).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:60][CH2:61][C:62]([CH3:65])([OH:64])[CH3:63]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[OH:64][C:62]([CH3:65])([CH3:63])[CH2:61][NH:60][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:32][CH2:31]1
Reactant: CC(C)(O)CN
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(O)CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 1-amino-2-methylpropan-2-ol (50 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (97 mg, yield 57%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([CH:40]=2)[NH2:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([NH:39][C:24]([C:16]3[C:17]4[O:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]=4[C:12]4[NH:11][C:10]([NH:9][C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])=[N:14][C:13]=4[CH:15]=3)=[O:25])[CH:40]=2)[CH2:33][CH2:32]1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Reactant: Nc1cc(C2CC2)ccc1F
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C4CC4)ccc3F)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 14.9 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.100 g, 0.255 mmol), thionyl chloride (1.0 mL), 5-cyclopropyl-2-fluoro aniline (Intermediate-47, 0.077 g, 0.511 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 1.0-2.0% MeOH:DCM to afford 0.020 g of the desired product 1HNMR (DMSO-d6): δ 0.62 (m 2H), 0.94 (d, J=6.3 Hz, 2H), 1.54 (s, 6H), 1.93 (m, 1H), 3.11 (s, 2H), 6.80 (m, 1H), 7.17 (m, 2H), 7.54 (m, 3H), 8.22 (s, 1H), 10.04 (s, 1H), 11-11.5 (s, 2H); MS [M]+: 525.15.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: CCOC(=O)c1cccc(N)c1
Product: CCOC(=O)c1cccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)c1
Yield: 89 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (60 mg, 0.306 mmol) was condensed with ethyl 3-aminobenzoate, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (7:2)] to obtain ethyl 3-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (93 mg, 89%) as colorless needles.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH2:40][CH2:41][NH2:42]>>[OH:39][CH2:40][CH2:41][NH:42][CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: NCCO
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCNCCO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2-hydroxyethylamine were converted to the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:25][C@:26]1([CH3:51])[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:29][C@H:27]1[OH:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.COCCOC>[C:1]([O:28][C@@H:27]1[O:29][C@H:30]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C@@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@:26]1([CH3:51])[O:25][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:25][C@:26]1([CH3:51])[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:29][C@H:27]1[OH:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[C@]1(OC(=O)c2ccccc2)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1

Procedure:
One preferred embodiment of the present invention is exemplified in FIG. 1 and comprises reacting D-fructose in the presence of CaO/water at 23-40° C. for 6-22 hours, and then adding CO2 and oxalic acid to the reaction mixture and allowing the reaction to proceed for 8-12 hours to form 2-C-methyl-D-ribonic-γ-lactone (1); reacting 2-C-methyl-D-ribonic-γ-lactone (1) with 4-dimethylaminopyridine (DMAP) and triethylamine (TEA) in 1,2-dimethoxyethane (DME) at temperature of from about 5° C. to 25° C. for about 30 minutes, and then cooling the mixture to about 5° C. and adding benzoyl chloride to provide 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribonic-γ-lactone (2); reacting 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribonic-γ-lactone (2) with Red-Al/ethanol in toluene at a temperature of from about −5 to 0° C. for about 40 minutes to provide 2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranose (3); and finally adding benzoyl chloride/TEA to a cold solution of 2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranose (3) in the presence of DMAP and DME and allowing the reaction to proceed for from about 4 hours to about 12 hours at a temperature of from about 5 to about 50° C., thereby providing the final product (4), 2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranose.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([Cl:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1CC2C(=CC=CC=2)C1)(=O)C.ClS(O)(=O)=O.[C:34]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([S:46]([Cl:49])(=[O:48])=[O:47])=[CH:43][CH:44]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[C:34]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([S:46]([Cl:49])(=[O:47])=[O:48])=[CH:43][CH:44]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35].[C:1]([N:4]1[CH2:5][C:6]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])[CH:11]=2)[CH2:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc21
Agent: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Agent: CC(=O)N1Cc2ccccc2C1
Agent: O=S(=O)(O)Cl
Product: CC(=O)N1Cc2ccc(S(=O)(=O)Cl)cc2C1

Procedure:
N-Acetylindoline-5-sulphonyl chloride was prepared by a literature method (A. L. Borrer, E. Chinoporos, M. Filosa, S. R. Herrchen, C. R. Petersen, C. A. Stern, J. Org. Chem. 53, 2047 (1988)) as was N-acetylindoline-6-sulphonyl chloride (P. R. Carlier, M. P. Lockshin, M. P. Filosa, J. Org. Chem. 59, 3232 (1994)). N-Acetylisoindoline-5-sulphonyl chloride was prepared from N-acetylisoindoline and chlorosulphonic acid in analogy to N-acetylindoline-5-sulphonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O>[C:1]([C:3]1[CH:4]=[C:5]([C:6](=[S:38])[NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[Si](C)(C)CNC(=O)c1ccc(-n2cncn2)c(C#N)c1
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CNC(=S)c1ccc(-n2cncn2)c(C#N)c1
Yield: 129.4 %

Procedure:
3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzamide (1.1 g) was dissolved with toluene. To the mixture was added Lawesson reagent (1.5 g) and heated to reflux for 5 hours. The reaction mixture was returned to room temperature, water was added thereto, and the aqueous layer was extracted with ethyl acetate. The combined organic layers, were washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbothioamide (1.5 g).