Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.C(Cl)Cl.[C:8]1([C:14]2[C:22]([CH:23]=[CH:24][C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[CH2:33][C:34]([OH:36])=O)=[O:26])=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH3:37]>CN(C)C=O>[C:8]1([C:14]2[C:22]([CH:23]=[CH:24][C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[CH2:33][C:34](=[O:36])[NH2:37])=[O:26])=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.2 ml) was added dropwise to a solution of methylene chloride (dry, 40 ml) and N,N-dimethylformamide (0.2 ml) at 0° C. and stirred for 30 minutes. To this cooled solution was added (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(carboxymethyl)piperidine (trans isomer) (1.0 g) and the mixture was stirred for 1.5 hours. To this solution was added a solution of 28% aqueous ammonia solution (20 ml) and stirring was continued for further 2 hours. The aqueous and organic phases were separated and the organic layer was evaporated. The oily residue was subjected to column chromatography (silica gel, 60 mesh) using ethyl acetate as eluent. Evaporation of the solvent afforded (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(carbamoylmethyl)piperidine (trans isomer) (405 mg) as a white granular solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=402.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH2:16]([N:2]1[C:3]([CH:6]=[O:7])=[CH:4][CH:5]=[N:1]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1nccc1C=O
Yield: 10.1 %

Procedure:
Pyrazole-3-carbaldehyde (3.00 g, 31.2 mmol) was dissolved in DMF (20 ml), and thereto were added potassium carbonate (6.47 g, 46.8 mmol) and allyl bromide (3.50 g, 32.8 mmol) with stirring. The mixture was stirred at room temperature for 6 hours, and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (429 mg, 10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21]C(O)=O.[C:25](Cl)(=[O:29])C(Cl)=O.C[Si]([N:35]=[N+]=[N-])(C)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][N:35]=[C:25]=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ccc(/C=C2/C(C)=C(CN=C=O)c3cc(F)ccc32)cc1
Reaction time: 1 h

Procedure:
To a suspension of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)inden-3-ylacetic acid (5.0 g, 14.7 mmol) in methylene chloride (50 mL) at room temperature there was added oxalyl chloride (2.8 g, 22 mmol) and DMF (2 drops) and the mixture stirred for 1 hour; the solution was evaporated and the crude acid chloride flushed twice with carbon tetrachloride (20 mL) then suspended in carbon tetrachloride (25 mL) and trimethylsilyl azide (2.53 g, 22 mmol) was added. The mixture was stirred at room temperature for 15 minutes, then gently heated on a steam bath as nitrogen was evolved. The heating was continued until gas evolution ceased, then the mixture was evaporated to afford the crude title compound as an oil which was used as such in the next step.
Reaction SMILES: [Si:1](Cl)(Cl)(Cl)Cl.[OH:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8]>C(Cl)Cl>[O-:9][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6].[Si+4:1].[O-:9][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6].[O-:9][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6].[O-:9][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: [Si+4]
Temperature: 25 °C

Procedure:
SiCl4 (3 g, 17.6 mmol) was dissolved in CH2Cl2 (75 mL) and triflic acid (10.6 g, 70.7 mmol) was added dropwise. The mixture was stirred at room temperature over the weekend. The solvent was removed and 4.8 g of brown liquid was collected. 19F NMR (DMSO-d6): δ-76.4 (intense), small broad peaks at -77.8 and -77.95.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:18])[CH2:16][CH3:17])[C:5](=[O:14])[O:6][C:7]=1[CH:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12].[Na].C([O-])(O)=O.[Na+]>ClCCl.N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:18])[CH2:16][CH3:17])[C:5](=[O:14])[O:6][C:7]=1[CH:8]([CH3:13])[CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CCC(=O)c1cc(O)c(C(C)CCCO)oc1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1cc(O)c(C(C)CCC=O)oc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(5-Hydroxy-2-oxo-3-propionyl-2-H-pyran-6-yl)pentanol (V; 0.38 g; 1.5 mmol; Aldrich) was dissolved in 20 ml dichloromethane and 0.6 ml pyridine. Sodium periodinate (0.7 g; 1.65 mmol; Aldrich) was added and stirred for 2 h at 25° C., after which reaction mixture was neutralized with saturated NaHCO3 and extracted with 3×20 ml CH2Cl2. The pooled organic extracts were dried with anhydrous Na2SO4, evaporated, and purified via silica chromatography (20% EtOAc in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F: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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F: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]([NH:39][C:38]3[CH:40]=[C:34]([CH:31]4[CH2:32][CH2:33]4)[CH:35]=[CH:36][C:37]=3[F:41])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)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(F)cccc4Cl)[nH]c23)O1
Yield: 22.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 5-cyclopropyl-2-fluoroaniline (Intermediate-47, 0.090 g, 0.600 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.62-0.63 (m, 2H), 0.93-0.96 (m, 2H), 1.54 (s, 6H), 1.93 (m, 1H), 3.13 (s, 2H), 6.80 (s, 1H), 7.14-7.50 (m, 5H), 8.24 (t, J=7.8 Hz, 1H), 10.07 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 509.23.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl[CH2:13][CH2:14][C:15](Cl)=[O:16].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:15](=[O:16])[CH2:14][CH2:13][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: C1COCCN1
Reactant: O=C(Cl)CCCl
Product: CC(C)(C)c1ccc(NC(=O)CCN2CCOCC2)cc1

Procedure:
In a manner similar to Preparation 1 react 4-(1,1-dimethylethyl)benzenamine with 3-chloropropanoyl chloride followed by morpholine to obtain the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:49][C:18]2[N:19]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][CH:36]=3)[C:20](=[O:33])[N:21]([CH2:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([C:15]1[S:49][C:18]2[N:19]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:37][CH:36]=3)[C:20](=[O:33])[N:21]([CH2:24][C:25](=[O:32])[C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccncc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccncc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.22 g), sodium hydrogencarbonate (0.33 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-2,4-dioxo-3-(2-oxo-2-pyridin-4-ylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.20 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (2 ml). N,N′-Carbonyldiimidazole (0.076 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.070 g, 32%).
Reaction SMILES: CC(CC(C)C)=O.[CH2:8]([C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:34]=[N:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].[OH-].[K+:58].C>CO.[OH-].[K+]>[CH3:11][CH2:10][CH2:9][CH2:8][C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]=[N:36][N-:35][N:34]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1.[K+:58]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
Under nitrogen, in a 500 ml flask a mixture of 180 ml of dry methanol, 20 g (0.026 mol) of 2-n-butyl-4-chloro -1-[(2′-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1′-biphenyl-4-yl)-methyl]-1H-imidazol-5-methanol methyl-isobutyl ketone solvate and 0.1 g (0.00178 mol) of potassium hydroxide was refluxed for 3 h. The reaction mixture was cooled to room temperature and after adding 1.35 g (0.0241 mol) of potassium hydroxide in 10 ml of methanol it was treated with 0.5 g of charcoal and filtered. The filtrate was concentrated to a volume of 30 ml under diminished pressure, and after addition of 80 ml of acetonitrile again to a volume of 35 ml. After addition of further 85 ml of acetonitrile the suspension was cooled to 0° C., the precipitated crystals were filtered after 1 h stirring, washed twice with 30 ml of cold acetonitrile and dried at 70° C. to give 11.3 g (93.4%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:8][C:7](=[O:9])[C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@@H](N)C(=O)O
Product: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
D-leucine (10 g, 76.23 mmol) is suspended in benzyl alcohol (157 mL) and warmed to 55° C. HCl gas is bubbled through the mixture and the reaction becomes quite viscous. 150 mL of benzene is then added with vigorous stirring. After 30 minutes of bubbling gas through with heating the mixture begins to thin and stirring is achieved more easily. The reaction stirs further at 55° C. for one hour until the solution becomes homogeneous. Flow of HCl is ceased and the reaction is closed off and allowed to stir further at 55° C. for 30 minutes. The reaction is allowed to cool to room temperature and is diluted with ethyl acetate. The product is extracted into 1M HCl (3×) and the organics are discarded. The aqueous washings are combined taken to pH 8 with 50% aqueous NaOH. The amine is extracted several times with ethyl acetate. The organics are dried over sodium sulfate and evaporated. Ether is added to the oil and HCl is bubbled through to precipitate D-leucine benzyl ester as the hydrochloride salt.
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[C:27](=[O:34])[CH:28]=[C:29](O)[C:30]([O-:32])=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][CH2:36]O>>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[C:27]1[O:34][N:2]=[C:29]([C:30]([O:32][CH2:35][CH3:36])=[O:31])[CH:28]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C
Yield: 80 %

Procedure:
Hydroxylamine hydrochloride (0.89 g, 12.8 mmol) was added to a suspension of 4-(2,4-bis(benzyloxy)-5-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate (5.0 g, 10.7 mmol) in EtOH (100 ml). The reaction mixture was heated to reflux for 3.5 h and then allowed to cool to RT. The resulting suspension was filtered, washed sequentially with EtOH (2×10 ml), water (2×10 ml), and EtOH (2×10 ml), and dried under vacuo to afford the title compound ethyl 5-(2,4-bis(benzyloxy)-5-chlorophenyl)isoxazole-3-carboxylate (3.97 g, 80%) as a flocculent light-yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:43][C:44]([F:74])([F:73])[C:45]1[CH:46]=[C:47]([C:55]([CH3:72])([CH3:71])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][NH:61][CH2:60]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>C1COCC1>[F:53][C:51]([F:52])([F:54])[C:49]1[CH:48]=[C:47]([C:55]([CH3:71])([CH3:72])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][N:61]([C:6]([C@@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:60]2)=[O:57])[CH:46]=[C:45]([C:44]([F:43])([F:73])[F:74])[CH:50]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)[C@@H]2CCCO2)C[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 21.3 %

Procedure:
To a stirred solution of (S)-tetrahydro-furan-2-carboxylic acid (described in J. Med. Chem., 1995, 38(15, 2830) (5.0 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 5.1 mg (25%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:45][CH3:46])=[C:35]([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:36]=2)[N:31]=[CH:30][N:29]=1>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:45][CH3:46])=[C:35]([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCS(C)(=O)=O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCS(C)(=O)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (92 mg, 0.32 mmol) was treated with cesium carbonate (113 mg, 0.35 mmol) in anhydrous tetrahydrofuran (2 mL) and the suspension stirred at 40° C. for 20 minutes. 4-Chloro-7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazoline from the previous step (100 mg, 0.32 mmol) was carefully added in portions and the resulting mixture heated at 40° C. for 2 h. Cesium carbonate was filtered off, the filtrate concentrated under reduced pressure and the residue purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazolin-4-ylthio)phenyl)urea (36.88 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.53-7.40 (m, 4H), 7.30-7.28 (d, 1H), 6.49 (s, 1H), 4.59-4.56 (m, 2H), 4.00 (s, 3H), 3.78-3.74 (m, 2H), 3.20 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 572 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:71][C:72]([CH3:76])([CH3:75])[CH2:73][OH:74]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:71][C:72]([CH3:76])([CH3:75])[CH2:73][OH:74])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: CC(C)(N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NC(C)(C)CO)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.076 mmol) in DMF (3 ml) was added BOP (40 mg, 0.091 mmol) and DIPEA (20 mg, 0.10 mmol), followed by 2-amino-2-methylpropan-1-ol (15 mg, 0.15 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a yellow oil.
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5].[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>C(Cl)Cl>[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([NH:3][C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)NC(=O)c1ccco1
Solvent: ClCCl
Product: O=C(Cl)C(=O)NC(=O)c1ccco1
Reaction time: 1 h

Procedure:
3.6 g. of N-(trimethylsilyl)-2-furancarboxamide are dissolved in 50 ml. of absolute methylene chloride and the solution is added dropwise at -10° to a solution of 1.8 g. of oxalyl chloride in 100 ml. of methylene chloride. The mixture is stirred for one hour at 0°. After evaporating the solvent, [(2-Furanylcarbonyl)amino]oxoacetyl chloride remains as a yellowish oil which is used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:31][CH2:27][CH2:28][CH2:29][CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (489 mg, 1.26 mmol) in CH2Cl2 (5 mL) was added neat butylamine (197 μL, 2.00 mmol) and the resulting mixture was stirred for 30 min. Saturated aqueous NaHCO3 (20 mL) was added, then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The resulting crude material was purified by flash chromatography on silica gel (hexane(EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-butylthioureido)tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (566 mg, 97% yield). 1H NMR (500 MHz, CDCl3) δ 0.94 (t, 3H, J=7.5 Hz), 1.35-1.41 (m, 2H, 1.53-1.59 (m, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 2.14 (s, 3H), 3.38 (br s, 2H), 3.82-3.85 (m, 1H), 4.13-4.16 (m, 2H), 4.20-4.25 (m, 1H), 4.29 (dd, 1H, J=4.5, 12.5 Hz), 5.17-5.22 (m, 2H), 5.73 (d, 1H, J=8.0 Hz), 6.10 (br s, 1H).