Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]([CH3:19])[CH3:18])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]([CH3:19])[CH3:18])[N:4]=1
Reactant: CC(C)c1nccn1-c1nc(Cl)nc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5ccnc5C(C)C)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1

Procedure:
The sodium salt of 2-chloro-6-(2-isopropylimidazol-1-yl)purine (0.132 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2 for 1 h (reaction complete, TLC). Sampling of the reaction mixture at the end of the reaction time showed no α-nucleoside by 1H NMR (500 MHz). The residue was chromatographed (25 g silica gel, EtOAc/hexanes˜1:1) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-isopropylimidazol-1-yl)purine (quantitative). Recrystallization (EtOAc) gave the compound (0.22 g, 70%): UV (MeOH) max 223, 241, 285 nm (∈ 32 100, 35 400, 14 800), min 230, 265 nm (∈ 30 300, 9200); 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J=1.0 Hz, 1H), 8.26 (s, 1H), 7.99 (d, J=7.8 Hz, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.30 (d, J=7.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.11 (d, J=1.0 Hz, 1H), 6.60 (t, J=6.8 Hz, 1H), 5.81 (br s, 1H), 4.78-4.83 (m, 1H), 4.67-4.71 (m, 2H), 4.08 (sept, J=6.8 Hz, 1H), 2.97-3.01 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.99, 156.18, 154.20, 153.21, 148.15, 144.72, 144.40, 142.25, 129.88, 129.55, 129.36, 129.33, 128.82, 126.44, 126.26, 123.00, 120.38, 85.23, 83.59, 74.93, 63.87, 38.63, 28.81, 21.78, 21.61; HRMS 77/z 637.1931 (MNa+[C32H31ClN6O5Na=637.1942]).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]=[CH:8][CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][C:15]([N:22]=[C:23]=[O:24])=[C:14]([F:25])[CH:13]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]=[CH:8][CH2:7][N:6]1[C:23]([NH:22][C:15]1[CH:16]=[C:17]([O:18][CH:19]([CH3:20])[CH3:21])[C:12]([Cl:11])=[CH:13][C:14]=1[F:25])=[O:24])=[O:4]
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: COC(=O)C1CC=CCN1
Solvent: Cc1ccccc1
Product: COC(=O)C1CC=CCN1C(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
To a stirred solution of 5,65 g (0,04 moles) of 1,2,3,6-tetrahydro-2-pyridinecarboxylic acid methyl ester in 75 ml of dry toluene are added dropwise without cooling 9,2 g (0,04 moles) of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate, dissolved in 200 ml of dry toluene.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[O:2].S(Cl)([Cl:14])=O>C1C=CC=CC=1.CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
In a suspension of 1.00 g of 4-formyl benzoic acid in 15 ml of benzene, 0.87 g of thionyl chloride and 2 drops of N,N-dimethylformamide were added, and stirred under reflux with heat for 2 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain 1.14 g of crude 4-formyl benzoic acid chloride as white crystal. In a solution of 0.66 g of 2,2,2-trifluoroethylamine and 0.81 g of triethylamine in 6 ml of chlororform, the solution of 1.14 g of the crude 4-formyl benzoic acid chloride in 6 ml of chloroform was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 18 hours. After the completion of the reaction, the reaction mixture was added in 30 ml of water, extracted with chloroform (20 ml×3). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residual solid was washed with hexane to obtain 1.32 g of the aimed product as white crystal.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH:15]=2)=[CH:8][C:7]=1[CH3:40].O.[OH-].[Li+].O>O1CCOCC1>[F:27][C:26]([F:28])([F:29])[C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([CH:15]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)[CH:17]=2)[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH3:40])[CH:8]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)COc1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)cc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCc2cc(-c3ccc(C(F)(F)F)cc3)cc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
The crude [4-(3,5-bis(4-trifluoromethylphenyl)-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester from Step A above is dissolved in dioxane (2 mL). Solid lithium hydroxide monohydrate (18 mg, 0.44 mmol, excess) is added, followed by water (0.2 mL). After 1 hour, the mixture is concentrated to dryness. Purification by reversed-phase HPLC yields [4-(3,5-bis(4-trifluoromethylphenyl)-benzyloxy)-2-methyl-phenoxy]-acetic acid A1 as a solid. 1H-NMR (400 MHz, CDCl3) δ=7.67 (m, 9H), 7.61 (s, 2H), 6.82 (d, J=2.8 Hz, 1H), 6.72 (dd, J=9.0, 2.8 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 5.08 (s, 2H), 4.58 (s, 2H), 2.22 (s, 3H). 19F-NMR (376 MHz, CDCl3) δ=−62.4. No MS could be obtained.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.[OH-].[Na+].C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to Example 113a from 3,4-diamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene with DCC in DMF and NaOH in ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 105 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In a 100 mL flask equipped with a reflux condenser, 6-nitro-quinazolin-4-one 2.85 g (15 mmol), phosphoryl chloride 25 mL were added. The mixture was stirred at 105° C. for 3 h, and then was dropped into 150 mL of ice water carefully, the squama solid deposited was filtered out, dried, and identified as the title compound. Yield: 78%.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:25][CH3:26])[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 3.0 g, 9.9 mmol) in 100 mL of DMF was added to a suspension of sodium hydride (0.47 g, 11.8 mmol) in 40 mL of DMF and stirred for 30 minutes. Ethyl iodide (7.9 mL, 99 mmol) was added, and the mixture was warmed to 50° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 3.2 g of the title compound as a solid, mp 133-135° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[CH:11]=[C:12]([C:21](=[O:23])[CH3:22])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[Cl:4][CH2:22][C:21]([C:12]1[CH:11]=[C:10]([C:6]([CH3:9])([CH3:7])[CH3:8])[C:15]([OH:16])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:13]=1)=[O:23]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)CCl)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.2 g (0.12 mol) of sulfuryl chloride in 50 ml of methylene chloride were added dropwise while stirring to a solution of 19.9 g (0.08 mol) of 1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone in 250 ml of methylene chloride at room temperature. After stirring for 3 hours at room temperature, the batch was washed by shaking first with water and then with a saturated sodium hydrogen carbonate solution, and the methylene chloride phase was dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[Br:12]C(Br)(Br)Br.O>ClCCl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:12])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: BrC(Br)(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-hydroxyphenyl)-1-propanol 3A (4.0 g) and tripohenylphosphine (7.96 g) in anhydrous dichloromethane (77 mL), cooled to 0° C., is added, dropwise, a solution of tetrabromomethane (9.59 g) in anhydrous dichloromethane (15.4 mL). The reaction mixture gradually warmed to room temperature and allowed to stir overnight. The solution is then poured into water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over magnesium sulfate. The solution is concentrated in vacuo.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])O[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1[CH:28]=[C:27]([CH2:29][NH2:30])[O:26][CH:25]=1>CO.C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:30]([CH2:29][C:27]3[O:26][CH:25]=[CH:24][CH:28]=3)[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1ccco1
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1cc(CO)n(Cc2ccco2)cc1OC(c1ccccc1)c1ccccc1
Reaction time: 96 h
Yield: 70.2 %

Procedure:
To a solution of 3.083 g of 3-diphenylmethoxy-6-hydroxymethyl-4-pyrone in 50 ml of methanol is added 7.645 g of 2-furfurylamine at room temperature, and the mixture is stirred for 4 days. The reaction mixture is condensed under reduced pressure, and the resulting residue is dissolved in 600 ml of chloroform. The organic solution is washed with water, a saturated aqueous potassium hydrogen sulfate solution in this sequence, dried over anhydrous magnesium sulfate and condensed under reduced pressure. The resulting crystal is collected by filtration, washed with a small amount of chloroform and dried under reduced pressure to give the title compound (2.72 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[CH3:15][C:16]([S@:19]([NH:21][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=1)[CH3:11])=[O:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OC(F)(F)F)c1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (0.38 g, a white solid) from 1-(3-(trifluoromethoxy)phenyl)ethanone (0.30 g, 1.47 mmol) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]([C:21]1[C:29]2[O:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH2:12][C:13]1([C:16]([F:19])([F:18])[F:17])[CH2:15][O:14]1>CCO>[O:28]1[C:29]2[C:21]([C:11]([CH3:20])([CH3:10])[CH2:12][C:13]([CH2:15][NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])([OH:14])[C:16]([F:18])([F:19])[F:17])=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Solvent: CCO
Product: C[C@@H](NCC(O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F)c1ccccc1
Temperature: 50 °C
Yield: 104.5 %

Procedure:
To an ice-cooled solution of (R)-(+)-1-phenylethylamine (4.43 mL, 34.9 mmol) in anhydrous EtOH (3 mL) was added, dropwise, racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (1 g, 3.49 mmol), which may be prepared according to WO04/063163. The reaction mixture was then heated at 50° C. overnight, cooled to room temperature and evaporated in vacuo. The residue was applied to a 50 g silica SPE cartridge and eluted with 0.5% NH3 in toluene. The appropriate fractions were combined and evaporated in vacuo to give a colourless oil (1.486 g). This oil was subjected to mass-directed autopreparation to give Intermediate 22 (2S isomer, 314 mg), Intermediate 23 (2R isomer, 334 mg) plus a mixed fraction (480 mg). The mixed fraction was re-subjected to mass-directed autopreparation to give further Intermediate 22 (90 mg), Intermediate 23 (125 mg) plus a mixed fraction (160 mg). The fractions containing Intermediate 22 were combined with each other as were the fractions containing Intermediate 23.
Reaction SMILES: [Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1Br.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Br
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Reaction time: 0.02 h
Yield: 98.4 %

Procedure:
To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (2.50 g, 7.06 mmol) in THF (100 mL) at room temperature was added 4-bromophenol (1.344 g, 7.77 mmol) and Cs2CO3 (6.90 g, 21.19 mmol). The reaction mixture turned green after ˜1 min of stirring. The mixture was stirred at room temperature for 18 h after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol, 98% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.83 (s, 3 H), 6.92-7.03 (m, 3 H), 7.25-7.35 (m, 2 H), 7.39-7.50 (m, 2 H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1([CH2:25]O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OCC1CCCCC1
Product: C=CCOC(=O)NC1CC(=O)OC1OCC1CCCCC1
Yield: 35 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclohexylmethanol to afford 1.04 g (higher RF) (35% yield) of anti diastereomer of the title compound and 1.295 g (lower Rf) (44% yield) of syn diastereomer. 1H-NMR (500 MHz, CDCl3) for anti diastereomer: δ 0.90-0.96 (m, 2H), 1.10-1.30 (m, 3H), 1.55-1.85 (m, 6H), 2.37-2.41 (d, H), 2.97-3.03 (m, H), 3.34-3.38 (m, H), 3.58-3.62 (m, H), 4.55-4.70 (m, 2H), 4.70-4.73 (m, H), 5.03 (bs, H), 5.22-5.37 (m, 3H), 5.87-5.93 (m, H); for syn diastereomer 0.91-0.97 (m, 2H), 1.10-1.31 (m, 3H), 1.56-1.90 (m, 7H), 2.44-2.48 (m, H), 2.81-2.87 (m, H), 3.35-3.39 (m, H), 3.63-3.67 (m, H), 4.53-4.70 (m, 3H), 5.20-5.50 (m, 3H), 5.89-5.95 (m, H); LC-MS: m/z=298 (M+H+) for both of diastereomers.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7](C(C)C)[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH2:7][C:6]([OH:39])=[O:5])(=[O:10])=[O:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-valine t-butyl ester (60 mg) was dissolved in a 95% solution of TFA in methylene chloride (5 mL). The solution was stirred at room temperature for 4 h and the solvent was removed under vacuum. The crude product was triturated with hexane/ethyl acetate (95:5) three times. The product was lyophilized with benzene to give 36 mg of N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine. LCMS MH+ (m/z) 493. 1H NMR (300 MHz, DMSO-d6): δ 10.53 ppm (s, 1H), 7.81-7.54 ppm (m, 11H), 7.34 ppm (dd, 1H, J1=8.4 Hz, J2=8.4 Hz), 7.20 ppm (dd, 1H, J1=8.4 Hz, J2=8.4 Hz), 3.35 ppm (d, 1H J=6.0 Hz), 1.79 ppm (m, 1H), 0.63 ppm (dd, 6H, J1=13.8 Hz, J2=6.6 Hz).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1>CN(C=O)C>[CH3:20][S:19][C:15]1[N:16]=[C:17]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[CH:18]=[CH:13][N:14]=1
Reactant: CSc1nccc(Cl)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3ccccc32)n1
Temperature: 100 °C
Yield: 38.6 %

Procedure:
A mixture of NaH (0.548 mg, 22.8 mmol), benzimidazole (0.52 g, 21.3 mmol) and 4-chloro-2-methylthiopyrimidine (2.48 mL, 21.3 mmol) in 30 mL of DMF was heated to 100° C. for 30 min. The reaction was quenched with H2O and extracted with EtOAc. The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (silica, 0-10% MeOH:CH2Cl2) to give 1.99 g of the title compound. 1H NMR (500 MHz, CDCl3): δ8.69 (s, 1H); 8.64 (d, J=5.5 Hz, 1H); 8.22 (dd, J=1.4, 7.3 Hz); 7.89 (dd, J=1.6, 7.3 Hz); 7.44 (m, 2H); 7.23 (d, J=5.7 Hz, 1H); 2.69 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28]#[N:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:31].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28](=[O:31])[NH2:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 13 %

Procedure:
A solution of 1-benzyl-4-(2-cyano-2,2-diphenylethyl)piperidine (7.57 g, 19.9 mmol) (Example 23) in 90% sulphuric acid (45 ml) was heated at 100° C. for one hour, allowed to cool to room temperature, poured into ice, basified with saturated aqueous sodium carbonate solution and extracted into dichloromethane. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.06 g, 13%) as a colourless foam which was characterised as a hemihydrate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:13]1[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=1.Cl>O.C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:13]2[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=2)[CH:6]=1
Reactant: COc1cc(N)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2ncc(C#N)s2)ncn1
Reaction time: 1 h

Procedure:
A flame dried flask under argon gas was charged with sodium hydride (39 mg, 60% dispersion, 0.97 mmol) and 2 mL anhydrous THF. 6-Methoxy-pyrimidin-4-ylamine (55 mg, 0.44 mmol) was added slowly followed, after 10 minutes, by the addition of 2-chloro-thiazole-5-carbonitrile (76 mg, 0.53 mmol). After 1 hour, the reaction was diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered, washed with water and air dried. The resulting solid triturated with ether, sonucated, filtered and washed with ether. 1H-NMR (400 MHz, DMSO-d6) 12.40 (s, 1H), 8.68 (1H, s), 8.31 (1H, s), 6.42 (1H, s), 3.92 (s, 3H). M+1=234.2. mp 246–248.