Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:37]4[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (120 mg), acetic acid (0.036 mL) and sodium acetate (52.3 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (200 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (169 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D84) (165 mg). The crude product was used for next step without further purification. MS (ES): C30H35N3O3S requires 517. found 518.3 (M+H+).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C(N(CC)CC)C.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1.[CH2:31]([N:38]=[N+:39]=[N-:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.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.[Cu]I>[CH2:31]([N:38]1[CH:6]=[C:5]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=2)[N:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cccnc21
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(-c2cn(Cc3ccccc3)nn2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.1 0.21 ml (1.50 mmol) of trimethylsilylacetylene and 0.28 ml (2.00 mmol) of triethylamine are added successively to a suspension, kept under argon, of 14 mg (0.02 mmol) of bis(triphenylphosphine)palladium dichloride, 8 mg (0.04 mmol) of copper(I) iodide and 344 mg (1.00 mmol) of tert-butyl 3-iodo-(1H)-pyrrolo[2,3-b]pyridine-1-carboxylate in 5 ml of THF, and the mixture is stirred at room temperature for one hour under argon. Then, for the removal of excess trimethylsilylacetylene, argon is passed through the reaction mixture for 5 minutes. 1.10 ml (1.10 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF are subsequently added, and the reaction mixture is stirred at room temperature for 30 minutes. A solution of 136 mg (1.00 mmol) of benzyl azide in 1 ml of THF is then added, and the reaction mixture is stirred at room temperature for 66 hours. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with petroleum ether/ethyl acetate 2:1, giving tert-butyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylate as yellow oil; ESI 376.
Reaction SMILES: [C:1]1([C:7]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16](ON4C5C=CC=CC=5N=N4)=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[C:1]1([C:7]2([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(On1nnc2ccccc21)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxole-5-carboxylate (300 mg, 0.689 mmol) in acetonitrile (2.0 mL) was added morpholine (100 mg, 1.15 mmol, 1.67 eq.) at 0° C. After 10 min, the cooling bath was removed and the reaction was stirred 3 h at 20° C. The reaction was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine and water and then dried in vacuo, affording the title compound (267 mg, quant.) as a white solid.
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.CCCCCC>[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:2])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphium bromide (7.85 g, 22 mmol) in THF (10 mL) was added potassium tert-butoxide (1.0M solution in THF, 22 mL). After 30 minutes, 4-phenoxybenzaldehyde (3.96 g, 20 mmol) was added to the above mixture. The reaction was diluted with equal volume of hexane after 20 minutes and filtered through silica gel. The residue was rinsed and washed with 20% ether in hexane. Concentration of the filtrate gave the crude product as an off white solid which was used without further purification.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[CH2:7]([NH:10][CH2:11][CH:12]=[CH2:13])[CH:8]=[CH2:9]>C(O)C>[CH2:7]([N:10]([CH2:11][CH:12]=[CH2:13])[C@@H:6]1[CH2:5][O:4][CH2:3][C@H:2]1[OH:1])[CH:8]=[CH2:9]
Reactant: C1OCC2OC12
Reactant: C=CCNCC=C
Solvent: CCO
Product: C=CCN(CC=C)[C@@H]1COC[C@H]1O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4-epoxytetrahydrofuran (57.4 g, 0.67 mol) in ethanol (344 mL) was added diallylamine (194 g, 2.00 mol). The reaction mixture was heated to 75° C. After 2 days, the reaction mixture was cooled and concentrated under reduced pressure to afford trans-4-(diprop-2-en-1-ylamino)tetrahydrofuran-3-ol. The material was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[N:7][C:6]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:36])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:37])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.O>C1COCC1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[O:9][C:5]([CH2:3][OH:2])=[C:6]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([OH:36])([C:32]([F:34])([F:35])[F:33])[C:28]([F:30])([F:29])[F:31])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH3:37])[N:7]=1
Reactant: COC(=O)c1oc(-c2ccccc2Cl)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1nc(-c2ccccc2Cl)oc1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
At 0° C., a solution of 10 mg (0.018 mmol) of 2-(2-chloro-phenyl)-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazole-5-carboxylic acid methyl ester (example 130) in 0.3 mL of THF was treated with 1 mg (0.026 mmol) of LiAlH4 and stirred at RT for 6 hrs. Ice was added and the mixture distributed between Et2O and water. Drying of the combined organic phases and evaporation yielded 9 mg (95%) of 2-{1-[2-(2-chloro-phenyl)-5-hydroxymethyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, off-white solid, MS:518 (MH+), 1 Cl.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]C(Br)(Br)Br>ClCCl>[Br:29][CH2:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCc1ncccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccnc1CBr
Temperature: 25 °C
Reaction time: 22 h
Yield: 11 %

Procedure:
A solution of 285 mg (2.242 mmol) of (3-fluoropyridin-2-yl)methanol (CAS: 31181-79-0) in dry dichloromethane (9 ml) in an ice-water bath and under an argon atmosphere was admixed with 882 mg (3.36 mmol) of triphenylphosphine and 1.12 g (3.36 mmol) of tetrabromomethane. The reaction mixture was stirred at room temperature for 22 hours. The solvent was evaporated off and the residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane-ethyl acetate, gradient 15% to 30%), which gave 156 mg (11% yield, 98% pure) of the target compound.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:38]1([CH3:57])[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]O)=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([S:20][CH2:21][CH2:22][C:23]([O:25][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH3:57])=[CH:39][CH:40]=1)=[O:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(OCCCCCCCCCCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(OCCCCCCCCCCCOC(=O)CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound 14 (1.86 g), 0.896 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and 0.029 g of 4-dimethylaminopyridine (DMAP) were dissolved in 300 ml of methylene chloride. After the compound 16 (3.04 g) was then added and stirred at room temperature for 24 hours, the reaction solution was moved into a separating funnel, and was washed twice with 100 ml of 10% aqueous potassium hydrogen sulfate solution, twice with 100 ml of aqueous saturated sodium hydrogen carbonate solution, twice with 100 ml of ion-exchange water, and twice with 100 ml of saturated brine. After the methylene chloride phase collected was dehydrated with magnesium sulfate, the desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The reaction mixture was purified by chromatography, and 2.63 g of 11-(p-tolyloxy)undecyl 3-(tritylthio)propioate 17, which was a white solid, was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11](Br)Br)=[CH:7][N:6]=1)=[O:4].C([OH:16])C>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[O:16])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C(Br)Br)cn1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(C=O)cn1
Temperature: 80 °C

Procedure:
A solution of 5-dibromomethyl-pyrazine-2-carboxylic acid methyl ester (1.00 g, 3.23 mmol) in a mixture of ethanol (20 mL) and THF (10 mL) was heated to 80° C. A solution of silver nitrate (2.20 g, 12.9 mmol) in H2O (4 mL) was added. The reaction mixture was heated at 80° C. for 1.25 h and was filtered while hot. The filtrate was concentrated to yield the title compound (1.36 g). This material was carried to the next step without purification.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C)C(=N)N(C)C>ClCCl>[C:1]1([CH:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCC(O)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-phenyl-2-aminoethanol (5.323 g, 38.80 mmole) in 50 mL dichloromethane was added tert-butyldimethylsilyl chloride (7.030 g, 46.63 mmole) followed, after 15 minutes by tetramethylguanidine (2.430 g, 21.09 mmole). The reaction mixture was stirred at room temperature for 15 minutes and quenched by addition of water (40 mL). Layers were separated. The aqueous phase was extracted with dichloromethane (40 mL). Combined organic phases were washed with brine (2×50 mL), dried over magnesium sulfate and concentrated in vacuo to give crude 2-phenyl-2-tert-butyl dimethylsiloxy1-ethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:35]([O:37][C:38](=[O:46])[CH2:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1)[CH3:36].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([NH:45][C:42]5[S:43][CH:44]=[C:40]([CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:46])[N:41]=5)=[O:29])[N:27]=4)[CH:21]=3)[C:5]3[CH:33]=[CH:34][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)cs2)c(=O)[nH]c1=S
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc(NC(=O)c2csc(Cn3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=S)[nH]c3=O)n2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from example 8(0.11 g) and 2-amino-4-thiazoleacetic acid ethyl ester (0.063 g) were dissolved in dry dimethylformamide (5 ml). Bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.11 g) and triethylamine (0.08 ml) were added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with brine/HCl and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 10% ethyl acetate in dichloromethane and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH:22][CH3:23].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of the oil containing the two diasteriomers of dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 15 g, 0.055 mole) in tetrahydrofuran (200 ml) and an aqueous solution of dimethylamine (40%, 200 ml) is refluxed for 24 hr. Aqueous sodium chloride solution is added and the solution is extracted with diethyl ether. The organic extract is dried and evaporated to afford an oil consisting of two diasteriomeric amides of the title compound. The oil is subjected to chromatography on silica gel using acetone-benzene(1:3). The eluates are evaporated and crystallized from benzene-hexane to obtain isomer A of the title compound as crystals (4.5 g), mp 158°-160° C. Further elution of the column with acetone-benzene(1:1), evaporation of the eluates and crystallization of the residue from benzene-hexane gives isomer B of the title compound as crystals (1.5 g), mp 159°-162° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:53])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)(=[O:37])=[O:36])[CH2:25][CH:24]2[C:44](=[O:52])[NH:45][CH2:46][CH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C(O)C>[Pd].C(Cl)Cl.CO>[CH3:49][C:48]([CH3:51])([CH3:50])[CH2:47][CH2:46][NH:45][C:44]([CH:24]1[CH2:25][CH:26]([S:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:37])=[O:36])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:53])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:52]
Reactant: CC(C)(C)CCNC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)CCNC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 83.3 %

Procedure:
A The process is performed as described in Example 2A, but starting with 3 g of (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-morpholinosulphonyl-2-(3,3-dimethylbutyl)carbamoylpyrrolidine, 0.3 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 2.2 g of (2RS,4SR,5RS)-3-(3-{2-[2-(3,3-dimethylbutyl)carbamoyl-5-(2-fluorophenyl)-4-morpholinosulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.25; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CO[C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(Cl)(Cl)Cl.[CH3:35][OH:36]>>[CH3:35][O:36][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH:29]=[CH:30][CH:24]=1
Reactant: CO
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: COc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: COc1cccc(Nc2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)c1
Reaction time: 18 h
Yield: 51 %

Procedure:
Using the general procedure described above, the reaction of 6 (80 mg, 0.26 mmol) and 4-methoxyaniline (244 mg, 1.98 mmol) was run for 18 hours, to provide 52 mg of 8 as a white solid in 51% yield, TLC Rf 0.55 (chloroform-methanol 15:1); mp 266.8-267° C.; 1H NMR (DMSO-d6) δ 1.23 (s, 9H, C(CH3)3), 3.75 (s, 3H, OCH3), 6.88-8.26 (m, 8H, Ar—H), 8.55 (s, 1H, 4-NH, exch), 9.41 (s, 1H, 2-NH, exch), 11.79 (s, 1H, 9-NH, exch). Anal. Calculated (C22H23N5O2, 0.4 H2O): C, 66.61; H, 6.04; N, 17.65. Found: C, 66.61; H, 6.00; N, 17.37.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>ClCCCl>[CH2:33]([N:16]([CH3:15])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:31][CH:32]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1
Yield: 58 %

Procedure:
Sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added to a solution of 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (75 mg, 0.31 mmol), benzaldehyde (34 mg, 0.32 mmol), acetic acid (19 mg, 0.32 mmol), and 1,2-dichloroethane (5 mL). Stirred the reaction at room temperature overnight, quenched with a pH=10 buffer, then extracted with dichloromethane (3×25 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (100 mg). The crude product is purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol, (60 mg): m/z=334.01 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. 1H NMR (CDCl3, 300.00 MHz): 7.42-7.28 (m, 7H), 7.11-7.05 (m, 2H), 6.97-6.79 (m, 4H), 3.63 (s, 2H), 2.86-2.78 (m, 2H), 2.71-2.63 (m, 2H), 2.33 (s, 3H),
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O.O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(N(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)CC1
Reaction time: 0.67 h

Procedure:
To a solution of O-tert-butyl (1-acetylpiperidin-4-yl)carbamate (0.97 g) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (0.18 g) at ambient temperature. After stirring for 40 minutes, 4-fluorobenzyl bromide (0.6 ml) was added to the reaction mixture. After additional stirring for 4 hours, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (10 ml). An organic phase was separated and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, toluene:ethyl acetate=1:1 to 1:2). After crystallization from diisopropyl ether and n-hexane, O-tert-butyl N-(4-fluorobenzyl)-N-(1-acetylpiperidin-4-yl)carbamate (922 mg) was obtained.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34](OCC)=[O:35])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:35])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(C)cc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: Cc1ccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-methylphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 81 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (162.0 mg, 68%).