Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]([SH:7])[CH3:6])C.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:33]=[CH:34][CH:35]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[CH3:1][O:3][C:4](=[O:8])[CH:5]([S:7][CH2:10][C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:6]
Reactant: CCOC(=O)C(C)S
Reactant: BrCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C(C)SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1

Procedure:
Ethyl-2-mercaptopropionate (31 mg, 0.29 mmol) was added to a stirred suspension of 4-(3′-bromomethyl-biphen-3-yl)-dibenzofuran (100 mg, 0.24 mmol) and cesium carbonate (198 mg, 0.6 mmol) in 5 ml DMF. diluted with diethyl ether (30 mL) and washed with water (2×) and brine (3×). The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 30% ethyl acetate in hexane as eluent, afforded the title compound; methyl-2-(3′-dibenzofuran-4-yl-biphen-3-ylmethylsulfanyl)-propionate, as a colorless oil (105 mg, 94).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.75 g, 10.48 mmol) and iPr2NEt (3.27 mL, 18.78 mmol) in THF (50 mL) was added tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (1.83 mL, 10.48 mmol) in THF (2 mL). The resulting solution was allowed to stir at room temperature for 2 hours. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 3.41 g of 7a, as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13](=[O:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-chlorothiophenol (47.1 g, 0.326 mole) in sodium hydroxide solution (14.3 g, 0.358 mole in 750 ml water) was treated dropwise over 20 minutes with freshly distilled chloroacetone (28.5 ml, 0.358 mole) and the resulting mixture was stirred for a further 30 minutes at room temperature. The mixture was extracted with ether (3×200 ml) and the organic solution then washed with 2% sodium hydroxide solution (2×200 ml) and water (2×200 ml), dried (MgSO4) and evaporated to dryness to give a quantitative yield of the title compound as a pale yellow solid. A small sample was recrystallized from pentane to yield a colourless crystalline solid m.p. 37°-38° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH:26]([CH3:28])[CH3:27])=[N:23][C:22]=2[CH:29]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]([CH3:27])[CH3:28])=[N:23][C:22]=4[CH:29]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC(C)c1nc2cc(CCl)ccc2o1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: CC(C)c1nc2cc(COc3ccc(CCCn4ccnc4)cc3)ccc2o1
Yield: 59 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-isopropyl benzoxazole to give 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-isopropyl-benzoxazole. The yield was 59%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 76-77° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]#[N:12])([CH3:3])[CH3:2].Cl.[C:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>ClC1C=CC=CC=1.NC1C2C(=CC=CC=2)C=CC=1>[C:14]1([NH:24][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[NH:12])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)c1ccccc1NC#N
Agent: Cl
Solvent: Clc1ccccc1
Product: CC(C)c1ccccc1NC(=N)Nc1cccc2ccccc12
Yield: 44 %

Procedure:
A solution of o-isopropylphenylcyanamide (1.13 g, 7.05 mmol), 1-naphthylamine hydrochloride (1.1 g, 7.04 mmol) and 1-aminonaphthalene (14.38 mg, 0.1 mmol) in chlorobenzene (20 ml) was heated to 150° C. for 4 hours and at room temperature for 10 hours. It was concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was concentrated and the resulting solid was recrystallized from EtOH-H2O (10:1) to give N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine (940 mg, 44%) as white crystals. mp 175°-177° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:16])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:16])[C:10]2[N:11]=[CH:12][N:13]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)C(=O)Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 10 (2.21 g, 10 mmol) and Na2CO3 (2.12 g, 20 mmol) were suspended in dry DMF, and the mixture was warmed to 80° C. with stirring. After 1 h the heating was terminated, and the reaction mixture was cooled to 0° C. and ethyl bromoacetate (1.22 mL, 11 mmol) was added dropwise for 1 h. The stirring was continued for an additional 2 h. The reaction mixture was filtered and the solid was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography ((DCM/MeOH; 9.5/0.5) to obtain 11 as a white solid: yield 0.77 g (25%); MS(+ESI): m/z 308 [M+H]+; 1H NMR (400 MHz, CDCl3): δ11.99 (s, 1H), 8.50 (s, 1H), 7.71 (s, 1H), 4.80 (s, 2H), 4.26 (q, 2H, J=6.8 Hz), 2.70 (septet, 1H, J=6.8 Hz), 1.31 (t, 3H, J=6.8 Hz), 1.28 (d, 6H, J=6.8 Hz); 13C NMR (400 MHz, CDCl3): δ178.3, 166.9, 155.4, 148.5, 147.6, 139.2, 120.8, 62.3, 44.5, 36.5, 18.9, 14.1.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15](=O)[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])=[S:35])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1OC
Temperature: 80 °C

Procedure:
To a solution of Example 6B (1.4 g, 3.7 mmol) in toluene (50 mL) was added Lawesson's reagent (1.6 g, 4 mmol) and the mixture was refluxed at 80° C. for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc, washed with 10% solution of bicarbonate, brine and dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (2:1 Hexane-EtOAc) provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.89 (t, J=7 Hz, 3H), 1.25 (sextet, J=7 Hz, 2H), 1.36 (s, 9H), 1.76 (m, 2H), 3.74 (s, 3H), 4.25 (t, J=7 Hz, 2H), 7.06 (d, J=9 Hz, 1H), 7.35 (m, 2H), 7.45 (s, 1H); MS (ESI+) m/z 397 (M+H)+. Anal. calcd for C19H25ClN2OS2: C, 57.48; H, 6.35; N, 7.06. Found: C, 57.26; H, 6.17; N, 6.79.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:12].[O-]CC.[Na+]>C(O)C>[C:13]12([C:11](=[O:12])[CH:10]=[CH:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-fluorobenzaldehyde (6.01 ml, 56.10 mmol, Aldrich) and 1-adamantyl methyl ketone (10.00 g, 56.15 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.08 ml, 5.61 mmol). A precipitate soon fell out of solution. After stirring at room temperature for 48 hours, the mixture was cooled to -10 ° C. and the precipitate was collected by filtration. The solid was washed with cold ethanol, dried in vacuo and recrystallized from hexane. The title compound was obtained as an off-white solid (9.20 g, 57.8%).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[N:13][N:14]=[C:6]3[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][C:17]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:18])=[N:13][N:14]=[C:6]3[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)N3CCOCC3)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
The mixture of 3-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H[1,2,4]triazolo[4,3-a]purin-3-yl]propanoic acid (50 mg, 0.126 mmol), morpholine (21.0 mg, 0.252 mmol), triethylamine (25.5 mg, 0.252 mmol) and BOP (61.5 mg, 0.139 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 2 hours. After evaporation of solvent, the residue was purified by preparative LC-MS to afford the desired product (37.2 mg, 60%) as white solid. LCMS calculated for C18H25BrN7O3 (M+H): 466.1. Found: 466.1.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38]>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:9]=[C:10]([O:21][C:29]2[C:30]([N+:37]([O-:39])=[O:38])=[CH:31][CH:32]=[C:33]([F:36])[C:34]=2[F:35])[CH:11]=[C:12]([C:14]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cc(O)cc(C(=O)NC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A 22 L round-bottom flask was charged with 3,5-bis-tert-butylcarbamoyl-phenol (20, 360 g, 1.23 mol) and THF (12.5 L). The resulting slurry was cooled to 0° C. and potassium tert-butoxide (1.35 L, 1.0 M in THF, 1.35 mol) was added dropwise over approximately 30 min. After the addition was complete, the reaction mixture was cooled to between −30 and −35° C. and 2,3,4-trifluoronitrobenzene (239, 1.35 mol) was added dropwise over approximately 5 min. The reaction mixture was stirred at approximately −30° C. for 1 h whereupon the cooling bath was removed. The reaction mixture was then stirred for 20 h with warming to ambient temperature. A mixture of water (2.0 L) and brine (1.0 L) was added, and the reaction mixture was stirred vigorously in a 20 L extractor ball. Following removal of the aqueous phase, the organic layer was washed with additional brine (1.5 L), and the resulting THF solution was transferred to a 22 L round bottom flask for distillation. The extractor ball was rinsed with THF (500 mL). After approximately 10 L of THF had been removed by distillation, addition of isopropyl alcohol (11 L) was initiated and the distillation was continued until approximately 23 L of distillate had been collected. When the residual volume was 5 L and the pot temperature was 82° C., water (2.0 L) was added dropwise. Heating was then discontinued, and the reaction mixture was stirred overnight with cooling to room temperature. The resulting solid was filtered through a 3 L course-frit sintered glass filter funnel. The filter cake was washed with IPA/H2O (1:1, 2×600 mL) and dried in a vacuum oven (70° C., 25 Torr) to afford N,N′-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide (21; 488 g, 88% theory).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[I:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[I:15][C:16]1[CH:21]=[CH:20][N:19]([CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:18](=[O:22])[C:17]=1[CH3:23]
Reactant: Cc1c(I)cc[nH]c1=O
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCn1ccc(I)c(C)c1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (2.08 g, 7.25 mmol) and 4-iodo-3-methylpyridin-2(1H)-one (1.42 g, 6.04 mmol) in tetrahydrofuran (60.4 mL) was added cesium carbonate (4.06 g, 12.1) at ambient temperature. The resulting mixture was stirred at 50° C. overnight. The mixture was allowed to cool to ambient temperature and filtered through a celite pad. The pad was washed with ethyl acetate and the filtrate was concentrated to a crude residue. The material was purified via filtration through a silica gel pad, eluting with heptanes/ethyl acetate. The desired fractions were isolated, the solvent removed via rotary evaporation affording ethyl 4-(4-iodo-3-methyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate as an oil. 1.97 g
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18].[CH3:19][NH:20][CH3:21]>O1CCCC1.CCOCC>[CH3:19][N:20]([CH3:21])[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18]
Reactant: C#CCn1c(-c2ccccc2)nc(Cl)c(C)c1=O
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCn1c(-c2ccccc2)nc(N(C)C)c(C)c1=O
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1.5 g (3.8 mmol) 6-chloro-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 4 mL of tetrahydrofuran, was added 22 mL (99 mmol) of 4.5M dimethylamine in ether portionwise (2-4 mL) over a period of 7 days. The reaction mixture was allowed to warm and stir at room temperature after each addition. The progress of the reaction was followed by gas chromatography and proceeded to 80% completion. The solvent was removed in vacuo and the residue was taken up in ether and washed twice with water. The organic layer was dried over MgSO4 and concentrated to yield 1.15 g crude solid product. Flash column chromatography on silica gel (gradient elution 25-30% ethyl acetate-hexane) afforded pure 6-dimethylamino-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 23), as a white solid. 1H-NMR (CDCl3) δ 2.2(3H,s); 2.35(1H,t); 3.5(6H,s); 4.6(2H,d); 7.65(3H,m); 7.75(2H,m).
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]2[NH:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[C:7]1([CH:13]2[N:17]([C:22](=[O:23])[CH2:21][Cl:20])[C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)COC(c2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccccc2)N1C(=O)CCl
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths (21.3) ml. of a benzene solution containing 5.3 g. of 2-phenyl-4,4-dimethyl oxazolidine was mixed with 50 ml. of benzene and 3.4 g. of chloroacetyl chloride. To this solution was added 3.1 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred for about 30 minutes after addition was complete and then washed with water, separated and dried over magnesium sulfate and the solvent stripped. There was obtained a yield of 6.5 g. of an oil, the title compound, ND30 =1.5364.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]([C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH2:22][CH2:23][NH2:24])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1>C1COCC1>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH:5]3[NH:12][C:13]([C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH2:22][CH2:23][NH:24][C:43]([N:40]5[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]5)=[O:44])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:11]1)[CH2:9]2
Reactant: O=C(Cl)N1CCC(O)CC1
Reactant: NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1ccc2c(c1)ncn2CCNC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (0.35 g, 0.988 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 4-hydroxypiperidine-1-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC cis and trans isomers of 1-{2-[(4-hydroxypiperidine-1-carbonyl)-amino]-ethyl}-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)amide.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH:9]1[CH2:11][CH2:10]1
Reactant: O=CC1CC1
Reactant: Nc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ccccc1NCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 2-bromoaniline (1.720 g, 10.00 mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid (2.86 mL, 50.0 mmol) in dichloromethane (50 mL) was heated at 50° C. for 1 hour. The solution was cooled in an ice bath and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added. This mixture was stirred for 2 hours while warming to ambient temperature and then partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate in heptane) to provide the title compound (1.05 g, 93% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C1C=CC(Cl)=CC=1)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.[K].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 60.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxymethyl-4-methanesulfonyloxypyrrolidine (23.7 g: ca. 50 mmole) in dimethylformamide (50 ml), potassium phthalimide (10.2 g: 55 mmole) is added in a nitrogen atmosphere, and the mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a stirring mixture of ice water (500 ml) and ethyl acetate (500 ml). The organic layer is successively washed with water (4 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from a mixture of n-hexane and toluene. The solid is filtered off and the filtrate is purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.41 g). Yield: 61%. Colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Clc1ccncn1
Product: C[C@@H](c1ccc(-c2ccncn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-chloropyrimidine in Step 4. LC-MS Method 2 tR=1.167, m/z=374; 1H NMR (CDCl3) 1.06 (s, 3H), 1.11 (s, 3H), 1.49 (d, 3H), 2.11 (s, 1H), 2.17 (s, 2H), 2.21 (m, 1H), 2.35 (m, 1H), 2.80 (m, 1H), 5.66 (m, 1H), 7.02 (d, 2H), 7.21-7.36 (m, 5H), 7.54 (d, 1H), 7.78 (d, 2H), 8.68 (d, 1H), 9.16 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[NH2:36]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:36][C:35]3[CH:37]=[CH:38][C:39]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[C:33]([F:32])[CH:34]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(N3CCOCC3)c(F)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-fluoro-4-morpholin-4-yl aniline (Bionet, 132 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.