Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][C:15]1[C:24]([N:25]=[C:26]=[O:27])=[C:23]2[C:18]([C:19](=[O:28])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:1]([NH:13][C:26]([NH:25][C:24]1[C:15]([CH3:14])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][CH2:21][CH2:20][C:19]2=[O:28])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: Cc1ccc2c(c1N=C=O)OCCC2=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)Nc1c(C)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
95 mg of dodecylamine was added to a solution of 100 mg of 7-methyl-4-chromanon-8-ylisocyanate in 5 ml of ethyl acetate, and the mixture was stirred at room temperature for 12 hr. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from ethyl acetate to afford 150 mg of the intended title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:31][O:32][NH:33][CH3:34].O>C(Cl)Cl>[CH3:31][O:32][N:33]([CH3:34])[C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a suspension of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (3 g, 12.33 mmol) in DCM (35 mL) was added CDI (4.00 g, 24.66 mmol) portion-wise. The resulting mixture was stirred for 1 hour, and then O,N-dimethylhydroxylamine hydrochloride (1.804 g, 18.50 mmol) was added, and the mixture was stirred at RT for 16 hours. Water (30 mL) was added, and the mixture was stirred for 1 hour and then extracted with DCM (50 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to afford tert-butyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (3.3 g, 93% yield).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20]3)=[CH:15][C:14]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:36](OC)[N:37]([CH3:39])[CH3:38]>C(#N)C>[CH2:27]([O:26][C:14]1[CH:15]=[C:16]([N:19]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20]2)[CH:17]=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1](=[O:3])[CH:2]=[CH:36][N:37]([CH3:39])[CH3:38])=[N:5]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(=O)C=CN(C)C)c1=O

Procedure:
A mixture of 3-acetyl-1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one (3.70 g), N,N-dimethylformamide dimethyl acetal (40 mL) and acetonitrile (40 mL) was heated under reflux for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound (3.85 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:22])=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (7.53 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate were dissolved in 18 ml of tert-butanol, and 5 ml of water were then added. After cooling to 0° C., 2.35 g (15.1 mmol) sodium dihydrogenphosphate dihydrate, 2.73 g (30.1 mmol) of sodium chlorite and 3.17 g (45.2 mmol) of 2-methyl-2-butene were added in succession. After 1 hour at 20° C., water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure (logP: 1.38)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[C:4]=2[CH:3]=[N:2]1.[NH3:15]>C(O)C>[OH:14][CH:12]([CH2:13][NH2:15])[CH2:11][O:10][C:9]1[C:4]2[CH:3]=[N:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: c1cc(OCC2CO2)c2cnsc2c1
Solvent: CCO
Product: NCC(O)COc1cccc2sncc12
Reaction time: 3 h

Procedure:
4.0 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane in 100 ml of aqueous ammonia and 300 ml of ethanol are left to stand for 3 hours at 35° C. The mixture is concentrated, the semi-crystalline residue is dissolved in ethanol and a solution of hydrogen chloride in ether is added dropwise. The hydrochloride which precipitates is filtered off, washed with dry ether and dried.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[NH:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[F:44])[N:31]=1>O1CCCC1>[F:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:32]1[N:31]=[C:30]([N:18]2[CH2:19][CH2:20][NH:21][C@@H:16]([C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH2:6][O:7][CH2:8][CH2:9]4)=[CH:15][CH:14]=3)[CH2:17]2)[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=1
Reactant: c1cc(N2CCOCC2)ccc1[C@@H]1CNCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCOCC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of the above prepared (3R)-3-(4-(morpholin-4-yl)phenyl)piperazine trihydrochloride (0.5 g, 1.40 mmol) and triethylamine (0.8 g, 7.91 mmol) in tetrahydrofuran (10 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-(3H)-pyrimidin-4-one (0.3 g, 1.25 mmol) which was prepared by Reference Example 2 portionwise. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-(4-morpholin-4-yl-phenyl)-piperazin-l-yl)-3H-pyrimidin-4-one (0.41 g, 0.91 mmol, 73%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Cc1cnn2cc(Cl)nc(O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C)c34)CC2=O)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
A mixture of 6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-ol 5.52 (48 mg, 0.262 mmol), (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (135 mg, 0.394 mmol), and cesium carbonate (136 mg, 0.417 mmol) in DMF (2 mL) was heated at 90° C. After 5 hours, reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate. Combined organics were washed with 50% brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate/hexanes) to yield (R)-4-((R)-1-((6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 5.53 (37 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:5]2.[Li]CCCC.[C:36]([O:43][CH2:44][CH3:45])(=[O:42])[C:37]([O:39]CC)=O>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=3)[CH:10]=[C:11]([CH3:12])[C:2]=2[C:37](=[O:39])[C:36]([O:43][CH2:44][CH3:45])=[O:42])=[CH:29][CH:28]=1
Reactant: Cc1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c(-c2ccc(Cl)cc2)c1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C)cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
To a solution of (6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-yloxy)triisopropylsilane (2.5 g, 4.9 mmol) in THF (50 mL) cooled to −78° C. was added n-BuLi (1.6 M in hexanes, 4.6 mL, 7.4 mmol) dropwise. The resulting solution was allowed to stir at −78° C. for 30 min before addition of diethyl oxalate (1.7 mL, 12.4 mmol). After 45 min at −78° C., the cold bath was removed and the reaction allowed to warm to room temperature over 1 h. 5% citric acid (50 mL) solution was added and the layers separated. Following extraction with EtOAc, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-10% EtOAc/Hex) to afford 2.10 g (81%) of the title compound as a colorless syrup. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H38ClO4Si: 526.16; found: 526.89.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5](N)=[N:6][CH:7]=1.N(OCCC(C)C)=O.C[Si](C)(C)[Br:26].C(=O)(O)[O-].[Na+]>BrCBr.CCCCCCC>[Br:26][C:5]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: C[Si](C)(C)Br
Reactant: Nc1ncc(Br)nc1-c1ccc(Cl)cc1
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: BrCBr
Product: Clc1ccc(-c2nc(Br)cnc2Br)cc1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
To a suspension of 12.00 g (0.033 mol) 5-bromo-3-(4-chloro-phenyl)-pyrazin-2-ylamine in 80 ml dibromomethane was added 5.93 g isoamyl nitrite. To the resulting mixture was added dropwise during ca 45 min a solution of 7.75 g trimethylbromosilane in 20 ml dibromomethane with stirring at ambient temperature. The mixture was stirred at room temperature for 2 h. To the resulting dark solution was added 100 ml of a 10% aqueous sodium bicarbonate. The phases were separated and the organic phase washed with brine. To the organic phase was added silica gel (ca. 100 g) and the solvent was removed under aspirator vacuum. The product was purified by chromatography with dichloromethane:heptane=1:3 to yield 11.93 g (79% yield) 2,5-dibromo-3-(4-chloro-phenyl)-pyrazine as white crystals melting at 123-125° C. and as a byproduct 0.300 g 5-bromo-3-(4-chloro-phenyl)-2-(3-methyl-butoxy)-pyrazine as a yellow oil. MS (ISP) (M+H+)=357.0 and 355.0.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@H:6]1[NH2:17])(=[O:3])[CH3:2].[Br:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](O)=[O:21]>>[C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:7](=[O:16])[C@H:6]1[NH:17][C:20](=[O:21])[CH:19]([Br:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(Br)c1ccccc1
Product: CC(=O)O[C@H]1[C@H](NC(=O)C(Br)c2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Yield: 58.9 %

Procedure:
Following the procedure of Reference Example 16B but using 0.385 g of (3S,4S)-4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine and 0.384 g of 2-bromo-2-phenylacetic acid there is obtained 0.40 g of (3S,4S)-4-acetoxy-3-(2-bromo-2-phenylacetamido)-1-t-butyldimethylsilyl-2-oxoazetidine.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][C:18]1[C:19](=[O:39])[O:20][C:21]2[CH:31]=[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[C:29]([Cl:38])=[CH:28][C:22]=2[C:23]=1[CH2:24][C:25](=[O:27])[NH2:26]>C(Cl)Cl>[C:25]([CH2:24][C:23]1[C:22]2[CH:28]=[C:29]([Cl:38])[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:35])[CH3:36])=[CH:31][C:21]=2[O:20][C:19](=[O:39])[C:18]=1[CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([NH:13][S:9]([CH3:8])(=[O:11])=[O:10])[CH:15]=1)(=[O:27])[NH2:26]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(N)c3)c(CC(N)=O)c2cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(C)(=O)=O)c3)c(CC(N)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
Et3N (13·L, 0.093 mmol) and methanesulfonyl chloride (3.6·L, 0.050 mmol) were added to a solution of dimethylcarbamic acid 3-(3-aminobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester (20 mg, 0.047 mmol) in methylene chloride (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled away by concentration under reduced pressure, and the resultant residue was purified by column chromatography to yield the title compound (5.0 mg, 22%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH:14]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20]Cl)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]([CH3:13])[C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH:19]([OH:22])[CH2:18][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: CC(C)NCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)NCC(O)COc1ccc(NC(=O)N(C)C)cc1
Reaction time: 5 h

Procedure:
A mixture of 20 g of p-(N',N'-dimethylureido)-phenol, 15 g of 3-isopropylamino-2-hydroxy-1-chloropropane, and 20 g of finely ground potassium carbonate in 250 ml of acetone is stirred at 50° for 5 hours. The solid part of the mixture is filtered off and the acetone solution is evaporated in a vacuum. The residue is dissolved in 100 ml of 2N hydrochloric acid, the undissolved part is filtered off and the remaining mixture is extracted with methylene chloride. The aqueous phase is rendered alkaline by adding 2N sodium hydroxide solution and is extracted with methylene chloride. After the evaporation of the solvent, 1-[p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylaminopropane is isolated which melts at 138°-139° after recrystallisation from benzene and has the formula ##STR22##
Reaction SMILES: [CH:1]1([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:1]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2]1)=[O:31]
Reactant: COC(=O)CC1CNCCc2ccccc21
Reactant: O=C(O)CCCCCCNc1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CN(C(=O)CCCCCCNc2ccccn2)CCc2ccccc21
Reaction time: 4 h

Procedure:
To a stirring solution of methyl 2-(1H,2H,3H,4H,5H-benzo[d]azepin-1-yl)acetate in dichloromethane (0.2 M) was added 7-(2-pyridylamino)heptanoic acid (1.2 eq), triethylamine (1.5 eq), and EDAC (2 eq). After 4 hrs, the reaction was washed with water, 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica; EtOAc) afforded a colorless oil.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:15]1([C@H:21]2CCC[C@H:22]2[NH2:26])[CH2:20][CH2:19][CH2:18]CC1>>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N[C@@H]1CCC[C@@H]1C1CCCCC1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: C1CCNC(=N[C@@H]2CCC[C@@H]2C2CCCCC2)CC1

Procedure:
By the procedure of Example 23, only employing a reaction time of 29 days and substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of cis-2-cyclohexylcyclopentylamine hydrochloride, the desired product is obtained, M.P. 179°-180° C.
Reaction SMILES: [F:1][CH:2]([F:23])[N:3]1[C:7]2[C:8](=[O:22])[NH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:11][C:6]=2[N:5]=[CH:4]1.O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[F:23][CH:2]([F:1])[N:3]1[C:7]2[C:8]([O:22][C@@H:25]([C@H:27]3[CH2:31][N:30]([C@@H:32]([C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)[CH3:33])[C:29](=[O:42])[CH2:28]3)[CH3:26])=[N:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: COc1ccc(-c2cc3ncn(C(F)F)c3c(=O)[nH]2)cc1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C(F)F)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.29 (49 mg, 0.153 mmol), lactam alcohol 1.05 (60 mg, 0.23 mmol), and PPh3 (60 mg, 0.23 mmol) were taken up in THF (2 mL). To the resulting suspension was added DEAD (38 μL, 0.24 mmol) dropwise. The resulting clear colorless solution was heated to 40° C. and stirred 15 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography gave (R)-4-((R)-1-(3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.30 that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33F2N4O5: 567.2; found 567.4.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCN1CCc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1SC(Cc2ccc(OCCN3CCc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
A procedure similar to that described in Preparation was repeated, except that 240 mg of 2-(indolin-1-yl)-ethanol (prepared as described in Preparation 9), 690 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 370 mg of 1,1'-(azodicarbonyl)dipiperidine and 5 ml of anhydrous tetrahydrofuran were used, to give 530 mg of the title compound having Rf=0.88 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]1([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][OH:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(CC2OCCC[O:43]2)C=CC=CC=1.O>CN(C=O)C>[C:22]1([CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([OH:43])=[O:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CC2OCCCO2)cc1
Reactant: OCCCOCCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCOCCc1ccccc1

Procedure:
Pyridinium dichromate (100 g) was added to a solution of 3-[2-phenylethoxy]-propanol (13.6 g) (prepared from 2-phenylmethyl-1,3-dioxane following the method described in Can. J. Chem., 1974, 52, 888) in DMF (400 ml). The whole was rapidly stirred for 6 hours at which point water was added. This was then extracted with ether (×3). The combined ethereal layers were extracted with 10% aqueous sodium hydroxide solution (500 ml). The basic solution was made acidic pH 1-2 with concentrated hydrochloric acid and extracted with ether. These ethereal extracts were then combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to yield the subtitled compound (7.6 g).
Reaction SMILES: [C:1](NC1NC(=O)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC)(=O)C(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CO>N1C=CC=CC=1>[S:33]([CH3:1])([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(see FIG. 8B) N2-Isobutyryl-2′-O-methylguanosine (6) (Inoue et al., Nucleic Acids Res. 1987, 15, 6131-6148, and is incorporated by reference herin in its entirety) (1.6 g, 4.36 mmol) was dissolved in dry pyridine (25 mL) and the solution was cooled to 0° C. while protected from moisture. p-Toluenesulfonyl chloride (1.0 g, 5.23 mmol) was added and the reaction mixture was left at 0-3° C. for 48 h. MeOH (10 mL) was added and the mixture evaporated to a syrup. After standard work up and column chromatography using 1-2% MeOH in CH2Cl2, 7 was obtained as a colorless foam, 1.06 g (47%), 1H NMR δ12.25 (br s, 1H, NH), 9.55 (br s, 1H, NH), 7.83 (d, JH,H=8.3, 2H, Ts), 7.78 (s, 1H, H8), 7.42 (d, JH,H=8.3, 2H, Ts), 5.83 (d, J1′,2′=6.2, 1H, H1′), 4.82 (app t, J2′,3′=5.7, 1H, H2′), 4.64 (m, 1H, H3′), 4.37 (dd, J5′,4′=2.2, J5′,5″=10.3, 1H, H5′), 5.23 (dd, J4′,5″=2.9, J4′,3′=5.2, 1H, H4′), 4.29 (dd, J5″,4′=2.9, J5″,5′=10.3, 1H, H5″), 3.47 (s, 3H), OMe), 2.76 (m, 1H, CH(CH3)2), 2.51 (s, 3H, Ts-Me),1.29 (m, 6H, 2×Me).