Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C2C3C(=C4C(=CC=3)C(C3C=CC=CC=3)=CC=N4)N=CC=2)C=CC=C[CH:2]=1.C(OCCCC)=C.[CH2:34]([O:36][C:37]([C:39]1[C:40]([CH3:52])=[N:41][N:42]([C:44]2[C:49]([CH2:50][OH:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:43]=1)=[O:38])[CH3:35]>C(N(CC)CC)C.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[CH3:52][C:40]1[C:39]([C:37]([O:36][CH2:34][CH3:35])=[O:38])=[CH:43][N:42]([C:44]2[C:49]([CH2:50][O:51][CH:1]=[CH2:2])=[CH:48][CH:47]=[CH:46][N:45]=2)[N:41]=1
Reactant: CCOC(=O)c1cn(-c2ncccc2CO)nc1C
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: [Pd+2]
Agent: C=COCCCC
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: C=COCc1cccnc1-n1cc(C(=O)OCC)c(C)n1
Temperature: 75 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
Palladium(II)trifluoroacetate (5.1 mg, 15.3 mmoles) and 4,7-diphenyl-phenanthroline (5.1 mg, 15.3 mmoles) are dissolved in n-butyl vinyl ether (6.1 mL, 61.2 mmol) and 1-(3-hydroxymethyl-pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (800 mg, 3.1 mmol) and a few drops of triethylamine are added. The flask is sealed and stirred at 75° C. for 24 hours. Then the mixture is cooled to 24° C. and filtrated through a pad of celite. The solvent is eliminated under reduced pressure and the residue is purified by normal phase Isco chromatography using hexane and ethyl acetate as eluents (5-20% in ethyl acetate) to give 605 mg of ethyl 3-methyl-1-[3-(vinyloxymethyl)-2-pyridyl]pyrazole-4-carboxylate. MS (m/z): 288 (M+1)
Reaction SMILES: O1C=CCCC1.[CH3:7][O:8][CH:9]1[CH:14]=[CH:13][CH2:12][CH:11]([C:15](OC)=[O:16])[O:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO.Cl.C(OCC)C.[Pt](=O)=O>[OH:16][CH2:15][C@@H:11]1[O:10][C@@H:9]([O:8][CH3:7])[CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1CC=CC(OC)O1
Agent: O=[Pt]=O
Agent: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CO[C@H]1CCC[C@H](CO)O1

Procedure:
The absolute configuration for the product was determined by first isomerizing the dihydropyran derivative product in methanol by use of hydrochloric acid as a catalyst so that the product had a trans-isomer content of 95%, subsequently converting the ester into an alcohol in diethyl ether by use of lithium aluminum hydride, and then hydrogenating the double bonds by using platinum dioxide in methanol to give trans-6-hydroxymethyl-2-methoxytetrahydropyran, followed by optical rotation measurement. As a result, the optical rotation [α]20 of the above compound was found to be -119.9° (c=1.07, solvent: benzene). This found value was compared with the optical rotation [α]20 of +129.7° (c=4.3, solvent: benzene) for (2S,6S)-6-hydroxymethyl-2-methoxy-3,4,5,6-tetrahydropyran as described in J. Jurczak et al., J. Chem. Soc., Chem. Commun., pp. 540-542 (1983). Based on the comparison, the trans-isomer and cis-isomer were judged to be a (2R,6R)-isomer and a (2S,6R)-isomer, respectively.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[CH:33]=[C:32]1[CH:40]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]([CH3:22])[C:40]([C:32]4[N:31]([CH2:30][C:29]([F:43])([F:42])[F:28])[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:34]5[CH:33]=4)=[N:23][C:17]=3[CH:16]=2)=[O:26])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cc2cccnc2n1CC(F)(F)F
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Temperature: 90 °C
Yield: 62.6 %

Procedure:
To a mixture of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (2.1 g, 5.55 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.3 g, 5.70 mmol) in ethanol (55 ml) was added portionwise a solution of sodium hydrosulfite (3.41 g, 16.65 mmol) in water (25 ml). The mixture was flushed with nitrogen and heated at 90° C. overnight for 17 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. DCM was added to the residue and the heterogeneous solution was dried over sodium sulfate. The solid was filtered off and the filtrate was concentrated under vacuo. The residue was loaded in dichloromethane and purified by SP4 SNAP on 2 silica (Si) 100 g columns using an initial gradient of 25-80% (15 CVs), followed by 80-100% (10 CVs) ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (1.934 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[OH:21][C:14]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[NH:16][C:15]1=[O:20]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(C)cc32)cc1
Yield: 81.2 %

Procedure:
With 5.61 g of 4-bromoanisole and 3.23 g of 5-methyl isatin as starting materials, 4.38 g of the title compound (light brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [OH2:1].S(=O)(=O)(O)O.C=O.[NH2:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[C:13](Cl)=[CH:12][C:11]=1[Cl:27]>O>[NH2:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[C:13]([OH:1])=[CH:12][C:11]=1[Cl:27]
Reactant: O
Reactant: Nc1c(Cl)cc(Cl)c2c1C(=O)c1ccccc1C2=O
Agent: C=O
Agent: O=S(=O)(O)O
Product: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A stirred reactor is charged with 184 parts of sulfuric acid monohydrate and 4.8 parts (1 equivalent) of paraformaldehyde are added, with stirring, over about 15 minutes. Stirring is continued until a solution is obtained. This solution is then heated to 60°-65° C. and 46.5 parts of 98% 1-amino-2,4-dichloroanthraquinone are added. The reaction mixture is heated for 1 hour to 110° C. and this temperature is maintained for 3 hours. The mixture is cooled to 100° C. and 870 parts of water are added. The resultant suspension is heated to 90°-95° C. and stirred for 2 hours at this temperature, then cooled and filtered. The filter cake is washed with hot water and the product is dried in vacuo at 80°-90° C., affording 43.3 parts (95% yield) of 1-amino-2-chloro-4-hydroxyanthraquinone. Rf =0.29 (eluant: concentrated formic acid, saturated with 1-bromonaphthalene).
Reaction SMILES: [Br-].[C:2]1([S+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([IH+:35])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].[C:36]([C:40]1[CH:45]=[CH:44][C:43]([IH+:46])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37].C([O-])(=O)C.[F:51][C:52]([F:70])([S:66]([OH:69])(=[O:68])=[O:67])[C:53]([F:65])([F:64])[C:54]([F:63])([F:62])[C:55]([F:61])([F:60])[S:56]([OH:59])(=[O:58])=[O:57]>O.CC(C)=O>[F:61][C:55]([F:60])([S:56]([O-:59])(=[O:58])=[O:57])[C:54]([F:63])([F:62])[C:53]([F:64])([F:65])[C:52]([F:51])([F:70])[S:66]([O-:69])(=[O:67])=[O:68].[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[C:25]([C:29]1[CH:30]=[CH:31][C:32]([IH+:35])=[CH:33][CH:34]=1)([CH3:28])([CH3:26])[CH3:27].[C:36]([C:40]1[CH:41]=[CH:42][C:43]([IH+:46])=[CH:44][CH:45]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc([IH+])cc1
Agent: [Br-]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
4.73 g of triphenyl sulfonium bromide was dissolved in water in a flask. Bis (4-t-butylphenyl iodonium) acetate (6.24 g) was dissolved in acetone and added to the flask. Perfluorobutane-1,4-disulfonic acid (5.0 g) was then added to the mixture and the mixture was stirred over night at room temperature. Bis (4-t-butylphenyl iodonium) triphenyl sulfonium perfluorobutane-1,4-disulfonate was isolated as in Example 1 (mixture of compounds); mp 93° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:21][CH:22]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CCOCC1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(C1CCOCC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(tetrahydro-pyran-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate G) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR=7.34 min (HPLC 2); ESI-MS: tR=1.21 min, [M+H]+ 465/467 (LC-MS 1); TLC: Rf=0.40 (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15]CC3C=CC=CC=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(OC)noc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c(OC)noc12
Reaction time: 3 h

Procedure:
A solution of 3-methoxy-6-benzyloxy-7-propylbenz-(4,5)-isoxazole (Step E; 181 mg) in ethyl acetate (4 mL) was treated with 10% palladium on carbon catalyst (25 mg). The mixture was shaken under a hydrogen atmosphere (40 psi) for 3 hours. The mixture was filtered through Celite and concentrated to a solid. The title compound was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Cl:37])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a carbon tetrachloride (10 mL) solution of (5-benzyloxy-pyridin-2-yl)-methanol (500 mg) described in Manufacturing Example 127-1-2 was added triphenylphosphine (791 mg), which was refluxed for 19 hours and 35 minutes under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (386 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:37])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.154 mmol) and Hunig's base (0.040 mL, 0.230 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.307 mmol) dropwise. The mixture was stirred at room temperature for 2 h. Purification via reverse phase flash chromatography afforded the title compound (15 mg, 18.26% yield). LCMS: rt=3.32 min, [M+H+]=535
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:11][CH:10]=1
Reactant: ClCCCN1CCOCC1
Reactant: Oc1ccc(OCc2cccc(F)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1cccc(COc2ccc(OCCCN3CCOCC3)cc2)c1

Procedure:
To a solution of 0.56 g (0.01 mol) of potassium hydroxide in 18 ml of absolute ethanol are added 2.18 g (0.01 mol) of 4-(3-fluorobenzyloxy)phenol. There is then added a solution of 1.64 g (0.01 mol) of N-(3-chloropropyl)morpholine in 2 ml of absolute ethanol. The mixture is stirred at reflux for 24 hours, allowed to cool and then refrigerated. The solid which forms is collected by filtration, washed with absolute ethanol and dissolved in diethyl ether. The ethereal solution is washed consecutively with water (20 ml), 10% aqueous sodium hydroxide (3×15 ml) and water until neutral to litmus. The solution is dried over sodium sulfate, filtered and evaporated and recrystallized from diethyl ether-petroleum ether and from diethyl ether alone to yield N-[3-(4-{3-fluorobenzyloxy}phenoxy)propyl]morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCSc3ccc(Cl)c(Cl)c3)ccc2N1
Product: O=C1CCc2cc(OCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[3-(3,4-dichlorophenyl-mercapto)-propoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.F[B-](F)(F)F.[Li+].[O:15]1[CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH2:17][CH2:16][OH:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1COC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC#N
Product: OCCCNc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 81.4 %

Procedure:
4-fluoroaniline (3.82 g) and lithium tetrafluoroborate (3.32 g) were added to a solution of oxetane (1.00 g) in acetonitrile (20 mL) at room temperature, and the reaction solution was stirred at room temperature for 64 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.37 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:8]1[NH:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1c[nH]c(Cc2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1c[nH]c(Cc2ccccc2)n1

Procedure:
A 125 gm. portion of 2-benzyl-4-imidazolemethanol and 500 g. of manganese dioxide in 2 liters of chloroform are reacted as described in Example 22 giving the desired product, m.p. 130°-136° C.
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-:14])=O)[S:11][C:4]=12.Cl.[CH3:16][O:17][C:18]([C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][NH:21]1)=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18]([C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]1[C:12]([C:10]1[S:11][C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:3]=2[Cl:2])[CH:9]=1)=[O:14])=[O:19]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1cc2nccc(Cl)c2s1
Reaction time: 24 h
Yield: 68.7 %

Procedure:
In 10 mL of DMF was added 3.0 g (16.7 mmol) of 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium salt, 3.20 g (14.66 mmol) of (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride, PyBop (9.12 g (17.5 mmol) and 5.59 mL (32.1 mmol) of DIEA and the mixture was stirred for 24 h. To the mixture was added 50 mL of EtOAc was washed with 50/50 aq. NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 and concentrated to give an amber oil. Purification through 100 mL of silica eluting with EtOAc:CH2Cl2 (1:1) gave crude product. Diethyl ethyl was used to triturate (2×5 mL) the residue to afford 3.43 g (70%) of (2S,4R)-1-(7-Chloro-thieno[3,2-b]pyridine-2-carbonyl)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester as off-white solid. HPLC: Rt 3.36 min. (98.2% area). LCMS (ESI) (M+H+) m/z: 341.0.
Reaction SMILES: C(C1C=CC(C(C)(CCCCC(=O)CCCCC(C2C=CC(CC(C)C)=CC=2)(C)C(O)=O)C(O)=O)=CC=1)C(C)C.C([O:43][C:44](=[O:68])[C:45]([CH3:67])([CH3:66])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](=[O:65])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]([CH3:64])([CH3:63])[C:58]([O:60]CC)=[O:59])C.[OH-].[K+]>C(O)C.O>[CH3:63][C:57]([CH3:64])([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][C:51](=[O:65])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([CH3:67])([CH3:66])[C:44]([OH:68])=[O:43])[C:58]([OH:60])=[O:59]
Reactant: CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 56.8 %

Procedure:
According to the procedure given for 210f, 209g (8.54 g, 21.4 mmol) was saponified with KOH (85%, 4.53 g, 68.6 mmol) in ethanol (13 mL) and water (5 mL) at reflux for 4 h. The solid product obtained after usual workup was recrystallized from Et2O/hexanes (50 mL/50 mL), affording 210g (4.16 g, 57%) as colorless needles. Mp 82-83° C. 1H NMR (CDCl3): δ 11.53 (br., 2H), 2.39 (t, 4H, J=7.3), 1.60-1.50 (m, 8 H), 1.30-1.20 (m, 8 H), 1.18 (s, 12 H). 13C NMR (CDCl3): δ 211.7, 185.0, 42.8, 42.3, 40.4, 29.7, 25.1, 24.8, 23.8. HRMS (LSIMS, gly): Calcd for C19H35O5 (MH+): 343.2484, found: 343.2444. HPLC: 92.6% pure. Anal. (C19H34O5) C, H.
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:9][C:10]1[C:15](Br)=[N:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1>C(#N)C>[NH2:9][C:10]1[C:15]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1
Reactant: SC1CCCC1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2ccccc2)nc1SC1CCCC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
To a solution of cyclopentanethiol (0.18 g, 1.80 mmol) in dry acetonitrile (20 mL), sodium hydride (NaH) (0.04 g, 1.80 mmol) was added the resulting mixture was stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.15 g, 0.6 mmol) was added and the mixture heated at 80° C. for 2 h, cooled and quenched with water. Then EtOAc was added and the organic layer was anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using dichloromethane-EtOAc (9:1 v/v) as eluent, to obtain 0.11 g of the title compound 18n as a yellow solid (mp 92-94° C., 67% yield). 1H-NMR (CDCl3): 1.68-1.83 (m, 6H), 2.28-2.31 (m, 2H), 4.21-4.28 (m, 1H), 4.93 (br s, 2H), 7.32-7.35 (m, 1H), 7.41-7.45 (m, 2H), 7.91-7.93 (m, 2H), 8.20 (s, 1H). MS (ESI): m/z 272 (Mile).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ccc(I)cn1
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(Cl)nc2)C1
Yield: 46.7 %

Procedure:
tert-Butyl 3-azetidinylcarbamate (0.70 g, 4.0 mmol) and 2-chloro-5-iodopyridine (1.46 g, 6.0 mmol; Aldrich) were processed according to the procedure described in Example 1A to provide the title compound (0.53 g, 47%). MS (CI/NH3) m/z 284/286.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([O:52][CH3:53])[C:38]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH:19]4[CH2:20][C:21]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:22][CH:23]([CH2:24][CH:25]2[CH2:26]5)[CH2:27]4)=[CH:3][C:2]([C:41]2[CH:40]=[C:39]([O:52][CH3:53])[C:38]([OH:54])=[C:37]([Cl:36])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(Nc1c(C(=O)C4CC4)cnc4ccc(Br)cc14)C(C3)C2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NC4C5CC6CC4CC(NC(=O)OC(C)(C)C)(C6)C5)c3c2)cc(Cl)c1O
Yield: 135.9 %

Procedure:
Following general procedure F, tert-butyl 4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]adamantylcarbamate (57 mg, 0.100 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the crude product (84 mg) as a brown oil: ESI MS m/z 619 [C35H40ClN3O5+H]+.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH2:9][CH2:10][N:11]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=1)[C:12]([NH2:14])=[O:13])C.Cl>C(O)C>[Br:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([N:11]2[CH2:10][CH2:9][C:8](=[O:7])[NH:14][C:12]2=[O:13])=[CH:16][C:17]=1[CH3:23]
Reactant: CCOC(=O)CCN(C(N)=O)c1cc(C)c(Br)c(C)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(N2CCC(=O)NC2=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
A solution of sodium ethoxide (15.7 mg, 0.033 mmol) in ethanol (0.1 ml) was added to a solution of 3-[1-(4-bromo-3,5-dimethyl-phenyl)-ureido]-propionic acid ethyl ester (11.4 mg, 0.033 mmol) in ethanol (0.9 ml), and the mixture was stirred at room temperature for 24 hours. The mixture was adjusted to pH 4 with 1 N hydrochloric acid and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 1-(4-bromo-3,5-dimethyl-phenyl)-dihydro-pyrimidine-2,4-dione (9.8 mg, 99%).