Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1Br)(=O)C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[OH-].[Na+]>C(O)C>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[N:11]([C@@H:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]3[OH:4])[C:12]([NH:26][CH:23]3[CH2:25][CH2:24]3)=[N:13][C:14]=2[CH:19]=1
Reactant: NC1CC1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1n1c(NC2CC2)nc2cc(Cl)c(Cl)cc21
Yield: 67 %

Procedure:
(±)trans-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl acetate (Example 45, part c, 1.00 g, 2.46 mmol) and cyclopropylamine (5.0 ml) were refluxed in absolute ethanol (15 ml) for 3 days. The solution was cooled and 1 N sodium hydroxide (2.4 ml) was added. The residual solid was crystallized from ethanol-water to provide title compound as off-white powder (0.56 g, 67%), m.p. 149-151° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 7.55, 7.39 (both s, each 1, 2 aromatic CH), 6.90 (m, 1, NH), 4.73 (d, J=5.2 Hz, 1, OH), 4.1-3.8 (m, 2, OCH and NCH), 2.8-2.65 (m, 1, CHNH), 2.2-1.9 and 1.8-1.2 (m, 8, 4 CH2), 0.75-0.45 (m, 4, 2 cyclopropyl CH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14](=[O:16])[CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14](=[O:16])[CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NS(=O)(=O)c1cccc(N)c1
Reaction time: 0.25 h

Procedure:
3-Nitro-N-(acetyl)benzenesulfonamide (452 mg) was dissolved in 40 ml of ethanol, treated with 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 30 psi for 15 minutes. The reaction mixture was filtered through Celite and concentrated to give 564 mg of a waxy solid. The title compound was obtained analytically pure after column chromatography on silica gel (chloroform-methanol, 9:1 v/v).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[NH2:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11](OCC)=[O:12].C1COCC1>O>[NH2:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)C[C@H](N)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
1.45 g (38.1 mmol) of lithium aluminum hydride were added in portions with ice-cooling to a suspension of 3.5 g (15.2 mmol) of ethyl (S)-3-amino-3-phenyl-propionate hydrochloride in 150 ml or absolute THF and the mixture was stirred at room temperature for 1 hour. 5 ml of water were then cautiously added dropwise with ice-cooling. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DCM and the solution was extracted with water. The organic phase was dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 1.84 g of (S)-3-amino-3-phenylpropanol were obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5](=[O:8])[N:4]=1)[CH3:13]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CN(C)C=Nc1nc(O)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(=O)n(COC(=O)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To DMF (3 mL) were added N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.6 mmol), and chloromethyl pivalate (90 mg, 0.6 mmol), and the mixture was shaken at room temperature for 16 h. The mixture was partitioned between EtOAc and H2O. The organic phase was dried over MgSO4, filtered, and evaporated. To the resultant crude oil Et2O (3.5 mL) was added and a precipitate formed which was collected by filtration. The title compound was isolated as a white solid (37 mg, 23%): mp 193-194° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.07 (d, J=6.3 Hz, 1H), 5.60 (s, 2H), 3.22 (s, 3H), 3.09 (s, 3H), 1.11 (s, 9H); ESIMS m/z 299 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I:11]Cl.C(OCC)(=O)C>C(#N)C>[I:11][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.9 %

Procedure:
To a solution of 4-nitroaniline (27.6 g, 0.2 mol) in 200 mL of dry acetonitrile was added a solution of ICl (31.0 g, 0.19 mol) in 50 mL of acetonitrile and the mixture was stirred at room temperature for 18 h. The reaction mixture was then poured into ethyl acetate, washed (20% aq. Na2S2O3, brine), dried (Na2SO4) and evaporated to give a brown solid. Chromatography (SiO2 /CH2Cl2 -hexane, 6:4 to 7:3) afforded the title compound (18.0 g, 36%) as a yellow solid, mp 104°-106° C.: IR (neat) 3480, 3380, 1610, 1300 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ8.38 (d, J=2.6 Hz, 1H), 7.97 (dd, J=9.0, 2.6 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 6.73 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C1COCC1.ClCCl>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH2:4][CH2:3]1
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(C)C(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
11 g (109 mmol) of 4-hydroxy-piperidine and 14.5 ml of triethylamine were dissolved in a mixture of 30 ml of THF and 80 ml of dichloromethane and cooled to 0° C. 10 ml (104 mmol) of methacryloyl chloride were added dropwise within 15 minutes. The solution was stirred at 10° C. for 5 hours. Subsequently, the reaction mixture was filtered over silica gel. After distillation of the solvent the crude product was purified by column chromatography on silica gel with ethyl acetate as the eluent. Therefrom there resulted 14.5 g of 1-(4-hydroxy-piperidin-1-yl)-2-methyl-prop-2-en-1-one in the form of white crystals.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[O:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH2:15][C:16](O)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][S:24][C:25]1[C:30]([NH2:31])=[C:29]([S:32][CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1>>[CH3:23][S:24][C:25]1[C:30]([NH:31][C:16](=[O:17])[CH2:15][CH:14]=[CH:13][C:12]2[CH2:11][O:10][C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:29]([S:32][CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1
Reactant: O=C(O)CC=CC1=C(c2ccccc2)c2ccccc2OC1
Reactant: CSc1cc(C)nc(SC)c1N
Product: CSc1cc(C)nc(SC)c1NC(=O)CC=CC1=C(c2ccccc2)c2ccccc2OC1

Procedure:
N-[2,4-Dimethylthio-6-methyl-3-pyridyl]-4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-enamide is prepared under the conditions of Example 1 from 4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-en-1-oic acid and 2,4-dimethylthio-6-methyl-3-pyridylamine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:19][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a flask containing a stir bar was added 5-bromo-2-benzofuran-1(3H)-one (12.0 g, 56.3 mmol) and NBS (15 g, 84 mmol). Triflic acid (50 mL) was then added at 0° C. and the resulting mixture was allowed to warm to rt and stir for 2 days. TLC analysis of the reaction mixture showed complete reaction. The reaction mixture was poured into ice and the organic layer was separated, washed with brine, water, dried over Na2SO4, filtered, and concentrated to dryness. The residue was then absorbed into silica gel and subjected for purification over a silica MPLC column to give 4,5-dibromo-2-benzofuran-1(3H)-one. LC-MS: M+1=291
Reaction SMILES: Br.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.O1CCCC1.[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[CH2:20]([O:19][C:18]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:10]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc2c(c1)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
7-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (3 g) was dissolved in 1N aqueous sodium hydroxide solution (46 ml) and tetrahydrofuran (10 ml) and benzyl chlorocarbonate (2.45 g) was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with chloroform and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (3.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.Cl.[F:13][C:14]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15]1>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:17][CH2:18][C:14]([F:19])([F:13])[CH2:15]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: FC1(F)CCNC1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1F)N1CCC(F)(F)C1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and 3,3-difluoropyrrolidine, hydrochloride salt and triethylamine (2 molar equivalent).
Reaction SMILES: CS[CH2:3][C:4]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:5]=1[NH2:6]>[Ni].C(O)C>[CH3:3][C:4]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:5]=1[NH2:6]
Reactant: CSCc1c(N)c(F)cc(F)c1F
Agent: [Ni]
Solvent: CCO
Product: Cc1c(N)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To 2-methylthiomethyl-3,4,6-trifluoroaniline (22.2 g) are added ethanol (400 ml) and Raney nickel (200 g) and the mixture is stirred at room temperature for 30 minutes. After the catalyst is filtered off, the filtrate is added with water and extracted with dichloromethane. The is dried over magnesium sulfate and concentrated to give 2-methyl-3,4,6-trifluoroaniline (12.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCN(c2ccc(Br)cc2)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1C(N2CCOCC2)=CCCCN1c1ccc(Br)cc1

Procedure:
N-[4-bromophenyl]-3-oxocaprolactam (0.37 g, 1.13 mmol), morpholine (0.25 mL, 2.81 mmol), and p-toluenesulfonic acid (catalytic amount) were refluxed with 30 mL benzene using a Dean Stark apparatus under N2 for 12 h. The solvent was removed in vacuo and the residue was dried under vacuum to give 1,5,6,7-tetrahydro-1-(4-bromophenyl]-3-(morpholin-4-yl)-2H-azepin-2-one. LRMS (AP+): 351.0, 353.0, (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[O:18][CH3:19])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24]Br)[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:24][CH:23]([CH2:26][CH3:27])[CH2:21][CH3:22])=[CH:13][C:12]=1[O:18][CH3:19])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)CBr
Reactant: COc1cc(O)ccc1[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)c(OC)c1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To 34 mg (0.122 mmol) of the [(R)-2-hydroxy-1-(4-hydroxy-2-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester and 2-ethylbutylbromide (20 ul, 0.182 mmol) dissolved in 1 ml DMF was added K2CO3 (34 mg, 0.244 mmol) and heated to 60° C. overnight. It was cooled to rt, diluted with ether, and quenched with water. The organic layer was washed with water and brine, and then dried over MgSO4. After removal of the solvent, the residue was purified by flash column (35% EtOAc in hexane) to give the titled compound (24 mg, 54%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+:27]>>[Na+:27].[O:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([NH:5][CH2:4][C:3]([O-:25])=[O:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CNC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CNC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 94.3 %

Procedure:
The title compound (23 mg, 94%) was prepared from the compound from step 1 (24 mg, 0.07 mmol) and 1N NaOH (0.07 mL. 0.07 mmol) by the procedure described in Example 2: MS (ESI) m/z 327 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 1.36 (m, 2H), 1.80 (m, 2H), 2.45-2.55 (m, 2H), 2.68 (dd, J=2.8, 12 Hz, 2H), 3.53 (m, 2H), 6.88-6.91 (m, 4H), 6.95 (m, 2H), 7.04 (m, 1H), 7.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:57]([O:64][C:65]1[CH:70]=[CH:69][C:68](O)=[CH:67][CH:66]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][O:24][C:68]3[CH:69]=[CH:70][C:65]([O:64][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:66][CH:67]=3)=[C:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(OCc3ccccc3)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Compound 6 (from Example A) (1 mmol) is added to a solution of diethylazodicarboxylate (1 mmol) and triphenylphosphine (1 mmol) in dry THF (10 mL). 4-Benzyloxyphenol (7) (1 mmol) is then added, and the progress of the reaction is monitored by tlc. When the reaction is complete, water is added and the product is extracted with ethyl acetate. The extract is dried and evaporated and the title compound 8 is then purified by HPLC.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[O:12]1[CH2:15][CH:14](O)[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:14]2[CH2:15][O:12][CH2:13]2)[CH:3]=1
Reactant: OC1COC1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1ncnc2c1c(Br)cn2C1COC1
Temperature: 85 °C
Yield: 42.1 %

Procedure:
To 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.291 mmol) were added 3-oxetanol (287 mg, 3.87 mmol), polymer bound triphenylphosphine (860 mg, 2.58 mmol) resin and 1,4-Dioxane (2 mL) into a 5 mL microwave vial then DEAD (0.409 mL, 2.58 mmol) was added. The reaction vial was then capped and heated in microwave reactor for 15 minutes at 85° C. The reaction was not complete so it was heated for a total of 1 hr and the reaction was filtered, concentrated, diluted with EtOAc (10 mL) then washed water (10 ml). The water was back extracted with EtOAc (2×10 ml). The organics were combined then washed with brine, dried over MgSO4, filtered and concentrated. The crude was loaded on to a 10 g Biotage column and purified with 0 to 40% EtOAc in Hexane gradient over 30 minutes to afford 5-bromo-4-chloro-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidine (157 mg 42.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 5.95 (t, J=7.07 Hz, 1H), 4.96-5.04 (m, J=7.07, 7.33, 7.45, 7.45 Hz, 4H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(C(C)(C)C)cc2C1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.58 h
Yield: 92 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 35 minutes while stirring through a solution, cooled to -70°, of 7.35 g of (RS)-2-(2-buten-1-yl)-6-tert-butyl-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.36 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 100 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 6.44 g (92%) of (RS)-2-(2-oxoethyl)-6-tert-butyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][CH:22](O)[CH3:23])=[CH:15][C:14]=1[N+:25]([O-:27])=[O:26].[CH2:28]([N:30](CC)CC)C>ClCCl>[CH3:28][NH:30][CH:22]([CH2:21]/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[C:14]([N+:25]([O-:27])=[O:26])[CH:15]=1)[CH3:23]
Reactant: Cc1ccc(/C=C/CC(C)O)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNC(C)C/C=C/c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
p-Toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added, in one portion, to a stirred solution of (4E)-5-(4-methyl-3-nitropheny)-4-penten-2-ol (1.70 g, 7.69 mmol) in triethylamine (5 mL) and dichloromethane (10 mL) at 10° C. under nitrogen. The cooling bath was removed, and the mixture was stirred at 25° C. for 16 h. Saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture was vigorously stirred for 2 h. The layers were separated and the aqueous layer was extracted once with dichloromethane (10 mL). The combined organic layers were dried (Na2SO4) and evaporated, and the residue was combined with DMF (7 mL) and 40% aqueous methylamine (20 mL). This mixture, also biphasic, was vigorously stirred at 25° C. for 18 h, poured into a mixture of 30% aqueous NaOH (2 mL) and saturated aqueous NaCl (50 mL), and extracted with ether (3×30 mL). The ether extracts were dried (Na2SO4) and evaporated, and the residue was column chromatographed on 100 g of Merck silica gel 60 (70-230 mesh) with 5% (v/v) methanol, 5% triethylamine (v/v) in benzene. This gave 453 mg (25.2% yield) of yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([CH2:16][CH3:17])[CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([CH2:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(Cl)c(Cl)cc1CC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(Cl)c(Cl)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of ethyl 2-(4,5-dichloro-2-ethylphenylamino)acetate (390 mg, 1.41 mmol) and LiOH.H2O (592 mg, 14.1 mmol) in THF (8 mL) and water (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in H2O and diluted with ethyl acetate. The mixture was acidified with aqueous HCl (10%) to adjust the pH to 3-4 and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (300 mg, 85.75% yield) as a yellow solid. ESI-MS m/z: 246.2 [M−H]−.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:22]1[CH:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=[CH:24][N:23]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ccn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 30 h

Procedure:
314 mg (1.08 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride were added to 300 mg (1.08 mmol) (4-chloropyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 373 mg (2.70 mmol) potassium carbonate in 5.0 mL N-methylpyrrolidone. The reaction mixture was stirred for 30 h at 130° C. Then the mixture was poured onto 100 mL water and extracted with EtOAc (3×100 mL). The combined organic phases were dried and evaporated down using the rotary evaporator. The residue was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac. The residue was triturated with 30 mL diethyl ether. The precipitated solid was suction filtered and dried in the air.
Reaction SMILES: C(OC([NH:11][CH:12]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.[BrH:30]>C(O)(=O)C.CCOCC>[BrH:30].[NH2:11][CH:12]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC(CCc1ccccc1)S(=O)(=O)c1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(CCc1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Method A: Z-Hph-α-SO2Ph (1.0 g, 2.44 mmol) was treated with 30% hydrogen bromide in acetic acid (5 mL). After 30 minutes, the mixture was diluted with ether (300 mL), filtered, washed with ether (2×30 mL), and dried in vacuo to give 0.74 g (86%) 1-amino-3-phenyl-1-phenylsulfonylpropane hydrobromide (HBr.Hph-α-SO2Ph). To a solution of Mu-PheOH (0.64 g, 2.3 mmol) in THF (15 mL) were added 4-methylmorpholine (0.302 mL, 2.3 mmol) and isobutyl chloroformate (0.312 mL, 2.3 mmol). The mixture was stirred for 10 minutes. HBr.Hph-α-SO2Ph (0.74 g, 2.1 mmol) was added, followed by 4-methylmorpholine (0.302 mL, 2.3 mmol). After 45 minutes, the mixture was diluted with ethyl acetate (30 mL), washed with 15 mL each of 1M HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 0.75 g (65%) of the product, Mu-Phe-Hph-α-SO2Ph.