Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Br:12]Br.C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[Br:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1].[Br:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CNc1ccc([N+](=O)[O-])cc1Br
Temperature: 10 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of methyl-(4-nitro-phenyl)-amine (15.2 g, 0.1 mol) in AcOH (150 mL) and CHCl3 (50 mL) was added Br2 (16.0 g, 0.1 mol) dropwise at 5° C. The mixture was stirred at 10° C. for 1 h and then basified with sat. aq. NaHCO3. The resulting mixture was extracted with EtOAc (100 in L×3), and the combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-bromo-4-nitro-phenyl)-methyl-amine (2-bromo-4-nitro-phenyl)-methyl-amine (23.0 g, 99%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J=2.4 Hz, 1H), 8.13 (dd, J=2.4, 9.0 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 5.17 (brs, 1H), 3.01 (d, J=5.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH2:24]([C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[CH3:25]>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:31]([C:29]3[O:30][C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: CCc1ccc(C=O)o1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Product: CCc1ccc(-c2nc3cc(Br)cc(N)n3n2)o1

Procedure:
The title compound, MS m/e (%): 309 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 5-ethyl-2-furaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: S(=O)(=O)(O)[OH:2].CO[CH:8]1[C:13]2[CH:14]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[S:16][C:12]=2[S:11](=[O:22])(=[O:21])[N:10]([CH3:23])[CH2:9]1.[C:24](#[N:26])[CH3:25]>>[C:24]([NH:26][CH:8]1[C:13]2[CH:14]=[C:15]([S:17]([NH2:20])(=[O:18])=[O:19])[S:16][C:12]=2[S:11](=[O:21])(=[O:22])[N:10]([CH3:23])[CH2:9]1)(=[O:2])[CH3:25]
Reactant: O=S(=O)(O)O
Reactant: COC1CN(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reactant: CC#N
Product: CC(=O)NC1CN(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To sulfuric acid (5.0 g) cooled to 0° C. was added the product from Step E (1.10 g, 3.81 mmol) dissolved in acetonitrile (35 mL) dropwise over 10 min. The mixture was stirred at ambient temperature for 2.5 days and quenched by the addition of ice and ammonium hydroxide to adjust the pH to 10. The acetonitrile was evaporated and the white precipitate was filtered and dried to give 0.41 g of the desired product. The filtrate was extracted with ethyl acetate. Evaporation to dryness gave an additional 0.33 g of the desired product (total yield 57%). Crystallization from methanol-methylene chloride gave colorless crystals: mp 252°-253° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]([OH:29])[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=[CH:16][CH:17]=1>>[OH:29][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:8]([CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][CH2:6]2)=[O:10])[CH:13]=1)[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CCC(C(=O)O)CN1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(N)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(NC(=O)C2CCC(=O)NC2)c1

Procedure:
Condensation between 6-oxopiperidine-3-carboxylic acid and tert-butyl (3-(3-aminophenyl)-3-hydroxypropyl)carbamate gives tert-butyl (3-hydroxy-3-(3-(6-oxopiperidine-3-carboxamido)phenyl)propyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:48][CH2:47][CH2:46][N:45]([CH2:49][CH3:50])[CH2:43][CH3:44])=[O:41]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCN(CC)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (52 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (64 mg, yield 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:28]=[C:27]([F:29])[C:26](F)=[CH:25][C:24]=1[F:31].CCN(C(C)C)C(C)C.Cl>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][N:19]([C:26]3[CH:25]=[C:24]([F:31])[C:23]([Br:22])=[CH:28][C:27]=3[F:29])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: Fc1cc(F)c(Br)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(Br)cc3F)CC2)CC1

Procedure:
Compound 69c (1.0 g, 3.4 mmol) and 1-bromo-2,4,5-trifluorobenzene were heated with iPr2NEt (1.7 mL, 10.2 mmol) in DMSO (5 mL) at 140° C. for 40 min 1M HCl and EtOAc were added and the organic phase dried over MgSO4 and concentrated. The mixture was purified by chromatography on silica gel eluting with EtOAc/Hexane to give 4-[1-(4-Bromo-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester 77a (720 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1.[H][H]>CO.[Pd]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1
Reactant: COC(=O)C=Cc1c[nH]cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1c[nH]cn1
Reaction time: 1 h

Procedure:
To a solution of ester 2 (5.3 g) in methanol at room temperature was added 10% palladium on carbon (20 mg) under a blanket of argon.. A balloon of hydrogen was applied, and the reaction was stirred for one hour. The solution was filtered, and then concentrated in vacuo to dryness to provide the crude product 3 which was sufficiently pure for use in the next step.
Reaction SMILES: C[O-:2].[Na+].Cl.Cl.[CH3:6][N+:7]1([O-:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C>CO.C(#N)C>[OH2:13].[OH2:2].[CH3:6][N+:7]1([O-:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C[O-]
Agent: C[N+]1([O-])CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 3.16N solution (6.7 cc.) of sodium methoxide in methanol is added to a suspension of 1-methylpiperazine-1-oxide dihydrochloride (2.0 g.) in anhydrous methanol (10 cc.). After stirring for 10 minutes at 25° C., the suspension is treated with decolourising charcoal (0.1 g.) and then filtered. The methanolic filtrate is evaporated under reduced pressure (20 mm.Hg) at 40° C. maximum. The oily residue (2.0 g.) is dissolved in anhydrous acetonitrile (50 cc.) and 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (2.15 g.) is added. The reaction mixture is heated for 4 hours at 50° C. and then stirred for 48 hours at a temperature of about 25° C., filtered and concentrated under reduced pressure. The residue (3.8 g.) is dissolved in methylene chloride (50 cc.). The solution is passed through a column of Merck silica (0.02 -0.05) (60 g.). Elution is carried out successively with methylene chloride (50 cc.), ethyl acetate (50 cc.), a mixture (50 cc.) of ethyl acetate and methanol (80-20 volume), a mixture (50 cc.) of ethyl acetate and methanol (50--50 by volume), and finally with the same mixture of solvents (100 cc.). This last fraction is evaporated under reduced pressure. The residue obtained (0.9 g., m.p. about 200° C.) is dissolved in acetonitrile (10 cc.) and distilled water (1 cc.), near the boiling point. After cooling to 2° C., the crystals which have appeared are filtered off, washed with ice-cold acetonitrile (0.5 cc.) and dried under reduced pressure (20 mm.Hg). 4-{[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-isoindolin-1-yl]oxycarbonyl{-1-methyl-piperazine-1-oxide dihydrate (0.62 g.), melting at about 200° C. (decomposition), is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=O.[Cr](Cl)([O-])(=O)=[O:14].[NH+]1C=C[CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:21](=[O:14])[CH2:20][CH2:19][CH2:6]2
Reactant: c1cc[nH+]cc1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C(=O)CCC2

Procedure:
3-Methoxy-4-methylbenzoic acid (30 g) was reduced to the benzylic alcohol with BH3 in THF (181 ml of 1 M solution). Oxidation of this product (28.7 g) with pyridinium chlorochromate (71g) gave the benzaldehyde derivative (21.3 g). Treatment of this alde hyde (19.6 g) with BrPh P(CH ) COOH (54.5 g) under Wit tig conditions afforded 4-(3-methoxy-4-methylphenyl)-3-butene carboxylic acid (26.9 g). Catalytic reduction of this product followed by polyphosphoric acid (PPA) cyclization gave the desired tetralone.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1>C(O)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N+:5]=1[O-:1]
Reactant: OO
Reactant: Cc1cccc(Br)n1
Solvent: CC(=O)O
Product: Cc1cccc(Br)[n+]1[O-]
Temperature: 90 °C
Yield: 75.2 %

Procedure:
Hydrogen peroxide (30%, 1.76 mL, 17.4 mmol) was added to a solution of 2-bromo-6-methyl-pyridine (1.0 g, 5.80 mmol) in acetic acid (20 mL), and heated for 24 h at 90° C. The reaction mixture was cooled to ambient temperature, and partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed thoroughly with water and dried over anhydrous sodium sulfate. Concentration in vacuo afforded 2-bromo-6-methyl-pyridine 1-oxide (820 mg, 75%) as a brown liquid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[CH:10][N:9]([Si](C)(C)C)[CH:8]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:9]1[CH:10]=[CH:11][C@H:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:8]1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)N1C=C[C@H]([Si](C)(C)C)C(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1, 4-dihydropyridine i (0.2 mL, 1.36 mol) in CH2Cl2 (6 mL) under Ar was added dropwise dimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture was stirred at RT for 1 day. It was then poured into a saturated solution of NaHCO3 (3 mL). The aqueous phase was extracted with CH2Cl2 (5 times). The combined organic layers were washed with water and brine and dried over MgSO4. Evaporation of the solvent under reduced pressure afforded 0.49 g of crude material that was purified by RPLC (silica gel, 5% EtOAc/hex) to give 59% (0.2506 g) of 3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylic acid dimethylamide iii as a clear oil. IR (in film, neat, NaCl): 3363, 2924, 2348, 1657, 1449, 1377 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.65 (d, 1 H, J=6.9 Hz), 6.35 (s 1 H), 4.83-4.78 (m, 1 H), 3.14-3.09 (m, 1 H), 2.88 (s, 6 H), 2.80-1.25 (m, 13 H), 0.085 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47, 38.53, 33.04, 30.34, 29.91, 22.37, 0.63 , −2.00. HRMS Calcd for C16H29N3OSi: 308.2157 [M+H]+. Found: 308.2157 [M+H]+. [α]25D−15.17 (CH2Cl2, c=0.145).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([OH:13])[CH2:9][C:10]([OH:12])=[O:11].C(O)(C(F)(F)F)=O.C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1>CN(C=O)C>[OH:13][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCCC[C@@H](O)CC(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC(O)CC(=O)O

Procedure:
Linear peptide (18) was completed by acylating the peptide resin with the Pfp-ester of D-3-hydroxydecanoic acid in DMF. Again, the use of Pfp ester activation allowed the acid to be coupled with its hydroxyl unprotected. 3-Hydroxydecanoic acid (mp 55°-56° C., 57° C.)21 was synthesized from n-octyl aldehyde by reaction with lithium tert-butyl acetate22 followed by TFA hydrolysis and resolution as the (-)-cinchonidine salt (mp 119°-120° C., 119°-120° C.) which upon neutralization gave (-)-D-3-hydroxydecanoic acid ([a]D =-21.4° C. (c 1.0, CHCl3); lit. [a]D=-17.5°).19The final peptide was cleaved from the resin with TFA (50% in CH2Cl2, 30 min) and lyophilized from dioxane to yield the crude peptide (18). This was readily purified by reverse phase HPLC using a C18 column and an H2O-acetonitrile gradient system containing 0.1% TFA, with the resulting peptide being relyophilized from dilute anhydrous dioxane --HCl to yield (18).HCl as a white solid in 25% overall yield based on resin substitution.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([F:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([F:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCCC(F)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCCC(F)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-fluoropiperidin-1-yl)quinolin-7-yl]ethanone (0.0287 g, 0.0936 mmol) and ammonium acetate (0.0721 g, 0.936 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.234 mL, 0.234 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H20ClFN3 (M+H)+: m/z=308.1; Found: 308.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1[Cl:20]>>[ClH:20].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)=[CH:15][C:14]=1[Cl:20]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2ccc(Br)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-bromo-3-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:25][CH:26]=[CH2:27])[C@:9]([NH:18][S@@](C(C)(C)C)=O)([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:25][CH:26]=[CH2:27])[C@@:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)([NH2:18])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N)c1ccc(Cl)cc1

Procedure:
A solution of (R)—N-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-yl)-2-methylpropane-2-sulfinamide (Example 418, Step C, 5.96 g, 14.04 mmol) in THF (56.2 ml) was treated with. hydrochloric acid in water (36-38% wt, 6.40 ml, 211 mmol) for three hours. The reaction was diluted with 300 mL ether and the acidic aqueous layer made alkaline with sat. aq. NaHCO3 solution. The organic layer was washed with sat. aq. NaHCO3 solution, dried over MgSO4 and concentrated to provide the title compound as a colorless glass.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3)c(=O)n12
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N)c(-c3ccccc3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.044 g, 0.14 mmol) in tetrahydrofuran (0.4 mL) and water (0.102 mL) was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.17 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added EtOAc and the mixture was extracted twice with 1N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step (36 mg, 89.3%). LCMS calculated for C15H16N3OS (M+H)+: m/z=286.1. Found: 286.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:14][C:15]([NH2:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1ccc(Cl)c2ccccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A mixture of 4-chloronaphthalen-1-ol (3.57 g, 20.0 mmol), 2-bromoacetamide (2.76 g, 20.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (40 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (2.32 g, 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[N:28][OH:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].IC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[N:28][O:29][CH3:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=NO)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CON=c1c(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)oc2ccccc12
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a stirred solution of {1-[4-(4-hydroxyimino-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (27 mg, 0.056 mmol) in DMF (2 mL) was added potassium carbonate (15.5 mg, 0.112 mmol) and iodomethane (0.011 mL, 0.168 mmol) at RT. After 2 hours, cesium carbonate (36.5 mg, 0.112 mmol) and iodomethane (0.021 mL, 0.336 mmol) were added and the mixture stirred for a further 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was isolated and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 25% EtOAc in cyclohexane) to afford the title compound (25.1 mg, 90%) as a colourless gum. LCMS (Method A): RT=5.20 min, [M+H]+=497.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:47]([Cl:49])[Cl:48]>C(O)(=O)C>[NH3:1].[CH2:47]([Cl:49])[Cl:48].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cncc(C2CCCCN2)c1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N
Product: c1cncc(C2CCCCN2Cc2ccc(OCCCN3CCCCC3)cc2)c1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (174 mg), 1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl (111 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (240 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (112 mg). 1H NMR (400 MHz, CDCl3): 8.63 (m, 1H), 8.49 (m, 1H), 7.80 (m, 1H), 7.27 (m, 1H), 7.11 (d, J=8.6 Hz, 2H) 6.80 (d, J=8.6 Hz, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.61 (d, J=13.4 Hz, 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.79 (d, J=13.4 Hz, 1H), 2.48 (m, 2H), 2.41 (br, 4H), 2.01–1.98 (m, 5H), 2.01–1.89 (m, 3H), 1.82–1.72 (m, 2H) 1.63–1.51 (m, 4H), 1.48–1.39 (m, 2H).