Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([Cl:12])=[N:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:7]=1
Reactant: Nc1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-chloroquinoline (1.0 g, 5.6 mmol) was dissolved in 10 mL pyridine and 4-fluorobenzenesulphonylchloride (1.1 g, 5.7 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched by addition of 100 mL water and 6.8 mL acetic acid. The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). N-(2-Chloro-quinolin-5-yl)-4-fluoro-benzenesulfonamide was obtained as a brown solid (762 mg, 40%), MS: m/e=337.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.Cl.NC[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([CH2:30][N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])=[CH:37][CH:38]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCCc1ccc(CN2CCCC2=O)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.1 g), 1-[4-(2-aminoethyl)benzyl]pyrrolidin-2-one hydrochloride (87 mg), N,N-diisopropylethylamine (44 mg) and ethanol (2 ml) was stirred at 70° C. for 3 hr. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (109 mg) as a colorless powder.
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>CN(C)C=O.O>[Br:1][CH2:2][C:3]1([CH2:11][O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:4][O:5][C:6]([CH3:9])([CH3:10])[O:7][CH2:8]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OCC(CO)(CBr)CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CBr)(CO[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
409 mg (1.71 mmol equivalents) of 5-bromomethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was dissolved in 5 mL of dimethylformamide, 233 mg (3.42 mmol equivalents) of imidazole and 309 mg (2.05 mmol equivalents) of t-butyldimethylchlorosilane were added thereto, and the mixture was stirred at room temperature (25° C.) for 18 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 578 mg (1.64 mmol equivalents) of 5-bromomethyl-5-(t-butyldimethylsiloxymethyl)-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([OH:9])=[N:6][C:7]=1[CH3:8].CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:9][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1cc(Br)c(C)nc1O
Product: Cc1cc(Br)c(C)nc1OCCC(C)(C)O
Yield: 75.8 %

Procedure:
According to the method of (Example 36) <Step 1>, from 5-bromo-3,6-dimethylpyridin-2-ol (0.74 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (1.0 g), the subject compound (0.80 g) was obtained as a white solid.
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H](NC2SC3C=CC=CC=3N=2)C1)(C)(C)C.Cl.[NH2:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:33]3=[N:34][CH:35]=[CH:36][CH:37]=[C:32]3[N:31]([CH3:38])[C:30]2=[O:39])[CH2:26]1.Cl[C:41]1[S:42][C:43]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:44]=2[N:45]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CS(C)=O>[F:50][C:47]1[CH:48]=[CH:49][C:43]2[S:42][C:41]([NH:24][C@H:25]3[CH2:28][C@H:27]([N:29]4[C:33]5=[N:34][CH:35]=[CH:36][CH:37]=[C:32]5[N:31]([CH3:38])[C:30]4=[O:39])[CH2:26]3)=[N:45][C:44]=2[CH:46]=1
Reactant: Fc1ccc2sc(Cl)nc2c1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Agent: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4cc(F)ccc4s3)C2)c2ncccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.147 g, 0.577 mmol), 2-chloro-5-fluorobenzo[d]thiazole (0.108 g, 0.577 mmol), diisopropylethylamine (1 ml, 5.75 mmol), and 4-dimethylaminopyridine (7.05 mg, 0.058 mmol) in DMSO (0.5 mL) and purified by ISCO on silica gel column using 0-80% EtOAc/hexanes to afford 3-(trans-3-((5-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.030 g, 0.081 mmol, 14.07% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (d, J=4.89 Hz, 1 H), 7.43-7.60 (m, 1 H), 7.23-7.34 (m, 1 H), 7.17 (d, J=7.43 Hz, 1 H), 6.98-7.10 (m, 1 H), 6.84 (t, J=8.71 Hz, 1 H), 6.18 (br. s., 1 H), 5.40 (quin, J=8.36 Hz, 1 H), 4.62 (br. s., 1 H), 3.50-3.67 (m, 2 H), 3.43 (s, 3 H), 2.55 (t, J=10.07 Hz, 2 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:15]=2)[C@H:10]([CH3:33])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH3:33])[N:15]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:17]=2)=[CH:25][CH:24]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1

Procedure:
Stir 4-[6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.5 g, 9.88 mmol) in 4M HCl-dioxane (50 mL) for 40 min. Concentrate and partition between EtOAc and sat. NaHCO3. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to yield the title compound.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[NH2:18][C@@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].[C:35]([N:38]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:41]([CH2:50][C:51](O)=[O:52])[C:40](=[O:54])[CH:39]1[CH:55]([CH3:57])[CH3:56])(=[O:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:35]([N:38]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:41]([CH2:50][C:51]([NH:18][C@@H:19]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:52])[C:40](=[O:54])[CH:39]1[CH:55]([CH3:57])[CH3:56])(=[O:37])[CH3:36]
Reactant: CC(C)OC(=O)C(O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)O)C(=O)C1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C(=O)OC(C)C)C(=O)C1C(C)C
Reaction time: 8 h

Procedure:
N-Methylmorpholine (67 μl), 1-hydroxybenzotriazole (103 mg) and isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (144 mg, Reference compound No. 4-1) are added to a solution of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (160 mg, Reference compound No. 51-1) in methylene chloride (5 ml). The mixture is cooled with ice, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg) is added to the mixture, and the whole is stirred overnight. Ethyl acetate is added to the reaction mixture, the whole is washed with a 0.1 N aqueous sodium hydroxide solution, saturated brine, 0.1 N hydrochloric acid and saturated brine successively, and the organic layer is dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (259 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O
Reactant: OB(O)c1ccc(O)cc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: Cn1cc(C(=O)CC(c2ccc(O)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)-1-methyl-pyridin-2(1H)-one (example 314, step 2) was reacted with 4-hydroxyphenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless foam, MS (ESI+): m/z=386.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[N:17]=1.[CH3:18]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:18])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[N:17]=1
Reactant: CC(=O)N(C)C
Reactant: COCCN1CCC(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.102 g (0.0004 mole) of 2-chloro-9-(2-methoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-40), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.087 g of 2-chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-40) as an yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:8][CH2:7]2)=[O:4].[Cl:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=1[C:36]1[CH:40]=[C:39]([CH2:41]O)[O:38][N:37]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:41][C:39]3[O:38][N:37]=[C:36]([C:29]4[C:30]([F:35])=[CH:31][CH:32]=[C:33]([F:34])[C:28]=4[Cl:27])[CH:40]=3)=[CH:16][CH:17]=1)[CH2:8][CH2:7]2)=[O:4]
Reactant: OCc1cc(-c2c(F)ccc(F)c2Cl)no1
Reactant: COC(=O)C1=C(c2ccc(O)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of compound B4 (6.80 g, 18.9 mmol), [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-methanol (6.97 g, 28.3 mmol), ADDP (9.55 g, 37.8 mmol) and PBu3 (85%, 13.8 mL, 56.6 mmol) in toluene (280 mL) was heated to reflux for 1 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:1) yielded the title compound (11.0 g, 99%). LC-MS: tR=1.14 min; ES+: 587.30.
Reaction SMILES: O([C:8]1[C:20]2[N:19]3[C:14]([CH2:15][O:16][CH2:17][CH2:18]3)=[CH:13][C:12]=2[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[C:24]([Cl:37])[CH:23]=1.Cl.N1C=CC=CC=1.CN1CCCC1=O>C(OCC)(=O)C>[ClH:37].[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:8]2[C:20]3[N:19]4[C:14]([CH2:15][O:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH:36]=[CH:35][C:25]=1[O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]
Reactant: c1ccc(Oc2ncnc3cc4n(c23)CCOC4)cc1
Reactant: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(Nc3ncnc4cc5n(c34)CCOC5)cc2Cl)c1
Temperature: 140 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
A mixture of 4-phenoxy-6,7-dihydro-9H-pyrimido[4′,5′:4,5]pyrrolo[2,1-c][1,4]oxazine (69 mg), 3-(4-amino-2-chlorophenoxy)benzonitrile (95 mg), pyridine hydrochloride (75 mg) and 1-methyl-2-pyrrolidone (1 mL) was stirred at 140° C. for 14 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=50/50→0/100). The obtained fractions were collected and concentrated, and the residue was dissolved in ethyl acetate (2 mL) and treated with 4N hydrochloric acid/ethyl acetate (0.13 mL) to give the title compound (81 mg) as hydrochloride crystals.
Reaction SMILES: C(OC(=O)[N:7]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]2[C:36]3[C:31](=[C:32](Br)[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[CH:30]=[CH:29][C:28]2=[O:40])[CH2:21][CH2:20]1)[CH2:8][C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:13]1[C:12]2[CH:17]=[CH:18][C:9]([CH2:8][NH:7][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=5)[CH:30]=[CH:29][C:28]4=[O:40])[CH2:21][CH2:20]3)=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1
Reactant: COc1cc(Br)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 mL of a dichloromethane solution containing 20 mg of tert-butyl(1-(2-(5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4- yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 1 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 13 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 16 mg of 5-bromo-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl-7-methoxyquinolin-2(1H)-one as a light brown oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:58])([F:57])[O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54](O)=[O:55])=[CH:49][CH:48]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:50]3[CH:51]=[CH:52][C:47]([O:46][C:45]([F:57])([F:44])[F:58])=[CH:48][CH:49]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-trifluoromethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), and the solution was washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2=4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-trifluoromethoxy-phenyl)-acetamide (0.7 g, 64%) as a white solid: mp 134-136° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.41 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.59 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.29-7.32 (d, J=8.6 Hz, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.63-7.82 (m, 2H), 8.72 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.85, 41.23, 48.83, 120.81, 118.37 (121.76, 125.15), 121.91, 127.14, 130.91, 131.52, 133.22, 134.65, 135.64, 139.02, 147.02, 166.88, 167.41, 169.78, 170.21, 172.72; Anal. Calcd. for C23H18N3O6F3: C, 56.45; H, 3.71; N, 8.59; F, 11.65. Found: C, 56.20; H, 3.39; N, 8.44; F, 11.87.
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([CH3:16])([CH3:15])[O:11][CH2:12][C:13]#[CH:14])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Si:10]([O:11][CH2:12][C:13]#[C:14][C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:27])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)c1ccccc1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A solution of n-BuLi in hexanes (1.6 M, 22.7 mL, 36.3 mmol, 1.20 equiv) was added to a solution of tert-butyl(dimethyl)(prop-2-yn-1-yloxy)silane (7.37 mL, 36.3 mmol, 1.20 equiv) in THF (150 mL) at −78° C. and the resultant mixture was stirred for 1 hour. N-methoxy-N-methylbenzamide (4.61 mL, 30.3 mmol, 1 equiv) was added and the reaction mixture was warmed to 23° C. and stirred for 16 h. The reaction mixture was partitioned between a 1:1 mixture of saturated ammonium chloride solution and brine (200 mL) and ethyl acetate (250 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes, grading to 50% EtOAc in hexanes) to provide 4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbut-2-yn-1-one (3-2) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.15 (m, 2H), 7.62 (m, 1H), 7.48 (m, 2H), 4.60 (s, 2H), 0.95 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][CH2:6][C:5]2=[CH:8][C:9]([N+:11]([O-])=O)=[N:10][N:4]2[CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:14])[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH2:11])=[N:10][N:4]2[CH2:3]1
Reactant: CC1(C)Cn2nc([N+](=O)[O-])cc2CO1
Agent: [Pd]
Solvent: CO
Product: CC1(C)Cn2nc(N)cc2CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 139c (0.21 g, 1.25 mmol), 10% palladium on carbon (50% wet, 125 mg), and methanol (10 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 2 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 139d (167 mg, 93%). MS-ESI: [M+H]+ 168.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20]CC2C=CC=CC=2)[N:7]=1.Cl>C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1
Reactant: COC(=O)/C=C/c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2O)n1

Procedure:
A stirred solution of unsaturated ester 14, (1.2 g, 2.9 mmol) and PtO2, 0.12 g in acetic acid (25 mL) and conc. HCl (5 mL) was hydrogenated at room temperature for 16 hours. The catalyst was removed by filtration through Hyflo and the filtrate was evaporated to dryness to afford the saturated ester 15, 0.8 g (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1-phenyl-1-ethanone (2, 1.93 g, 8.37 mmol) in 25 ml pyridine (dried over molecular sieves) under nitrogen was added at room temperature methoxylamine hydrochloride (873 mg, 10.5 mmol). The resulting slightly cloudy, pale orange mixture was stirred at room temperature overnight. The pyridine was removed in vacuo with heating. The residual solids were stirred with ether (60 ml), isolated by filtration, and discarded. The filtrate was dried over sodium sulfate, and concentrated in vacuo to give a mixture of the oxime geometrical isomers as 2.00 g of a clear, pale yellow syrup (92% yield). 1H NMR showed the isomers to be formed in a 5:3 ratio: Rf 0.64, 0.50; IR (CDCl3) 3068 (w), 2940 (m), 2819 (w), 1602 (w), 1493 (s), 1442 (m); 1H NMR (CDCl3) 7.63 (m, 2H), 7.37-7.11 (m, 11.5 H), 4.12 (s, 2H), 4.05 (s, 3H), 3.91 (s, 1.6H), 3.82 (s, 1.2H); low resolution mass spec. 259 (M+, 8), 227 (100), 192 (28), 165 (18), 134 (12), 125 (62), 119 (37).