Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:10]=3[C:11]3[C:21]([CH3:22])=[N:20][O:19][C:12]=3[C@H:13]([CH2:15][C:16]([NH2:18])=O)[N:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:10]=3[C:11]3[C:21]([CH3:22])=[N:20][O:19][C:12]=3[C@H:13]([CH2:15][C:16](=[S:37])[NH2:18])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=S
Yield: 64.1 %

Procedure:
To a solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide (Compound 110, 0.120 g, 0.30 mmol) in THF (5 mL) was added Lawesson reagent (0.248 g, 0.60 mmol). The mixture was refluxed overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized by petroleum and ethyl acetate to give 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)ethanethioamide (0.080 g, 64% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:20][OH:21])([CH2:18][CH3:19])[CH2:13]1.O1C2C=CC=CC=2OC[CH:23]1CN1CCCC(COC)(C)C1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:18][CH3:19])([CH2:20][O:21][CH3:23])[CH2:13]1
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: CCC1(CO)CCCN(CC2COc3ccccc3O2)C1
Product: CCC1(COC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared from [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol according to the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 95.7 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic acid ethyl ester (0.50 g, 1.0 mmol) in ethyl acetate(15 mL) in a Parr bottle was added platinum dioxide on carbon (0.25 g, 5% on carbon). The mixture was shaken under a positive pressure of hydrogen at 30 psi for 15 minutes at ambient temperature. The mixture was filtered through a pad of celite and concentrated to give the title compound (0.47 g).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=O.Cl.[NH2:16]O.O.C(=O)([O-])O.[Na+]>C(O)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:16]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution (20 ml) of methyl 4-formyl-3-methoxybenzoate (870 mg, 4.48 mmol) in formic acid was added hydroxylamine hydrochloride (405 mg, 5.82 mmol), and the mixture was stirred at room temperature for 1 hr. The temperature was raised to 50° C., and the mixture was further stirred for 24 hrs. Water was added to the reaction mixture, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (780 mg, 91%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][OH:11])=[C:6]([Cl:12])[C:5]([F:13])=[CH:4][CH:3]=1.[CH:14](O)=O>>[Cl:12][C:6]1[C:7]2[N:8]([CH2:9][CH2:10][OH:11])[CH:14]=[N:1][C:2]=2[CH:3]=[CH:4][C:5]=1[F:13]
Reactant: Nc1ccc(F)c(Cl)c1NCCO
Reactant: O=CO
Product: OCCn1cnc2ccc(F)c(Cl)c21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-[(6-Amino-2-chloro-3-fluorophenyl)amino]ethanol (2.07 g, 10.2 mmol) is dissolved in formic acid (50.0 mL), and the resulting solution is heated to 100° C. for 1 hour. The solution is cooled to room temperature and then evaporated to dryness. The residue is suspended in NH3 (50.0 mL, 2N in EtOH) and stirred for 1 hour. The solution is concentrated to dryness, and the residue is suspended in EtOAc (50.0 mL). The organic phase is washed with 2N NaOH (50.0 mL), and the resulting aqueous phase is extracted 4 times with EtOAc (4×50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is dissolved in EtOAc, filtered and recrystallized from EtOAc (895 mg, 41%). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.74 (t, J=5.27 Hz, 2H) 4.52 (t, J=5.47 Hz, 2H) 4.99 (s, 1H) 7.25 (dd, J=10.16, 8.79 Hz, 1H) 7.64 (dd, J=8.79, 4.49 Hz, 1H) 8.21 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 4-(trifluoromethoxy)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[C:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:7]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1>FC(F)(F)C(O)=O>[CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:7]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2C=CCC2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2C=CCC2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid 10 mL was added to tert-butyl 4-(2-cyclopenten-1-yl)-2-(4-fluoroanilino)benzoate 27 mg, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 4-(2-cyclopenten-1-yl)-2-(4-fluoroanilino)benzoic acid 22 mg of white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:32])[CH:27](O)[CH:28]([CH3:30])[CH3:29].CO>C(OCC)(=O)C>[CH3:24][O:25][C:26](=[O:32])[CH:27]([O:23][C:21]1[N:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH:28]([CH3:30])[CH3:29]
Reactant: COC(=O)C(O)C(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)C(C)C
Yield: 58 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and subjected to flash chromatography (SiO2, gradient 0-5% methanol in ethyl acetate) to give racemic 2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-3-methyl-butyric acid methyl ester as a yellow oil (160 mg, 58%). LCMS: RT=3.60 min, [M+H]+=427
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=[CH:22][N:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: COC(OC)N(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 145 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A mixture of 3-benzyl-7-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.60 g, 5.85 mmol), N,N-dimethylformamide dimethyl acetal (5.6 mL, 39.6 mmol) and MgSO4 (5.0 g, 41.5 mmol) in DMF (20 mL) was sealed under nitrogen and heated at 145° C. overnight. The reaction mixture was cooled to 0° C., poured into ice water and stirred for 1 h. The solid was collected and washed with water, dried under vaccum over P2O5 to give the title compound (1.84 g, 96%): 1H NMR (CDCl3) δ 7.50 (d, 1H, J=12.56 Hz), 7.30 (m, 2H), 7.24 (m, 4H), 6.96 (d, 1H, J=4.48 Hz), 6.38 (d, 1H, J=4.68 Hz), 5.27 (s, 2H), 2.83 (s, 3H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14].CN(C1C=CC=CC=1)[CH:17]=[O:18].S(=O)(=O)(O)O>O1CCCC1.CCOCC>[Cl:14][C:8]1[C:7]([Cl:6])=[CH:12][CH:11]=[C:10]([F:13])[C:9]=1[CH:17]=[O:18]
Reactant: CN(C=O)c1ccccc1
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(F)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution was stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:13]Br>O1CCOCC1>[Br:13][CH2:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)CCO2
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc2c(c1)CCO2
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred solution of 1-(2,3-dihydro-benzofuran-5-yl)-ethanone (2.5 g, 15.4 mmol) (Lancaster) in dioxane (2 mL) was added dropwise a solution of bromine (2.96 g, 18.5 mmol) in dioxane (60 mL). After stirring 15 minute the mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (2:1 hexane-dichloromethane) to provide 1.41 g (38%) of 2-bromo-1-(2,3-dihydro-benzofuran-5-yl)-ethanone.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].O>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccn1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1cnc2c(c1)cc(-c1ccccn1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of the compound obtained in Example 5 (1) (100 mg), 2-ethynylpyridine (30.4 mg), bis(triphenylphosphine) palladium(II) dichloride (17.3 mg) and cuprous iodide (4.7 mg) in triethylamine (2.5 ml) was stirred in a sealed tube at 100° C. for 1 hour. After completion of the reaction, the reaction suspension was poured into water, extracted with methylene chloride, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 71.9 mg of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][NH:31][NH2:32].O1CCCC1>C(OCC)(=O)C>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26]3[CH2:27][CH2:28][N:31]([CH3:30])[N:32]=3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: CNN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(CC2CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (250 mg), methylhydrazine (0.050 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the insoluble substance was filtered off, and the filtrate was concentrated. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (156 mg, yield: 59%) as colorless needle crystals. MS: 474 (MH+). melting point 149-150° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:36]([NH:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>CN(C=O)C>[CH:36]([N:39]([CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)NC(C)C
Reactant: O=C(c1ccc(CCl)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1)C(C)C

Procedure:
A solution of 1-(4-chloromethylbenzoyl)-4-(2-naphthalenesulfonyl)piperazine (300 mg), potassium carbonate (200 mg) and diisopropylamine (4 ml) in DMF (6 ml) was stirred at 100° C. for 10 hours and concentrated. To the residue was added ethyl acetate, and the mixture was washed with water, and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give the title compound (70 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:12][Br:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(C(C)(C)C)c1

Procedure:
5-tert-butyl-m-xylene (15g) was dissolved in carbon tetrachloride (80ml), N-bromosuccinimide (16.45g) and a catalytic amount of azoisobutyronitrile were added and the reaction was heated at reflux for 4h. The reaction was cooled and the mixture filtered to remove the succinimide. The solvent was removed in vacuo to afford a light brown oil. Purification was carried out by chromatography on silica gel (eluting silica with 100% petroleum ether, bp 60°-800° C.) to afford 3-t-butyl-5-methylbenzyl bromide as a clear oil (15.3g). 1H NMR (360MHz, CDCl3) d 1.31 (9H; s; t-Bu), 2.34 (3H; s; CH3), 4.47 (2H; s; CH2Br), 7.04 (1H; s; Ar H), 7.13 (1H; s; Ar H), 7.25 (1H; s; Ar H). m/z (CI+)=258 (M+NH4+).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)#[N:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:47]([NH:54][CH3:55])[CH2:48][N:49]2[CH2:52][CH:51]([OH:53])[CH2:50]2)[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:54]([C@@H:47]([CH:43]2[CH2:46][CH2:45][CH2:44]2)[CH2:48][N:49]2[CH2:50][CH:51]([OH:53])[CH2:52]2)[CH3:55])=[O:18])=[CH:19][CH:20]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN[C@H](CN1CC(O)C1)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(C#N)cc1)[C@H](CN1CC(O)C1)C1CCC1
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
DIPEA (2.504 mL, 14.38 mmol) was added to a stirred suspension of 4-cyanobenzoic acid (0.670 g, 4.55 mmol) and TBTU (1.462 g, 4.55 mmol) in DCM (10 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound Z2.1) (0.960 g, 4.79 mmol) in DCM (10 mL) was added over 5 min. The ice-bath was removed after 10 min and the reaction was stirred at rt for 3 h. The reaction mixture was diluted with DCM (20 mL), washed with NaHCO3 (8% aq., 35 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The selected fractions were concentrated and NaHCO3 (saturated, 40 mL) was added. The water layer was extracted with DCM (3×75 mL) and the combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.925 g, 62%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 1.32-1.62, 1.65-1.97, 1.97-2.08, 2.17-2.28, 2.32-2.60, 2.62-2.74, 3.16-3.27, 3.39-3.45, 3.46-3.52, 4.07-4.18, 4.40-4.52, 5.19-5.24, 7.42-7.46, 7.57-7.62, 7.87-7.95.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:19]([F:24])[CH:18]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2c1

Procedure:
The method of Example 281 was used with 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile, 174.7 mg (1.2 mmol) of 4-chloro-2-fluoro-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. This afforded 319.8 mg of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 325.9, 327.9
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1>CCOC(C)=O.CO.[Pt]>[CH3:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 48 h
Yield: 83.6 %

Procedure:
To 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (26 g, 73 mmol) in EtOAc (1 L) and MeOH (200 mL) was added platinum on carbon (sulfided) (14 g, 73 mmol) as a slurry in EtOAc (100 mL). The mixture was stirred under H2 (1 atm.) for 2 days. The catalyst was filtered off and rinsed with EtOAc, MeOH, and DCM and the filtrate was rotovapped down. The resultant solid was triturated with diethyl ether to provide the title compound of Step J (20 g, 61 mmol, 82%). 1H NMR (400 MHz, DMSO-d6) δ 6.50 (s, 1H), 6.39 (s, 1H), 4.24 (s, 2H), 3.66 (s, 3H), 3.05-3.16 (m, 2H), 2.92 (s, 3H), 2.83 (d, 2H), 2.39-2.54 (m, 2H), 2.01 (s, 3H), 1.55-1.76 (m, 4H), 1.32-1.46 (m, J=10.6, 7.0, 3.5, 3.5 Hz, 1H), 1.24 (qd, J=11.7, 3.4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:30]=[CH:29][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]4[CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[CH:20]=3)[C:15]([OH:17])=O)=[CH:9][CH:8]=2)=[N:4][N:3]=1.N#N.CCN=C=NCCCN(C)C.Cl.[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]4[CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[CH:20]=3)[C:15]([NH:45][C:46]3[S:47][CH:48]=[CH:49][N:50]=3)=[O:17])=[CH:29][CH:30]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc(Oc3cc(O[C@@H]4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(Oc3cc(O[C@@H]4CCN(C)C4=O)cc(C(=O)Nc4nccs4)c3)cc2)o1
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a stirring solution of (R)-(+)-3-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenoxy]-5-[(1-methyl-2-oxo-pyrrolidin-3-yl)oxy]benzoic acid (0.2 g) (Intermediate 18) in dry DCM in single necked round bottomed flask fitted with stop cock with N2(g) balloon, N,N′-dimethylamino pyridine (0.060 g) followed by EDCI. HCl (0.23 g) were added at room temperature. After stirring at the same temperature for 15 min, 2-aminothiazole (0.054 g) was added and stirring was continued for 16 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with DCM (20 mL), washed with dil HCl (5 mL, 0.05 N), saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude brown solid (0.080 g). The crude brown solid was purified by solvent trituration.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)CNCN2
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CNc2ccccc2C1
Reaction time: 0.08 h

Procedure:
0.17 ml of methanesulfonyl chloride is added to a mixture of 300 mg of 1,2,3,4-tetrahydroquinazoline (prepared by the method described by R. F. Smith et al. in J.Heterocycl. Chem.2 (1965)) and 0.47 ml of triethylamine in 14 ml of methylene chloride at 0° C., while stirring. After 5 min, saturated sodium chloride solution is added, the mixture is subsequently stirred briefly and, after drying over sodium sulfate, the organic phase is concentrated. Purification of the crude product by means of FC over 30 g of silica gel (mobile phase P) gives 3-methylsulfonyl-1,2,3,4-tetrahydroquinazoline: Rf (K)=0.65; IR(KBr): 3360(m), 1600(m), 1500(m), 1320(s), 1145(s), 770(s).