Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][OH:9])[S:4][N:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH:8]=[O:9])[S:4][N:3]=1
Reactant: OCc1snc(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1snc(Cl)c1Cl
Temperature: 40 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
A mixture of (3,4-dichloroisothiazol-5-yl)methanol (1.1 g), chloroform (150 mL) and manganese dioxide (4.7 g) was stirred at 40° C. for 20 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH:36]1[CH2:30][CH2:31][CH2:32][N:33]([CH3:37])[CH2:34][CH2:35]1)[CH:10]=3
Reactant: CN1CCCC1CCCl
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: CN1CCCC(Oc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)CC1
Yield: 36.7 %

Procedure:
According to Example 34, the compound (100 mg) produced in Example 37 was reacted with 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (54 mg) to obtain the ring expanding title compound (46 mg; 37%).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].IC(C)C.N1NC(=O)C=CC=1.Cl.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:42]=[CH:41][CH:40]=[CH:39][C:31]=1[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13](=[O:15])[N:36]2[CH2:35][CH2:34][CH:33]([O:32][C:31]3[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=3[C:29]([F:28])([F:43])[F:44])[CH2:38][CH2:37]2)=[CH:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: CC(C)n1nccc(NCC(=O)O)c1=O
Agent: Cl
Agent: O=c1cccn[nH]1
Solvent: CC(C)I
Product: CC(C)n1nccc(NCC(=O)N2CCC(Oc3ccccc3C(F)(F)F)CC2)c1=O
Yield: 69 %

Procedure:
Compound 49 is prepared from (2-isopropyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-acetic acid (obtained following the operating mode for 4e using 2-iodo-propane to alkylate nitrogen 2 of pyridazinone) and from intermediate 1a in base form, following synthesis method 2 (yield: 69%).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[C:41]3[C:36](=[C:37]([Cl:43])[CH:38]=[C:39]([Cl:42])[CH:40]=3)[CH2:35][N:34]([CH3:44])[CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[Cl:42][C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([Cl:43])[CH:38]=1)[CH2:35][N:34]([CH3:44])[CH2:33][CH:32]2[C:29]1[CH:28]=[CH:27][C:26]([S:23]([NH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[C:41]5[C:36](=[C:37]([Cl:43])[CH:38]=[C:39]([Cl:42])[CH:40]=5)[CH2:35][N:34]([CH3:44])[CH2:33]4)=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:12])=[CH:10][CH:9]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCNS(=O)(=O)c4ccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)cc4)cc3)cc2)C1
Yield: 12.7 %

Procedure:
Compound 231 was prepared following the procedure outlined in Example 215 using terephthalic acid (11.4 mg, 0.0684 mmol) and 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(2-(2-(2-hydroxyethoxy)ethoxy)-ethyl)benzenesulfonamide (Compound 175.1, 100 mg, 0.136 mmol). Purification by preparative HPLC gave the title compound (9.8 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.86-7.85 (m, 9H), 7.83 (s, 2H), 7.50 (s, 1H), 7.41 (d, 4H), 6.80 (s, 1H), 3.68-3.42 (m, 26H), 3.34 (m, 2H), 3.09-3.01 (m, 12H). MS (m/z): 1135.07 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].ClC1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CSc1ccc(NC(C)=O)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
The product from Example 39c (1.00 g, 5.0 mmol) and t-BuSNa (1.88 g, 15.1 mmol) in anhydrous DMF (10 mL) was heated at 160° C. for 4 hours under N2 flow, and then cooled to room temperature. To the reaction mixture was added 1-chloro-4-methyl-2-nitrobenzene (2.36 mL, 17.6 mmol) at room temperature and then the mixture was heated at 80° C. for 4 hours under N2 flow. The mixture was diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by silica gel column chromatography eluting with 2:1 EtOAc/hexane to give the title compound as yellow crystals (1.04 g, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].Br[CH2:14][CH:15]1[CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([O:1][CH2:14][CH:15]2[CH2:17][O:16]2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(C)cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C)cc1OCC1CO1
Temperature: 55 °C
Yield: 41.7 %

Procedure:
A mixture of N-(2-hydroxy-4-methylphenyl)acetamide (10 g, 60 mmol), 2-(bromomethyl)oxirane (9.86 g, 72 mmol, 6.0 ml) and potassium carbonate (16.8 g, 120 mmol) in DMF (100 ml) was heated at 55° C. for 2 h. Then the reaction mixture was diluted with ethyl acetate and washed with aq. HCl (1.5%), aq. sat. NaHCO3, and brine. Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 35 to 70%) afforded the title compound (5.65 g, 25 mmol, 43%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:3]1=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:34]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:35])[C:3]1=[O:25])[CH3:24]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 228°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16](I)[C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:23]=[CH2:24])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1cc(Cl)c(-n2cc(I)c(C(F)(F)F)n2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodo-3-trifluoromethylpyrazole (1 g) in dimethylformamide (5 ml) containing vinyltri-n-butyltin (2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.1 g) was stirred at 75° C. for 3 hours. The reaction mixture was evaporated and then partitioned between water and ether. The organic layer was separated, washed with water (×5), dried (Na2SO4) and evaporated. The residue was crystailised from hexane and further purified by column chromatography on silica gel eluted with ether. Combination and evaporation of appropriate fractions gave a yellow solid which was further purified by reverse phase high performance chromatography on C18 silica eluted with acetonitrile: methanol: water (40:10:50). Combination and evaporation of appropriate fractions, followed by recrystallisation from propan-2-ol, gave the title compound as a light yellow solid, m.p.95-98° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12].O>C(O)(=O)C>[CH3:12][C:11]1[N:1]([C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[C:8]([CH3:7])=[CH:9][CH:10]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc[nH]n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.4 h

Procedure:
To a solution of 3-aminopyrazole (100 g) in acetic acid (1000 ml) was added 2,5-hexanedione (148 ml), and the mixture was stirred for 2.4 hours at reflux. This reaction solution was cooled to room temperature, water (1000 ml) was added thereto, and the precipitated solid was collected by filtration. The resulting solid was washed with water (1000 ml), and dried under reduced pressure to give the titled compound (183 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH2:15][C:16](=[S:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:22][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(N)=S
Product: CCOC(=O)c1nc(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (14 g, 41 mmol) was added ethyl amino(thioxo)acetate (5.0 g, 38 mmol), and the mixture was stirred at 80° C. for 3 hr. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by recrystallization (ethyl acetate) to give the title compound (5.6 g, 49%) as colorless crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16](=[O:30])[NH:17][C@@H:18]1[C:24](=[O:25])[NH:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH3:43].[Na+].[I-]>C1COCC1>[CH3:43][C:34]1[CH:35]=[CH:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]=1[CH2:32][N:23]1[C:24](=[O:25])[C@@H:18]([NH:17][C:16](=[O:30])[O:15][C:11]([CH3:14])([CH3:12])[CH3:13])[CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]1=2
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
1 M lithium bis(trimethylsilyl) amide in THF (3.07 mL, 1 eq) was added to a solution of ((S)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid-t-butyl ester (855 mg, 3.07 mmol, 1.0 eq) in THF (10 mL) at −78° C. After 30 min. 1-(chloromethyl)-2-methylnaphthalene (586 mg, 3.07 mmol, 1 eq) and NaI (461 mg, 3.07 mmol, 1 eq) were added and the mixture warmed to RT over 2 h. The solvent was removed and the residue was suspened in EtOAc and washed with H2O. The aqueous extracts were extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography to afford (S)-tert-butyl 5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.01 g, 75%) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[OH:18])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:18][C:12]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Nc2ccc(O)cc2O)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccc(O)cc3o2)cn1
Temperature: 25 °C

Procedure:
4-{[(6-methoxypyridin-3-yl)methylene]amino}benzene-1,3-diol was dissolved in CH2Cl2 (30 mL) and DDQ was added. The reaction mixture was stirred over night at r.t., SiO2 was added and the solvents were removed under reduced pressure. The crude product was purified by flash column chromatography to give the title compound (189.1 mg). 1H NMR δ ppm 9.88 (s, 1H) 8.90 (dd, 1H) 8.35 (dd, 1H) 7.56 (d, 1H) 7.09 (d, 1H) 6.85 (dd, 1H) 3.95 (s, 3H); MS m/z 243 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[CH:26]=[CH:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:17][C:16]2=[O:18]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Product: CCCOc1ccc(C=CC(=O)OC(C)(C)C)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
The title compound was prepared from 2-(5-bromo-2-n-propoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 11) and t-butyl acrylate following the procedure of Example 9 and was obtained as colorless crystals (18%), m.p. 196-197° C.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[CH2:9]=[CH:10][CH3:11]>[Cr].[Co]>[CH3:8][C:1]1[CH:6]=[C:5]([CH:10]([CH3:11])[CH3:9])[CH:4]=[C:3]([CH3:7])[CH:2]=1
Reactant: Cc1cccc(C)c1
Reactant: C=CC
Agent: [Co]
Agent: [Cr]
Product: Cc1cc(C)cc(C(C)C)c1

Procedure:
A reaction was carried out using a Hastelloy C autoclave having an inside volume of 6,000 mL and equipped with an electromagnetic stirrer, a baffle plate, a gas blowing port and a liquid feed port in the same manner as that in Example 1. For the reaction, 2,003 g (18.9 moles) of metaxylene, 943 g (47.1 moles) of anhydrous HF and 715 g (17.0 moles) of propylene were used. After the reaction was terminated, the reaction mixture was fed at a rate of 300 mL per hour together with 600 g per hour of benzene to a distillation column (column internal pressure: 0.38 MPa, 122° C.) in which benzene was recirculated. A benzene solution of 3,5-dimethylcumene was separated and collected from the bottom of the column, while discharging BF3 from the top and HF from a discharge port below the condenser. The benzene solution of 3,5-dimethylcumene obtained from the bottom of the column was condensed using an evaporator and then distilled (column internal pressure: 0.0133 MPa, stage number: 12, a reflux ratio: 10) to obtain 1,925 g of desired 3,5-dimethylcumene (distillation temperature: 129° C.). The purity was 99.2% and isolation yield was 76%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH:19]1[OH:25])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:25][CH:19]2[CH:20]([CH3:24])[CH2:21][CH2:22][CH2:23][CH:18]2[C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: CC1CCCC(C(C)(C)C)C1O
Product: CC1CCCC(C(C)(C)C)C1Oc1cccc(C#N)c1C#N
Yield: 50 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-3-nitrobenzene and 3.40 grams of 2-t-butyl-6-methylcyclohexanol, there was obtained 1.48 grams of 1,2-dicyano-3-(2-t-butyl-6-methylcyclohexyloxy)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.48 grams of this benzene compound and 0.42 gram of BBr3, there was obtained 1.1 grams of the end product (yield 68%, mp 154°-155° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=C[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:4].[ClH:18]>CO>[ClH:18].[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH2:6])[C:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8]
Reactant: COC(=O)c1ncoc1-c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)C(=O)c1ccc(F)cc1F
Temperature: 60 °C

Procedure:
To a 1 liter three neck round bottom flash equipped with mechanical stirrer and reflux condensor is added 5-(2,4-Difluoro-phenyl)-oxazole-4-carboxylic acid methyl ester (30.66 g, 128 mmole), 200 mL of 2 normal hydrogen chloride in methanol, and 200 mL of dry methanol under nitrogen. The mixture is stirred and heated to 60° C. for three hours. The reaction is cooled and concentrated to a thick slurry. The slurry is treated with 100 mls of dry methanol and 400 mL of diethyl ether to precipitate solids. The solids are collected by vacum filtration and washed thoroughly with diethyl ether and air dried to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
2-(4-chlorophenyl)ethanamine (0.321 ml, 2.27 mmol) was diluted with DCM (10 mL) followed by the addition of DIEA (d 0.742) (0.395 ml, 2.27 mmol) and 4-fluorobenzoyl chloride (0.231 ml, 1.89 mmol). After stirring for 30 minutes the reaction was loaded directly onto a biotage 40S cartridge and eluted with hexanes:ethyl acetate (2:1) to yield N-(4-chlorophenethyl)-4-fluorobenzamide (393 mg, 74.8% yield) as a white solid.
Reaction SMILES: Br.Br[CH:3]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=O.[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C.Cl>[NH2:22][C:20]1[S:21][C:3]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:19]=1
Reactant: N#Cc1cccc(C(=O)C(Br)n2cncn2)c1
Reactant: NC(N)=S
Agent: Br
Agent: Cl
Solvent: CCO
Product: N#Cc1cccc(-c2nc(N)sc2-n2cncn2)c1
Temperature: 95 °C

Procedure:
A mixture of 3-(2-bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrile hydrobromide (1.848 g, 5.00 mmol), thiourea (0.46 g, 1.2 mol) in ethanol is heated to 95° C. for 8 h. The solvent is removed under vacuum to give a foam which is dissolved in 3M hydrochloric acid. The product is precipitated as a white powder by the addition of concentrated aqueous ammonia to pH11. M.S. (MH+) 269.54.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([O:24][C:32]2[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(S(C)(=O)=O)cc1
Yield: 58.5 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (518 mg), which is obtained in a similar manner to that described in Reference example 39(a), 4-methanesulfonylphenol (394 mg), tributylphosphine (0.57 ml) instead of triphenylphosphine and 1,1′-(azodicarbonyl)dipiperidine (578 mg) instead of diethylazodicarboxylate and the reaction mixture was treated to afford the desired compound (441 mg) as a mass of foam.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]12[O:25][CH2:24][CH2:23][O:22]1)[CH3:2].[H][H]>C1C=CC=CC=1.[Pd]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:22][CH2:23][CH2:24][O:25]1)[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC21OCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Yield: 64.6 %

Procedure:
Hydrogenate 13β -ethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (2.0 g.) in benzene (70 cc.) at atmospheric pressure using a 5% palladium on calcium carbonate catalyst (0.70 g.). Uptake of hydrogen ceases after 150 cc. has been absorbed. Isolate the product and recrystallize from 95% ethanol to obtain the title product (1.3 g.), m.p. 135°-137°; ultraviolet absorption peak at 2.78 mμ (15,100).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[N:14]=[C:1]([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: CC(=Nc1cccc(Cl)c1)c1ccccc1

Procedure:
A solution of acetophenone (130 ml), m-chloroaniline (130 ml) and benzene (200 ml) was refluxed in the presence of molecular sieve (50 g) with continuous removal of water. m-Chloro-N-(α-methyl benzylidene) aniline (XIX) was obtained by fractional distillation. XIX had a boiling point of 110° C. at 0.025 millimeter.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[CH:13][CH:12]=[CH:11]2)(C)(C)C.[OH-].[Na+]>>[F:18][C:17]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1cc2cccnc2cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cc2cccnc2cc1F
Temperature: 90 °C
Yield: 79.8 %

Procedure:
A mixture of (7-fluoro-quinolin-6-yl)-acetic acid tert-butyl ester (3.67 g) and 4N aquous sodium hydroxide (14.8 mL) were heated at 90° C. for 3 h. The solution was extracted with ethyl acetate. The aqueous layer was adjusted to acidic pH with acetic acid and filtered and dried to afford the title compound (2.3 g, 79.8%). 1H NMR (300 MHz, DMSO-d6) δ 12.52 (1H, s), 8.88˜8.90 (d, 1H), 8.34˜8.38 (d, 1H), 7.97˜7.99 (d, 1H), 7.73˜7.76 (d, 1H), 7.50˜7.54 (m, 1H), 3.85 (s, 2H). ES-MS m/z: 206.2 (M+1).