Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc2ccccc2c1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc3ccccc3c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and naphthalene-2-thiol (0.392 g, 2.45 mmol). The title compound was obtained as a cream colored solid (0.585 g, 73% yield). 1H NMR (300 MHz, CDCl3) δ: 8.23 (1H, m), 8.09 (1H, s), 7.99 (1H, d), 7.92 (2H, m), 7.63 (3H, m), 2.46 (3H, s).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.O>C(O)C>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:18][C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cccc1C=O
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1C=C[NH+](C)C1C=Cc1cccn1C
Yield: 74.3 %

Procedure:
A mixture of 12.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2g of potassium hydroxide and 12.0 g of N-methylpyrrole-2-carboxaldehyde in 60 ml of absolute ethanol is refluxed for 15 minutes during which time a precipitate is formed. The mixture is cooled and 10 ml of water is added. The solid is filtered off and crystallized from absolute ethanol to yield 12.3 g of the title compound, melting point 289°-291° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Si:18]([O:25][CH2:26][CH:27]1[CH:31]([CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:30][C:29]([CH2:41]Br)=[CH:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:18]([O:25][CH2:26][CH:27]1[CH:31]([CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:30][C:29]([CH2:41][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CC(CO[Si](C)(C)C(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)C2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 g, 0.66 mmol) and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide (0.30 g, 0.66 mmol) in dimethylformamide (10 ml) were heated at 50° C. for overnight in the presence of sodium bicarbonate (66 mg, 0.79 mmol). After the concentration of dimethylformamide, 1-{[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl}-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF (10 ml) was reacted with n-tetrabutylammonium fluoride at room temperature for 1 hr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product (48 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][C:21]1[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Cc1ccc(CBr)cc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 4-methylbenzyl bromide (0.71 g; 3.85 mmol) and K2CO3 (1.5 g; 10.9 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (10 ml) and hydrochloric acid (6 N; 30 ml). Pure 5-amino-3,3-dimethyl-1-(4-methyl-benzyl)-6-nitro-1,3-dihydro-indol-2-one (1.18 g) precipitates by pouring the reaction mixture in ice-water.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[NH:15][CH3:16]>>[CH3:16][N:15]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CNc1ccncc1N
Reactant: OC1CCCCO1
Product: Cn1c(CCCCO)nc2cnccc21

Procedure:
The title compound was prepared by the method of Preparation 18 using 2-hydroxytetrahydropyran and 3-amino-4-(methylamino)pyridine as the starting materials
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18]C(=O)C)[C:12]=1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+]>>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][OH:18])[C:12]=1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCOc1ccnc(CO)c1C
Yield: 126.6 %

Procedure:
15.4 g (0.05 mol, 1.0 eq.) of 4-nonyloxy-2-acetoxymethyl-3-methylpyridine was added dropwise to a 20% aqueous solution of sodium hydroxide (20.0 g) at 11 to 21° C., and the mixture was allowed to react for one hour at room temperature, and then extracted with water (77 mL) and toluene (128 mL). The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 16.8 g of 4-nonyloxy-2-hydroxymethyl-3-methylpyridine as a brown oily matter.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=O.C(O)C>CO>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[N:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CO
Solvent: CCO
Product: O=C(O)Cc1cccc(N=Cc2cc(Cl)ccc2O)c1
Yield: 69.6 %

Procedure:
Using the procedure of Sheeman et al [J.A.C.S., Vol. 84, (1982), p. 2457], 1.5 g of 3-amino-phenylacetic acid, 1.72 g of 5-chloro-2-hydroxy-benzaldehyde, 480 ml of 100% ethanol and 35 ml of methanol were reacted to obtain 2 g of 3-[(5-chloro-2-hydroxy-benzylidene)-amino]-phenylacetic acid.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[C:12]1(=O)[O:16][CH2:15][CH2:14][CH2:13]1.N>Cl>[CH3:3][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=[C:12]1[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: O=C1CCCO1
Reactant: CNc1ccccc1N
Agent: Cl
Agent: N
Product: Cn1c(CCCO)nc2ccccc21
Yield: 71.2 %

Procedure:
N-Methyl-ortho-phenylenediamine dihydrochloride (4.88 g), and butyrolactone (3.22 g) were stirred at reflux for 18 hours in 4N hydrochloric acid (25 ml). The reaction mixture was cooled, the pH adjusted to 8 with concentrated aqueous ammonia and filtered. The solid was recrystallised from ethyl acetate to yield the title compound as a white solid (3.39 g 71%), m.p. 107° C. Found: C, 69.22; H, 7.38; N, 14.73. C11H14N2O requires C, 69.45; H, 7.42; N, 14.72%.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:13][CH2:14][CH3:15])=[N:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)C.[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O>C(Cl)Cl.CCCCCC>[CH2:6]([NH:5][C:4]([NH:3][N:2]=[CH:26][C:25]1[C:24]([Cl:23])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:32])=[N:13][CH2:14][CH3:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCNC(=NCc1ccccc1)NN
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCN=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
A 10.0 g. portion of 1-amino-2-benzyl-3-ethylguanidine hydroiodide in a mixture of 100 ml. each of diethyl ether, n-hexane and methylene chloride is shaken with 10 ml. of 5N NaOH. A 5.46 g. portion of 2,6-dichlorobenzaldehyde is added and the mixture is shaken and then allowed to stand at room temperature overnight. The organic layer is washed with saturated aqueous sodium chloride, passed through hydrous sodium magnesium silicate and concentrated under reduced pressure. The residue is crystallized from diethyl ether-hexane to give the desired product as a bright yellow solid, m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[S:32].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]3[O:26][C:31](=[S:32])[NH:28][N:27]=3)=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1Sc1ccc(Cl)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3n[nH]c(=S)o3)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}benzohydrazide (Step 1 of Example 48, 50 mg, 0.115 mmol) and 1,1′-carbonothioylbis(1H-imidazole) (41 mg, 0.23 mmol) in dichloromethane (1 mL) was added triethylamine (46 mg, 0.46 mmol) at rt. After 1 h, the reaction was quenched with aq NaHCO3 and the product was extracted 3 times with EtOAc. The combined extracts were concentrated, and the residue was subjected to reverse phase HPLC. The fractions containing the product were collected and concentrated. The residue was diluted with EtOAc, washed with aq NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.65 (d, 1H), 8.38 (broad d, 1H), 8.36 (d, 2H), 8.19 (s, 1H), 8.03 (d, 2H), 7.84 (m, 1H), 7.38 (m, 1H), 7.27 (d, 2H), 7.07 (d, 2H), 4.16 (s, 3H). LCMS: m/z 478 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: CCOC(=O)CCCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), ethyl 7-oxo-7-phenylheptanoate (959 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoate (800 mg, yield 72%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH:26]=[C:25]([CH2:34][C:35]([O:37]CC)=[O:36])[CH:24]=3)=[O:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH:26]=[C:25]([CH2:34][C:35]([OH:37])=[O:36])[CH:24]=3)=[O:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C(=O)OCC)CC3)cc2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)c3cc(CC(=O)O)cc4ccc(F)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-[4-(3-ethoxycarbonylmethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester (0.110 g, 0.20 mmol) in tetrahydrofuran (12 mL) was added a solution of lithium hydroxide monohydrate (0.042 g, 0.99 mmol) in water (3 mL) and the reaction mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water (6 mL) and washed with ethyl acetate (2×5 mL). The aqueous layer was acidified with an aqueous solution of hydrochloric acid (1 N), then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.058 (56%) of 4-[4-(3-carboxymethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 8.10-8.20 (m, 2H), 8.00 (d, J=8.3 Hz, 2 H), 7.90 (d, J=8.3 Hz, 2 H), 7.82-7.88 (m, 1 H), 7.72 (s, 1 H), 7.57 (td, J=8.7, 2.2 Hz, 1 H), 3.99 (q, J=6.9 Hz, 2 H), 3.82 (s, 2 H), 3.46 (br. s, 4 H), 2.96 (br. s, 4 H), 1.13 (t, J=6.9 Hz, 3 H). MS cald. for C26H25FN2O7S ([M+H]+) 529, obsd. 529.3.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[N:8][C:7]=1[CH3:15])=O.[C:16]([O:20]CC)(=[S:19])[NH:17][NH2:18]>C(#N)C>[BrH:2].[CH3:15][C:7]1[N:8]=[C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:6]=1[C:4]1[CH2:3][S:19][C:16](=[O:20])[NH:17][N:18]=1
Reactant: CCOC(=S)NN
Reactant: Cc1nc2ncccn2c1C(=O)CBr
Agent: Br
Solvent: CC#N
Product: Cc1nc2ncccn2c1C1=NNC(=O)SC1
Yield: 37.8 %

Procedure:
A mixture of 5.4 g of 3-bromoacetyl-2-methylimidazo[1,2-a]pyrimidine hydrobromide, 3 g of ethyl thiocarbazate and 100 ml of acetonitrile is stirred under reflux for 4 hours. After cooling, crystals are collected by filtration and recrystallized from methanol twice to give 2 g of 5-(2-methylimidazo[1,2-a]pyrimidin-3-yl)-3,6-dihydro-1,3,4-thiadiazin-2 -one hydrobromide as pale yellow crystals, melting at 285°-288° C. with decomposition.
Reaction SMILES: IC.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[CH:19]1(C#CC2C=CC(OC)=CC=2C(O)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH3:19][O:17][C:16]([C:13]1([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[CH2:14][CH2:15]1)=[O:18]
Reactant: COc1ccc(C#CC2(C(=O)O)CC2)cc1
Reactant: COc1ccc(C#CC2CC2)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: COC(=O)C1(C#Cc2ccc(OC)cc2)CC1
Reaction time: 4 h

Procedure:
Iodomethane (3.6 g, 0.026 mol) was slowly added to a mixture of 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid and 2-cyclopropylethynyl-5-methoxy-benzoic acid (5.0 g) and potassium carbonate (4.8 g, 0.034 mol) in DMF (100 mL). After stirring for 4 hours, the mixture was diluted with ether (200 mL) and washed with water. The ether layer was dried over sodium sulfate, evaporated to dryness, and the residue was purified by column chromatography to yield 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid methyl ester as a yellow oil (2.2 g). 1H NMR (CDCl3): δ 7.36 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz. 2H), 3.79 (s, 3H), 3.76 (s, 3H), 1.62 (m, 2H), 1.41 (m, 2H). 2-cyclopropylethynyl-5-methoxy-benzoic acid methyl ester (1.0 g). 1H NMR (CDCl3): δ 7.89 (d, J=2.4 Hz, 1H), 7.46 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.8 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 1.43 (m, 1H), 0.86 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]4[O:38][C:37](C)(C)CC[C:34]=4[C:41]=3[CH3:42])(=[O:29])=[O:28])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.NC1C2C(=CC(C[CH:58](NC(=O)OC(C)(C)C)[C:59](=[O:66])[N:60]3CCCCC3)=CC=2)C=CN=1.NC(=O)C[C@H](NS(C1C(C)=CC(OC)=C(C)C=1C)(=O)=O)C(O)=O.N[C@H](C(O)=O)CC(=O)N.[Cl-]>>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[C@@H:25]([NH:26][S:27]([C:30]3[C:41]([CH3:42])=[CH:34][C:33]([O:38][CH3:37])=[C:32]([CH3:43])[C:31]=3[CH3:44])(=[O:28])=[O:29])[CH2:58][C:59]([NH2:60])=[O:66])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)c(C)c1C
Agent: Cl
Agent: NC(=O)C[C@H](N)C(=O)O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c1C

Procedure:
The procedure described for 5c was used. Deprotection of 100 mg of 5a and coupling with 105 mg of (2S)-4-amino-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-4-oxobutanoic acid (prepared from Asn-OH and 4-methoxy-2,3,6-trimethylsulfonylchloride (Mtr-chloride)using the procedure described for Sb) yielded the title compound (66 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.20-1.68 (6H, m), 2.15 and 2.16 (3H, 2× s), 2.27-2.58 (2H, m), 2,57 (3H,s), 2.64 (3H, s), 2.93-3.57 (6H, m), 3.83 and 3.87 (3H, 2× s), 3.98-4.09 (1H, mn), 5.07-5.19 (1H, m), 6.75 and 6.76 (1H, 2× s), 7.22-7.27 (1H, m), 7.55-7.79 (3H, m), 8.33-8.38 (1H, m).
Reaction SMILES: [H-].[K+].[H-].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]3[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[N:19][C:13]=3[N:14]([CH2:17][CH3:18])[C:15]=2[N:16]=1.[N+]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=1)([O-])=O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]3[CH:22]=[C:21]([CH2:23][O:24][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:20]=[N:19][C:13]=3[N:14]([CH2:17][CH3:18])[C:15]=2[N:16]=1
Reactant: Cc1cc([N+](=O)[O-])ccn1
Reactant: CCN1c2ncc(CO)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Product: CCN1c2ncc(COc3ccnc(C)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 69 %

Procedure:
Using a procedure analogous to that described in Example 91, except potassium hydride was employed as the base instead of sodium hydride, the title compound, m.p. 163°-164° C., was prepared from 2-chloro-5,11-dihydro-11-ethyl-8-hydroxymethyl-5-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-nitro-2-picoline. The yield was 69% of theory.
Reaction SMILES: CC([O-])(C)C.[K+].O.[OH:8][C:9]1([C:15]2[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[NH2:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:9]2([OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C2(O)CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(C2(O)CCCCC2)cc1
Temperature: 25 °C

Procedure:
355 mg (3.16 mmol) KOtBu and 14 μl (0.79 mmol) H2O were added to a solution of 386 mg (0.79 mmol) tert-butyl 4-(1-hydroxycyclohexyl)benzylcarbamate in 3.9 ml THF. Refluxed for 2 h. Cooled to r.t. The reaction was quenched with NH4Cl (sat.) and the pH was adjusted to 10-11 with 2 M NaOH. The mixture was extracted 3 times with EtOAc. The organic phase was dried (MgSO4) and concentrated. Gave 164 mg (quant. yield). Used directly in the next step.
Reaction SMILES: C([S:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:24])[CH:14]=2)[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[Cl:24][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:7][CH2:6][CH2:5][SH:4])[N:17]=[C:16]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)SCCNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: SCCNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1

Procedure:
A mixture of 108 ma of 2-(2-acetylthioethylamino)-6-chloro-4-phenylquinazoline (compound No. Ic3-14), 2 ml of ethanol and 362 mg of an aqueous 10% sodium hydroxide solution was stirred at room temperature for 2 hours and stirred under heating under reflux for 30 minutes. Then insoluble substances were collected by filtration from the reaction solution. The collected product (solid) was purified by silica gel column chromatography (chloroform:ethyl acetate=10:1) to obtain 50 mg of 6-chloro-2-(2-mercaptoethylamino)-4-phenylquinazoline, first. Mp.165.9° C. 1H NMR (CDCl3): 1.46 (1H, t, J=8.5 Hz), 2.84 (2H, q-like, J=7.2 Hz), 3.66 (2H, q-like, J=6.4 Hz), 5.79 (1H, br. t, J=5.4 Hz), 7.55-7.57 (3H, m), 7.60 (2H, s), 7.66-7.69 (2H, m), 7.77-7.78 (1H, m). Then, 28 mg of bis[2-(6-chloro-4-phenyl-2-quinazolinyl)aminoethyl]disulfide (compound represented by the following formula) was obtained.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(O)=O)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C=CN=CC=1)CCCC.[OH:26]O>C(O)(=O)C.C(Cl)Cl>[CH2:1]([C:6]1[CH:11]=[CH:10][N+:9]([O-:26])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OO
Reactant: CCCCCc1ccnc(C(=O)O)c1
Agent: CCCCCc1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCc1cc[n+]([O-])cc1
Yield: 100 %

Procedure:
4-Pentylpyridine-2-carboxylic acid (10b) (R9=pentyl) was made by employing general Method P. To 4-pentylpyridine (3 g, 20 mmol) in acetic acid (30 mL), hydrogen peroxide (0.7 g, 30%, 20 mmol) was added and refluxed overnight. Removal of solvent resulted in residue which was dissolved in DCM (100 mL) dried over MgSO4 and filtered. Removal of DCM resulted in a brown liquid, 4-pentylpyridine-N-oxide, (3.3 g, 100%). To trimethylsilyl cyanide (2.37 g, 24 mmol), 4-pentylpyridine N-oxide (3.3 g, 20 mmol) in DCM (10 mL) was added followed by dropwise addition of dimethylcarbamoyl chloride (2.56 g, 24 mmol) in DCM (10 mL). After stirring at room temperature overnight, sodium bicarbonate (100 mL, 10%) was added and the organic layer was separated. The aqueous layer was extracted twice with DCM (50 mL) and the combined organic layer was dried over magnesium sulfate. Removal of solvent resulted in compound 10a (R9=pentyl) (4.1 g, 100%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH:15]([F:17])[F:16])[C:10]=1[CH:18]=[O:19]>C(O)C.[Pd]>[CH3:14][N:13]1[CH:9]=[C:10]([CH:18]=[O:19])[C:11]([CH:15]([F:16])[F:17])=[N:12]1
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1cc(C=O)c(C(F)F)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In an autoclave, 10 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde were dissolved in 150 ml of ethanol, and 10.4 g of triethylamine and 500 mg of 5% palladium on calcium carbonate were added. The autoclave was flushed with nitrogen and subsequently pressurised to 5 bar hydrogen. The reaction mixture was then stirred at 30° C. for 4 h. After filtration of the catalyst, the solvent was removed under reduced pressure and the product was obtained as a solid (7.4 g) having a melting point of 46-47° C.