Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:23][S:24]SC>>[CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([S:24][CH3:23])[C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CSSC
Reactant: CCCCCCCCCCc1ccc2ccc(OC)cc2c1
Product: CCCCCCCCCCc1ccc2cc(SC)c(OC)cc2c1
Yield: 93 %

Procedure:
7-Decyl-3-methylthio-2-methoxynaphthalene (compound (4)-12) was synthesized from 7-decyl-2-methoxynaphthalene (compound (3)-12) and dimethyl disulfide by the same method as that in Example 14 (yield of 93%, recrystallized from hexane to obtain yellow crystals).
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:22][NH2:23].[OH-].[K+]>CO>[C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13]([NH:23][OH:22])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)NO)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12.6 parts of ethyl p-(2-thenoyl)hydratropate in 35 parts of methanol is added successively and while cooling, first a solution of 6.05 parts of hydroxyl amine hydrochloride in 35 parts of methanol and then a solution of 7.3 parts of potassium hydroxide in 35 parts of methanol. Upon completion, the whole is stirred for 30 minutes. The mixture is filtered and the filtrate is stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The aqueous solution is acidified with hydrochloric acid solution and the product is extracted with ether. The extract is washed with water, dried, filtered and evaporated. The residue is taken up in water, alkalized with sodium hydroxide solution, washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid solution. The product is extracted with ether. The latter is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in a mixture of petroleumether and diisopropylether. The solid product is filtered off and crystallized from 2-propanol, yielding p-(2-thenoyl)hydratropohydroxamic acid; mp. 143.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:33][CH2:32][C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:31][CH:30]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccc(OCCN2CCOCC2)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3ccc(OCCN4CCOCC4)cc3)c3ccccc3nc21
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol), 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine (0.75 g, 3.2 mmol) and DMSO (3 mL) was heated on a steam bath for 8 hours. Additional 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol) was then added and the reaction mixture was heated on a steam bath for another 4 hours. The reaction mixture was cooled to room temperature and then was poured into water. The mixture was extracted with CH2Cl2 (3×100 mL) and then CH2Cl2 layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (95/5), followed by recrystallization from ethyl acetate, to afford 1.0 g of 1-ethyl-N-[4-[2-(4-morpholinyl) ethoxy]phenylmethyl]-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 170-172° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][C@H:4]([C@H:9]([OH:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6]>CCOC(C)=O.[Pd]>[CH3:1][CH:2]([CH3:12])[CH2:3][C@H:4]([C@H:9]([OH:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(C)C[C@@H](C(=O)OC)[C@@H](C)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)[C@@H](C)O
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
Methyl (2R,3R)-2-(2-methyl-2-propen-1-yl)-3-hydroxybutanoate (8.1 g, 47.1 mmol) in 85 mL of EtOAc is treated with 800 mg of 10% palladium on carbon and the mixture is evacuated and purged with nitrogen. The heterogeneous solution is stirred under 52 psi of hydrogen for 1.5 h. Filtration and concentration of the filtrate in vacuo affords 7.99 g (96%) of methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](=[O:11])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9].[I-].[Na+].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15]>CC(=O)CC.C(OCC)C>[O:10]=[C:7]([CH2:8][CH3:9])[CH:6]([C:5](=[O:11])[CH2:4][CH3:3])[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCC(=O)CC(=O)CC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCC(=O)C(Cc1ccc(C#N)cc1)C(=O)CC
Yield: 58 %

Procedure:
Sodium hydride (60% dispersion in oil, 3.43 g, 86 mmol) was added to a solution of 3,5-heptanedione (10 g, 78 mmol), in 2-butanone (200 ml), under nitrogen. A slight exotherm was observed during gas evolution. Sodium iodide (11.7 g, 78 mmol) was then added, followed by 4-cyanobenzyl bromide (15.29 g, 78 mmol) in 2-butanone (20 ml) and a precipitate was formed. The reaction mixture was heated at reflux for 16 hours. It was then filtered to remove the precipitate and concentrated under reduced pressure. The residue was stirred in dichloromethane (100 ml) and solid sodium bromide was removed by filtration. The dichloromethane filtrate was then washed with water (100 ml) and brine (100 ml). The organic layer was collected, dried over magnesium sulphate and concentrated under reduced pressure to give an orange solid. This was slurried in diethyl ether and filtered off to provide the title compound (11.01 g, 58%) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): δ=0.98 (t, 6H), 2.29-2.35 (m, 2H), 2.42-2.52 (m, 2H), 3.19 (d, 2H), 3.97 (t, 1H), 7.25 (d, 2H), 7.56 (d, 2H); LRMS: APCl−: m/z 242 [M−H].
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:33]2[C:32](=[O:34])[NH:31][C:30]([C:35]([O:37]CC)=O)=[N:29][C:28]=2[S:27][CH:26]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:83]2[CH:87]=[N:86][C:85]([O:88][CH2:89][CH2:90][O:91][C:92]3[CH:93]=[C:94]([CH2:98][NH2:99])[CH:95]=[CH:96][CH:97]=3)=[N:84]2)C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:33]2[C:32](=[O:34])[NH:31][C:30]([C:35]([NH:99][CH2:98][C:94]3[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH2:90][CH2:89][O:88][C:85]4[N:86]=[CH:87][NH:83][N:84]=4)[CH:93]=3)=[O:37])=[N:29][C:28]=2[S:27][CH:26]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccccc3OC)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: COc1ccccc1-c1csc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(2-methoxyphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 71 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (114.4 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[S:5][CH:6]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([N:17]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11])[S:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)CCNC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1)S(=O)(=O)c1ccccc1
Temperature: 75 °C

Procedure:
N-[1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-3-methylbutan-1-amine (248 mg, 0.610 mmol) and DMAP (3.7 mg, 0.031 mmol) were dissolved in 2 mL pyridine and benzenesulfonyl chloride (234 μl, 1.830 mmol) was added. The resulting mixture was heated at 75° C. overnight, after which the mixture was cooled to room temperature, toluene was added and the mixture was concentrated in vacuo. The title compound was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12]C)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14].F[C:16]1C=CC(S(C(C)C)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:12])[CH3:16])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: CC(C)S(=O)(=O)c1ccc(F)cc1
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Product: CC(C)S(=O)(=O)c1ccc(F)c(Br)c1
Yield: 89 %

Procedure:
Following the general method as outlined in Intermediate 106, starting from 1-fluoro-4-(isopropylsulfonyl)benzene, the title compound was obtained as an oil which solidifies upon standing in 89% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:6]1[CH2:8][CH2:9][OH:10])=[O:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:6]1[CH2:8][CH2:9][O:10][S:20]([CH3:19])(=[O:22])=[O:21])=[O:4]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.5 %

Procedure:
1-tert-Butoxycarbonylamino-2-(2-hydroxyethyl)-cyclopropanecarboxylic acid methyl ester (0.500 g, 1.93 mmol, from Example 104) was diluted in 8 mL DCM and cooled to 0° C. under an Ar atmosphere. TEA (0.54 mL, 3.9 mmol) and methanesulfonyl chloride (0.30 mL, 3.9 mmol) were added sequentially. After 2.5 h, the solvent was removed in vacuo and the residue taken up in EtOAc and H2O (15 mL each). The aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, the residue was purified by column chromatography on SiO2 (0 to 50% Hex/EA) to produce 1-tert-butoxycarbonylamino-2-(2-methanesulfonyloxyethyl)cyclopropanecarboxylic acid methyl ester (0.55 g, 84%). LCMS found 360.1 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH:12]([CH3:34])[C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (24.2 mmol) of (S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 66, Step A) and iodomethane (1.813 mL, 29.1 mmol) in THF (120.0 mL) was added a lithium bis(trimethylsilyl)amide, (1M solution in THF; 26.6 mL, 26.6 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched (sat. aqueous NH4Cl) and extracted (2×EtOAc). The combined organic layers were washed with water and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was absorbed onto a plug of silica gel and purified by chromatography on silica gel, eluting with a gradient of 10% to 30% EtOAc in hexane, to provide the title compound as a mixture of stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([NH:22][NH2:23])[C:3]=1[O:24][CH3:25].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([NH:22][NH:23][C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[C:3]=1[O:24][CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NNC(=O)C1CC1
Reaction time: 1 h

Procedure:
3-[4-chloro-2-diazanyl-6-fluoro-3-methoxyphenyl]-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.15 g, 0.4 mmol) was dissolved in dioxane (10 ml) and added with cyclopropanecarbonyl chloride (0.04 g, 0.4 mmol) and triethylamine (0.04 g, 0.4 mmol). After stirred for 1 hr, the mixture was poured into water (15 ml) and extracted with ethyl acetate (10 ml×3). Organic phase was washed with brine and dried over Na2SO4. Final purification involved column chromatography (silica gel, ether). Yield: 0.15 g, 0.34 mmol.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:26][C:21]=4[S:20][C:19]3=[N:32]C(=O)C(F)(F)F)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[ClH:1].[ClH:1].[ClH:1].[NH:32]=[C:19]1[N:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[C:22]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:26][C:21]=2[S:20]1
Reactant: COc1ccc(N2CCN(CCn3c(=NC(=O)C(F)(F)F)sc4cc(OC(F)(F)F)ccc43)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCN(CCn3c(=N)sc4cc(OC(F)(F)F)ccc43)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 214.3 %

Procedure:
3-{2-[4-(4-Methoxyphenyl)-1-piperazinyl]ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.53 g), methanol (33 cc) and 7% strength potassium carbonate solution (21 cc) in a mixture of methanol (2 volumes) and water (5 volumes) are stirred for 4 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure and then extracted with ethereal sulphuric acid. The organic phase is dried over magnesium sulphate and then treated with an excess of alcoholic hydrochloric acid solution. The precipitate is drained, washed with ethereal sulphuric acid and dried at 50° C. at 20 mmHg. 2-Imino-3-{2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline trihydrochloride (1.05 g), m.p. 240° C., is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](Cl)(Cl)([Cl:44])[Cl:43]>>[CH3:1][C:2]([CH3:22])([CH:3]=[C:42]([Cl:44])[Cl:43])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C=O)COCc1ccc(F)c(Oc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C=C(Cl)Cl)COCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-al (0.5 g), triphenylphosphine (0.43 g) and carbon tetrachloride (1.0 cm3) was heated at the reflux temperature for 1 hour. After cooling to the ambient temperature the mixture was diluted with petroleum ether (boiling range 40°-60° C.) and the solid component removed by filtration. The filtrate was concentrated by evaporation of the solvent under reduced pressure and the redidual oil subjected to purification by flash chromatography using a silica column eluted with petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent to yield 2,2-dimethyl-1-(4-fluoro-3-phenoxybenzyloxy)-4,4-dichlorbut-3-ene (0.1 g) as a colourless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32]>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNc1nc(SC)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (K), is treated with glycine ethyl ester hydrochloride, a compound of formula (D), to yield 2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (L).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7]Br.[C-:16]#[N:17].[Na+]>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7][C:16]#[N:17]
Reactant: Fc1ccc(CBr)c(OCC(F)(F)F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(F)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl bromide (0.80 g, 2.7 mmol) from Step 3 above in DMF (14 mL) was added NaCN (0.20 g, 4.0 mmol). The mixture was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-fluorophenyl-acetonitrile as an oil (HPLC retention time=8.7 min (method A)).
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]1[CH2:22][CH2:21][C@@H:20](O)[CH2:19]1.O>CN(C=O)C>[CH3:17][N:18]1[CH2:22][CH2:21][C@@H:20]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:19]1
Reactant: CN1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
0.545 g (0.0025 mol) of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid were dissolved in 8 ml of dry DMF. To this solution 0.481 g (0.003 mol) of 1,1′-carbonildiimidazol were added and the mixture was stirred at room temperature for 1 h. After this time, the mixture obtained was added to a suspension of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19, 0.531 g, 0.0046 mol) and HNa (0.065 g, 0.0027 mol) in 3 ml of dry DMF. After stirring 26 h at room temperature the reaction mixture was treated with water and extracted two times with Et2O. The organic layers were combined, washed with water and dried. The residue was purified by silica gel column chromatography (eluent: CHCl3 plus isopropanol 0%→10%) to obtain 450 mg (60%) of the title product as an oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]3[C:7](=[CH:8][C:9]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10][CH:11]=3)[N:6]=2)[CH2:2]1.Br[CH2:26][C:27]#[N:28].C([O-])([O-])=O.[K+].[K+].CC#N>O>[CH3:15][N:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][C:9]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]1[CH:3]1[CH2:2][N:1]([CH2:26][C:27]#[N:28])[CH2:4]1
Reactant: Cn1c(C2CNC2)nc2cc(C#Cc3ccccn3)ccc2c1=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1c(C2CN(CC#N)C2)nc2cc(C#Cc3ccccn3)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
The mixture of 2-(azetidin-3-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one (100 mg, 0.316 mmol), 2-bromoacetonitrile (0.024 mL, 0.348 mmol), K2CO3 (87 mg, 0.632 mmol) and CH3CN (5 mL) was stirred at room temperature for 3 h, then diluted with water (10 mL). The mixture was then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by column chromatography to give 50 mg of the desired product. MS (ESI): 356 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.68-8.67 (d, J=4.4 Hz, 1H), 8.27-8.24 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.77-7.71 (m, 1H), 7.67-7.64 (dd, J=8.2, 1.5 Hz, 1H), 7.60-7.58 (d, J=7.8 Hz, 1H), 7.33-7.28 (m, 1H), 3.92-3.89 (m, 5H), 3.56 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.N>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Clc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dt, J=9.0, 2.3, Hz, 2H), 7.82 (s, 1H), 7.94 (dt, J=9.0, 2.4 Hz, 2H), 9.32 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+, 258 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:2].S(Cl)([Cl:16])(=O)=O>C(O)(=O)C>[Cl:16][C:5]1[NH:6][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:4]=1[CH2:3][C:1]#[N:2]
Reactant: N#CCc1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: N#CCc1c(Cl)[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-cyanomethylpyrrolo[2,3-b]pyridine (1,55 g, 0.098 mol) was treated in 5 ml acetic acid with an equimolecular amount of sulfurylchloride at 0° C. for 5 min. The mixture was allowed to warm to room temperature and was stirred 5 min. After evaporation the residue was dissolved in methylen chloride and was treated with bicarbonate. The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel eluting with ethyl acetate gave the desired product. (0,4 g 21%).