Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[Br:28]Br>C(Cl)(Cl)(Cl)Cl>[Br:28][CH:13]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10]2)=[O:26]
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(Br)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC

Procedure:
To a solution of 1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (37 g, 0.1 mol, Chemistry and Biology 2000, 7, 979) in carbon tetrachloride (300 mL) is added bromine (16.0 g, 0.1 mol) at such a rate to obtain a continuous discoloration of the reaction mixture. After the addition is complete (about 10 minutes), the reaction mixture is evaporated under reduced pressure to obtain 2-bromo-1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone, which is used in the next step without further purification.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH2:6][CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>ClCCl>[Cl:5][S:1]([NH:6][CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:3])=[O:2]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCNS(=O)(=O)Cl)OCC
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sulfuryl dichloride (1.1 g, 8.15 mmol, 1.47 equiv) in dichloromethane (10 mL). This was followed by the addition of a solution of diethyl 2-aminoethylphosphonate (intermediate 1.9) (1.0 g, 5.52 mmol, 1.00 equiv) and triethylamine (800 mg, 7.92 mmol, 1.43 equiv) in dichloromethane (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of ice water. The organic layer was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.5 g (crude) of the title compound as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[S:11]2)=[CH:7][C:6]=1[C:23]([CH3:26])([CH3:25])[CH3:24])(=O)C.O1CCCC1.[OH-].[Li+].Cl>O.CO>[C:23]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:5]=1[OH:4])[CH:9]=[C:10]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(=O)Oc1ccc(C=C2Sc3ccccc3NC2=O)cc1C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3NC2=O)ccc1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 2-(4-acetoxy-3-tert.-butylbenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Reference compound No. 1-2, 0.31 g) in the mixture of tetrahydrofuran (12 ml) and methanol (3 ml), lithium hydroxide (0.18 g) dissolved in water (8 ml) was added dropwise under ice cooling. After the addition, the mixture was stirred for additional 10 minutes. The reaction mixture was poured into 1N hydrochloric acid and the whole was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.25 g (91%) of 2-(3-tert.-butyl-4-hydroxybenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][S:15]([CH3:17])=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>ClCCl>[CH3:17][S:15]([CH2:14][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:12])=[O:16]
Reactant: CCCCCCCCN
Reactant: CS(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C(CCS(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a mixture of 2-((tert-butoxycarbonyl)amino)-4-(methylsulfinyl)butanoic acid (10.0 g, 37.7 mmol) and HOBt (6.35 g, 41.5 mmol) in dichloromethane (200 mL) at 0° C. was added triethylamine (10.5 mL, 75.4 mmol) and EDAC (7.95 g, 41.5 mmol). After stirring for 20 minutes octylamine was added and the solution was allowed to warm to room temperature and stirred for 3 days. The reaction was washed with saturated sodium bicarbonate (2×100 mL), 1N HCl (2×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil which solidified upon standing. The solid was purified by silica gel chromatography with 0-5% methanol/dichloromethane to give a white solid (13.1 g, 92%). m/z 377 (MH+).
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[CH3:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=1[C:29]1[NH:33][C:32]([C:34]2([CH3:38])[CH2:37][O:36][CH2:35]2)=[N:31][C:30]=1[CH3:39].CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[CH3:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[C:29]1[NH:33][C:32]([C:34]2([CH3:38])[CH2:35][O:36][CH2:37]2)=[N:31][C:30]=1[CH3:39]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C)c1
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)COC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate (compound 177.1) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 287 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=Nc1ccccc1F
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccccc3F)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-fluoro-2-isocyanatobenzene (Aldrich, Cat. #159352) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=462.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.C(OCC)(=O)C>CN(C=O)C.CCCCCC>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Fc1ccccc1CBr
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1cc(I)cn1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To a stirred solution 4-iodo-1H-pyrazole (1.5 g, 7.7 mmol) in DMF (15 ml) was added potassium carbonate (3.2 g, 23.2 mmol) followed by drop wise addition of 2-fluoro benzyl bromide (2.56 g, 8.5 mmol) and stirred the reaction at RT for 15 h. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was diluted with ice water (150 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 2.25 g (96.56% yield) of 1-(2-fluorobenzyl)-4-iodo-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[F:29][C:25]1[C:24]([CH3:30])=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(F)cccc1CBr
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)cccc1Cn1c(C)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.51 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS (ES+) m/e 383.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reactant: N
Product: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
A mixture of 74.9 g. (0.25 mole) of 2,4-dichloro-3,5-dinitrobenzoyl chloride and 200 ml. of concentrated ammonia is placed in a mortar and ground with a pestle for ten minutes. The mixture stands for 2 hours at room temperature. The yellow precipitate is removed by filtration and washed with water. There is obtained 67.7 gm. (97%) of yellow needles melting at 263°-265°. Recrystallization of 1.00 g. of material from ethanol yields 390 mg. of yellow needles melting at 262°-263°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH:5]=[CH:6][C:7]=1[O:8]COC.OS(O)(=O)=O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1ccc(CCCn2ccnc2)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Oc1ccc(CCCn2ccnc2)cc1Cl
Yield: 92.3 %

Procedure:
A mixture of 1-[3-(3-chloro-4-methoxymethoxyphenyl)propyl]imidazole (4.50 g), 10% H2SO4 (50 ml) and acetone (50 ml) was refluxed for 3 h. Sodium hydroxide (7.0 g) was added to the mixture at 0° C., and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to obtain 1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole (3.50 g, 92%). Recrystallization from ethanol gave colorless prisms, 112-113° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([NH:13][OH:14])=[O:12])=[N:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:14][NH:13][C:11](=[O:12])[C:10]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][N:6]=1
Reactant: CC(CCc1ccc(Br)cn1)(C(=O)NO)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Product: CC(CCc1ccc(-c2ccccc2)cn1)(C(=O)NO)S(C)(=O)=O
Yield: 1.3 %

Procedure:
The title compound (2 mg, 1%) was prepared from 4-(5-bromopyridin-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (151 mg, 0.43 mmol) and phenylboronic acid (79 mg, 0.65 mmol) by a procedure analogous to that described in Step F of Example 3. LCMS m/z 349.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.68 (s, 3H), 2.25 (m, 1H), 2.66-2.82 (m, 2H), 2.95 (m, 1H), 3.08 (s, 3H), 7.38-7.51 (m, 4H), 7.63-7.66 (m, 2H), 8.02 (dd, J=8.1, 2.3 Hz, 1H), 8.71 (dd, J=2.4, 0.8 Hz, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]4[CH:17]=[C:18]5[C:24](=[CH:25][CH:26]=4)[C:21]4([CH2:23][CH2:22]4)[N:20](C(=O)C(F)(F)F)[CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37]CC)=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCOCC1>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]4[CH:17]=[C:18]5[C:24](=[CH:25][CH:26]=4)[C:21]4([CH2:22][CH2:23]4)[NH:20][CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(-c3ccc4c(c3)CN(C(=O)C(F)(F)F)C43CC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1c(-c2ccc3c(c2)CNC32CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a suspension of 210 mg of ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-[2-trifluoroacetyl-spiro[isoindolin-1,1'-cyclopropan]-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate in 4.2 ml of ethanol were added 2.1 ml of 1N aqueous sodium hydroxide solution and 4.2 ml of dioxane, after which the resulting mixture was heated with stirring at 40° C. for three hours. The reaction mixture was cooled to room temperature, and thereafter, insolubles were removed by filtration, after which a carbon dioxide gas was blown in the filtrate obtained. The crystals precipitated were collected by filtration, to obtain 140 mg of pale yellow, crystalline 1-cyclopropyl-6-fluoro-8-methoxy-7-[spiro[isoindolin-1,1'-cyclopropan]-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]1([C:28]#[CH:29])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1[O:20][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:4][CH2:5][C@@:6]1([C:28]#[CH:29])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1[OH:20])(=[O:3])[CH3:2]
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a THF (4 mL) solution of 11 (169.7 mg, 0.402 mmol) was added tetrabutylammonium fluoride (1M in THF, 602 μL, 0.602 mmol) under Ar atmosphere. After being stirred for 1 h at room temperature, the solvent was evaporated. Silica gel column chromatography (CHCl3/MeOH=100/1) of the residue gave 12 (114.7 mg, 93%) as a foam: UV (MeOH) λmax 265 nm (ε8400), λmin 233 nm (ε1700); 1H NMR (CDCl3 after addition of D2O) δ1.93 (3H, d, J6,Me=1.3 Hz, Me), 2.14-2.18 (1H, m, H-2′a), 2.18 (3H, s, Ac), 2.59 (1H, s, ethynyl), 2.94-3.02 (1H, m, H-2′b), 4.22 (1H, d, Jgem=11.4 Hz, H-5′a), 4.31 (1H, d, J2′b,3′=5.5 Hz, H-3′), 4.68 (1H, d, Jgem=11.4 Hz, H-5′b), 6.24 (1H, dd, J1′,2′a=2.9 Hz and J1′,2′b=9.0 Hz, H-1′), 7.60 (1H, d, J6,Me=1.3 Hz, H-6); 13C NMR (CDCl3) δ12.52, 20.84, 38.76, 63.30, 74.73, 76.23, 79.85, 82.08, 85.33, 111.41, 137.93, 150.53, 163.63, 171.98; FAB-HR-MS m/z calcd for C14H17N2O6 309.1087 (M++H). Found 309.1074.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[O:13]=[C:14]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)[CH2:15][CH2:16][C:17](O)=[O:18]>>[O:13]=[C:14]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][N:22]=1)[CH2:15][CH2:16][C:17]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: O=C(O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(CCC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of phenylmethanol (3 mL) was added dropwise thionyl chloride (3 equiv., 2.29 mmol, 0.169 mL). After 5 min, 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoic acid A19 (prepared as described before, 201 mg, 0.766 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was stopped and the solution was partitioned between ethyl acetate and a saturated solution of sodium hydrogenocarbonate. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was washed with water (×2) and brine, dried on magnesium sulfate and concentrated under vacuum. To remove the benzyl alcohol, water was added until the ester precipitated. The ester was filtrated and then washed with water and cyclohexane (20 mL). The residue was first dissolved in ethyl acetate then precipitated with cyclohexane and the solid obtained was filtered to give benzyl 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoate A34 (32%). 1H NMR (400 MHz, CDCl3) 8.7 (s, 1H), 8.31 (m, 1H), 8.22 (bs, 1H), 7.90 (m, 1H), 7.35 (m, 5H), 5.15 (s, 2H), 2.78 (m, 4H) ppm. Compound A51, A52, A53, A54, A73, A74, A78, A79, A80 and A81 from table A were prepared by the same method using the corresponding alcohol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(=O)([O-])O.[Na+]>>[CH2:22]([NH:25][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: CCCCCCCCCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCCCCCC)c2scc(C)c2n1
Yield: 57.2 %

Procedure:
In a sealed tube were heated 391 mg (1.2 mmol) of 2-chloro-4-nonylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 238 mg (yield: 57.2%) of the title compound.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[OH:1][CH:2]([CH2:20][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1cc2c(OCC3CO3)cc(C)cc2[nH]1
Product: CCOC(=O)c1cc2c(OCC(O)CNC(C)(C)C)cc(C)cc2[nH]1
Reaction time: 72 h
Yield: 71 %

Procedure:
1.7 g 4-(2,3-epoxypropoxy)-2-ethoxycarbonyl-6-methyl-indole are dissolved in 25 ml tert.-butylamine. The solution is stored at room temperature for three days and then evaporated in vacuum. The residue is triturated with ether and aspirated. The crude product is dissolved in hot acetic ester and the solution is mixed with 0.3 ml glacial acetic acid. The precipitate resulting after cooling of the solution is aspirated and dried. There is obtained 1.8 g (~71% of theory) of 4-(2-hydroxy-3-tert.-butylamino-propoxy)-2-ethoxycarbonyl-6-methylindole as acetate; m.p. 181°-183° C.
Reaction SMILES: [C:1]1([CH:7]([O:10][CH2:11]CC)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(C1C=CC=CC=1)CO>>[C:1]1([CH:7]([O:10][CH3:11])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCOC(CO)c1ccccc1
Agent: COC(CO)c1ccccc1
Product: COC(C=O)c1ccccc1
Yield: 69.8 %

Procedure:
The procedure in Example 3 was repeated except that 180.25 g of 2-phenyl-2-propoxyethanol was replaced with 152 g of 2-methoxy-2-phenylethanol, to obtain 104.8 g of 2-phenyl-2-methoxyethanal (yield: 69%).
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([C:20]([O:22][CH3:23])=[O:21])[N:6]([CH3:19])[C:7]=1[C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:16][CH3:17].B(Br)(Br)Br>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[C:8](=[O:18])[C:7]3[N:6]([CH3:19])[C:5]([C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:3]=3[CH2:17][O:16][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(CBr)c(C(=O)c2ccc(Cl)cc2OC)n1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2c(n1C)C(=O)c1ccc(Cl)cc1OC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-(bromomethyl)-5-(4-chloro-2-methoxybenzoyl)-1-methylpyrrole-2-carboxylate (0.45 g, 0.0011 m) in dry methylene chloride (20 ml) at dry-ice/acetone bath temperature was added boron tribromide (1.3 ml of a 1.0 M solution in methylene chloride) all at once. After 2 hours at these temperatures, the reaction mixture was allowed to warm to 0° C. and kept in a wet-ice bath for an additional 4 hours. Methylene chloride (30 ml) was added, followed by 50 g of ice-water. The mixture was separated, the methylene chloride layer dried and concentrated to crude methyl 4-(bromomethyl)-5-(4-chlorosalicyloyl)-1-methylpyrrole-2-carboxylate which was subsequently dissolved in dry N,N-dimethylformamide (25 ml), stirred and cooled to about -50° C. before sodium hydride (57% suspension in mineral oil, 0.07 g) was added all at once. After 10 minutes, the dry-ice bath was replaced by a wet-ice bath for 2 hours, and the reaction mixture then allowed to rise to room temperature. After 1 hour, excess ether was added, followed by ice-water. The ether layer was separated, dried over sodium sulfate, and concentrated to a white solid. Trituration with hexane yielded methyl 7-chloro-4,10-dihydro-1-methyl-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole-2-carboxylate as a white solid, m.p. 169°-170° C.