Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:9][C:10](=[O:33])[N:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[O:31][CH3:32])/[C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)(=O)C>O1CCCC1>[CH:3]1([NH:9][C:10](=[O:33])[N:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](/[CH:25]=[C:26](\[O:31][CH3:32])/[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NC3CCCCC3)c2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO/C(=C\c1ccc(-c2cccc(N(C)C(=O)NC3CCCCC3)c2)cc1)C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
2.2 mL (2.2 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.6 g (1.5 mmol) of methyl (Z)-3-[3′-(3-cyclohexyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in 12 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 2.4 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 500 mg (82%) of (Z)-3-[3′-(3-cyclohexyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white solid with a melting point of 192° C.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].I[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][N:4]([CH:26]([CH3:28])[CH3:27])[C:3]1=[O:24]
Reactant: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1C(=O)N(C(C)C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (75 mg, 0.220 mmol, Compound 32), in N,N-Dimethylformamide (DMF) (1 mL) was added 2-iodopropane (0.024 mL, 0.242 mmol) and sodium hydride (8.81 mg, 0.220 mmol). The resulting reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 equivalent of 2-iodopropane and 0.5 equivalent of sodium hydride and stirred for an additional 24 h at room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 2N NaOH solution (10 mL). The aqueous phase was extracted with ethyl acetate (2×10 mL). All of the organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The crude product was purified by MDAP. The relevant fractions were combined, concentrated and dried to give the title compound as a colourless oil (8 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=O)[CH3:7].Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[N:11][OH:12])[CH3:7]
Reactant: NO
Reactant: CC(=O)CCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(CCCN(C)C)=NO
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 20 gm (167 mMol) N,N-dimethyl-5-amino-2-pentanone, 14.5 gm (208 mMol) hydroxylamine hydrochloride, and 8.8 gm (83 mMol) sodium carbonate in 50 mL water was heated at reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residual oil crystallized on standing at room temperature. The solid was washed with hexane to provide 12.8 gm (54%) of the desired oxime as a colorless solid in two crops.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>O1CCCC1>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[N:25]([CH:22]([CH3:24])[CH3:23])[C:26]2=[O:27])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N=C=O
Reactant: O=S(=O)(c1ccccc1)N1CC1c1cccc(Br)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1

Procedure:
In analogy to example 1, step 2,1-benzenesulfonyl-2-(3-bromo-phenyl)-aziridine (example 5, step 1) was reacted with sodium iodide and isopropyl isocyanate in tetrahydrofuran to give 1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1
Yield: 87.4 %

Procedure:
4-bromophenol (10.46 g, 60.5 mmol), 1-bromooctane (15.43 g, 79.9 mmol) and potassiumcarbonate (90 g, 0.65 mol) in N,N-dimethylformamide and was heated to 90° C. for 4 h and then the potassiumcarbonate was filtered off The reaction mixture was quenched with water and extracted three times with ether. The ether was then washed three times with 1M hydrochloric acid (HCl), one time with water, evaporated, and purified by distillation to obtain 1-bromo-4-(octyloxy)benzene (15.1 g, 52.9 mmol) as a colourless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][NH:9][C@H:10]([CH3:39])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][N:9]([C@H:10]([CH3:39])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[C:1](=[O:3])[CH3:2]
Reactant: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
Acetic anhydride (66 μl, 0.70 mmol) was added drop wise to a solution of 5-{[(2R)-2-(methylamino)propyl]oxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (250 mg, 0.58 mmol, obtained as described in Example 115, preparation of starting materials) and potassium carbonate (161 mg, 1.16 mmol) in acetone (10 ml). The mixture was stirred at room temperature for 2 hours. After evaporation of the solvents, the residue was diluted in DCM. The solution washed with aqueous sodium bicarbonate and dried over magnesium sulfate. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 5% 7N ammonia-methanol in DCM) to give the title compound (230 mg, 84%); NMR Spectrum: (CDCl3) 1.28 (d, 3H), 1.94 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.90 (s, 3H), 4.30-4.10 (m, 2H), 5.38 (m, 1H), 6.92 (m, 2H), 7.08 (d, 1H), 7.14 (dd, 1H), 7.48 (d, 2H), 7.53 (s, 1H), 7.64 (t, 1H), 8.27 (d, 1H), 8.60 (s, 1H), 9.51 (s, 1H); Mass spectrum: MH+ 472.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(I)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 5-iodovanillin (7 g, 25.18 mmole), potassium carbonate (8.78 g, 63.53 mmole) and iodomethane (6.43 g, 45.30 mmole) was suspended in 60 mL of DMF and stirred at room temperature for 14 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to obtain a solid which was recrystallized from hexane/ethyl acetate (2:1) (6.28 g, 85.4%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[C:33](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH:24]([N:14]([C:12](=[O:13])/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:33](=[O:34])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:2]=1)[NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C(=O)C(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (60 mg, 0.17 mmol, 1.0 equivalent), K2CO3 (71.6 mg, 0.51 mmol, 3.0 equivalent), and DMAP (cat, 0.12 equivalent) were introduced and dissolved in DMF, after which Piv-Cl (0.04 ml, 0.34 mmol, 2.0 equivalent) was introduced. After stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=7:3:1) and dried so that solid form of (E)-N′-(3-(1-acetyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (10.3 mg, 14%).
Reaction SMILES: [CH2:1]([C:4]1[C:8](=[O:9])[CH2:7][CH:6]([OH:10])[CH:5]=1)[CH:2]=[CH2:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:16]([O:10][CH:6]1[CH2:7][C:8](=[O:9])[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC1=CC(O)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Yield: 81 %

Procedure:
To a solution mixture of 8.8 g of (RS)-3-allyl-4-oxo-2-cyclopenten-1-ol, 100 ml of N,N-dimethylformamide and 4.75 g of imidazole was added t-butyldimethylsilyl chloride under ice-cooling, and the resulting mixture was stirred under ice-cooling for 8 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 13.1 g of (RS)-3-allyl-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 81%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])[NH:29][CH:28]=1)=[O:26])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (90.4 mg, 76.5%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:16])=[C:9]([C:14]#[N:15])[S:10][C:11]=1[S:12][CH3:13])=O.[C:18]1([NH:24][C:25]([NH2:27])=[NH:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.CO>[CH3:16][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:27]=[C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=2)=[C:11]([S:12][CH3:13])[S:10][C:9]=1[C:14]#[N:15]
Reactant: CSc1sc(C#N)c(C)c1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1ccccc1
Solvent: CC#N
Solvent: CO
Product: CSc1sc(C#N)c(C)c1-c1ccnc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-dimethylamino-acryloyl)-3-methyl-5-methylsulfanyl-thiophene-2-carbonitrile (0.2 mmol) in acetonitrile (0.25 mL) was added N-phenyl guanidine (1 equivalent, 0.2 mmol) and the reaction heated at reflux for 24 hours. The resulting mixture was cooled to room temperature then diluted with methanol (3 mL). The resulting slurry was filtered washed with methanol to afford IIb-7.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11]N3CCC(NCC4CC4)CC3)=[CH:8][C:6]=2[N:7]=1.[C:29]([O:33][C:34]([N:36]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[C:40]2([CH2:45][CH2:44][N:43]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNCC2
Product: CC(C)(C)OC(=O)N1CCCC12CCN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CC2

Procedure:
Prepared according to the method used in the preparation of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-cyclopropylmethyl-amine using 1,8-diaza-spiro[4.5]decane-1-carboxylic acid tert-butyl ester in place of cyclopropanemethylamine. The title compound was obtained as a white solid (184 mg, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:17][C:18]1[CH:23]=[C:22]([CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25])[C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirring solution of p-nitrobenzoyl chloride (76.1 g, 0.410 mol) in 250 mL nitrobenzene were added 82 g of AlCl3 (0.62 mol). To this mixture a solution of 50 grams of 2,6-dimethylphenol (0.41 mole) in 250 mL nitrobenzene was added dropwise over a period of 45 minutes, and the resulting mixture was stirred 16 hours at room temperature. The reaction was poured into 2 L of 3% HCl and ice and extracted 3×1 L with Et2O (i.e. times with 1 L each time f diethyl ether). The combined ethereal layers were washed with 1 L of saturated NaHCO3, then extracted 2×1 L with 10% NaOH. The combined basic extracts were acidified with concentrated HCl to give a white precipitate; filtration followed by recrystallization from CH3OH/H2O gave 37 g (33%) of white powder consistent with the desired product by TLC, IR, mass spectroscopy, NMR and elemental analysis, m.p. 182.5-184.5.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36]>>[CH3:32][O:31][C:13]1[CH:14]=[C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH2:20][CH2:19]2)[CH:16]=[CH:17][C:12]=1[NH:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([C:40]3[CH:41]=[CH:42][C:37]([C:35]([NH:34][CH3:33])=[O:36])=[CH:38][CH:39]=3)[N:10]2[N:9]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Product: CNC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCC(N6CCN(C)CC6)CC5)cc4OC)nn23)cc1
Yield: 54.1 %

Procedure:
Following a procedure similar to Example 241, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.10 g, 0.00020 mol) and 4-(N-Methylaminocarbonyl)phenylboronic acid (0.039 g, 0.00022 mol). Purification by Isco chromatography gave 4-(2-{2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-methyl-benzamide as a tan solid (0.06 g, 50%). MP 112-114° C.; LCMS (m/e) 555 (M+1); 1H-NMR (DMSO, 400 MHz) δ 8.94 (s, 1H), 8.28 (d, 1H, J=8.53 Hz), 7.90 (d, 1H, J=8.52 Hz), 7.85 (s, 1H), 7.71 (d, 1H, J=8.68 Hz), 7.28 (d, 1H, J=4.80 Hz), 6.94 (d, 1H, J=4.80 Hz), 6.69 (d, 1H, J=2.40 Hz), 3.83 (s, 3H), 3.74 (d, 1H, J=2.00 Hz), 2.82 (d, 2H, J=4.52 Hz), 2.68 (m, 3H), 2.33 (m, 4H), 2.15 (s, 3H), 1.90-1.75 (m, 2H), 1.60-1.48 (m, 2H), 1.25 (s, 1H), 1.18 (br s, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.Cl([O-])(=O)(=O)=O.[Li+].[CH3:14][CH2:15][O:16][CH2:17][CH3:18]>>[O:16]1[C@H:17]2[C@@H:4]3[C@@H:3]([C@@H:15]1[C:14]1[CH2:1][CH2:2][CH2:3][CH2:4][C:18]=12)[C@@H:2]([CH3:1])[O:6][C:5]3=[O:7]
Reactant: C[C@@H]1C=CC(=O)O1
Reactant: CCOCC
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: C[C@H]1OC(=O)[C@H]2[C@H]1[C@H]1O[C@@H]2C2=C1CCCC2
Yield: 72 %

Procedure:
Similarly to Example 1, 1.37 g(13.9 mmol) of (R)-5-methyl-2(5H)-furanone and 1.70 g(1 equivalent) of 4,4,6,7-tetrahydroisobenzofuran in 2 ml of dehydrated ether solution were reacted with 1.06 g of lithium perchlorate to obtain 2.20 g of (3R,3aR,4R,9S,9aS)-4,9-epoxy-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one(yield 72%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]3[C:31](=[O:52])[CH2:32][C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28]([O:30][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:27][N:26]3[C:31](=[O:52])[CH2:32][C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC[C@H]1CCCN(CC2CCCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 30 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.6 ml of chloroform, 0.018 ml of triethylamine and 0.004 ml of methanesulfonyl chloride were added under cooling with ice, followed by 50 minutes' stirring at room temperature. The reaction liquid was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 33 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51])#[N:43]>C(#N)C>[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51])#[N:43]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3C#N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 87.8 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.115 g, 0.249 mmol) was dissolved in acetonitrile (5.0 mL), and the solution was treated with triethylamine (0.104 mL, 0.747 mmol) and 2-cyanobenzenesulfonyl chloride (0.0750 g, 0.374 mmol) to obtain 4-(2-cyanobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.137 g, yield 88%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([CH2:33][S:34]([C:36]2[N:40]([CH2:41]O)[C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[N:37]=2)=[O:35])[C:27]=1[CH3:47].[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:41][N:40]1[C:39]2[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=2[N:37]=[C:36]1[S:34]([CH2:33][C:28]1[C:27]([CH3:47])=[C:26]([O:25][CH3:24])[C:31]([CH3:32])=[CH:30][N:29]=1)=[O:35])=[O:6]
Reactant: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2CO)c1C
Reactant: CN(C)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2COC(=O)CCN(C)C)c1C
Temperature: -10 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N,N-dimethyl-β-alanine (0.76 g 0.005 mol) and N-methyl morpholine (0.99 g 0.01 mol) was added to CH2Cl2 (15 ml). The solution was cooled to -10° C. and isobutylchloroformate, (0.68 g 0.005 mol) dissolved in CH2Cl2 (15 ml), was added under inert atmosphere. The solution was stirred for about 20 min at -10° C. [2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazol-1-yl]methanol dissolved in CH2Cl2 (15 ml) was added dropwise to the mixed anhydride at -10° C. The solution was stirred 2 h at -10°, and the temperature was thereafter raised to room temperature. NaOH solution (25 ml 0.24) was added under stirring and the mixture was stirred for about 5 min. After separation the CH2Cl2 phase was dried over Na2SO4, filtered and the solution was evaporated off, giving the desired compound (yield 0.7 g 32%). The identity of the title compound was confirmed with NMR.