Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:42][CH2:41][CH2:40][N:37]7[CH2:36][CH2:35][N:5]([CH:8]([CH3:11])[CH3:9])[CH2:39][CH2:38]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: OCCN1CCOCC1
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C(C)C)CC5)ccn34)c12
Yield: 48 %

Procedure:
Prepared according Example 1, Step B, substituting N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and substituting 2-(4-isopropylpiperazin-1-yl)ethanol for 2-morpholinoethanol to give the title compound (48%). MS (APCI), positive scan, m/z=593.8 (M+H).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: NCCO
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C1/C(=C(\NCCO)c2ccccc2)Sc2ccccc21
Yield: 13 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and an aqueous 40% ethanolamine solution with a yield of 13% of theory. M.p. 122°-123° C. (ethyl acetate/petroleum ether 1:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[NH:14][CH:13]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:6]=[CH:7][N:8]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[NH:14][CH:13]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c(OC)ncnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[nH]cc(-c3cc4c(OC)ncnc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
A solution of 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [448 mg, Reference Example 5] in methanol (15 mL) was treated with potassium hydroxide (1.96 g). The reaction mixture was stirred for 2 hours at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (80:20, v/v) to give 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (320 mg) as a yellow solid m.p. >260° C. MS: 295 [MH]+.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[CH2:33]([O:32][C:30]([N:14]1[CH2:17][CH:16]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To 3.40 g (8.91 mmol) of diethyl (1-benzhydryl-3-azetidinyl)malonate dissolved in 30 ml of dichloromethane was added 1.91 ml (13.36 mmol) of benzyl chloroformate, followed by overnight stirring at room temperature. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (250 ml, 3-5% methanol-dichloromethane) to yield 2.64 g (84%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:33][C:34](=[O:37])[CH2:35]Br)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]([C@@H:8]([NH:9][C:10]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:35][C:34]([OH:37])=[O:33])=[CH:15][CH:16]=2)=[O:18])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-5-hydroxypicolinamide (Example 173) (0.145 g, 0.371 mmol) in DCM (2 mL) and DMF (0.2 mL) were added bromoacetic acid t-butyl ester (0.072 mL, 0.445 mmol) and cesium carbonate (0.241 g, 0.741 mmol). The resulting mixture was then stirred at rt for 2 h. Then, the mixture was filtered and the solid was washed with DCM (1×1 mL) and MeOH (1×1 mL). The combined filtrates were concentrated and dried to give the desired product, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][NH:40][CH3:41])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][N:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=1)[CH3:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Yield: 64.2 %

Procedure:
A solution of toluene-4-sulfonic acid (1R,2R)-2-benzyloxycarbonylamino-cyclohexylmethyl ester (632 mg, 1.51 mmol) in acetone (8 mL) was treated with N-[3-(4-fluorophenyl)-propyl]-methylamine (253 mg, 1.51 mmol) and potassium carbonate (209 mg, 1.51 mmol) and heated at reflux for 23.5 hours. The mixture was cooled and filtered, the solid was rinsed with acetone, and the filtrate was concentrated to provide a yellow-orange oil. Flash chromatography on silica gel, eluting with 50% ethyl acetate in hexane, followed by 50% ethyl acetate in hexane containing 5% ethanol, provided a light yellow viscous oil (400 mg, 64%).
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]([OH:9])[CH3:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H](O)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 102.7 %

Procedure:
To a solution of borane-tetrahydrofuran (77.6 mL, 77.62 mmol, Aldrich, 1 M solution in THF) and (R)-MeCBS (12.9 mL, 12.9 mmol, Aldrich, 1M solution in toluene) was added a solution of 3-chloroacetophenone (20.0 g, 129.37 mmol) in anhydrous tetrahydrofuran slowly over 30 min at room temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched with 2N hydrochloric acid over 30 min. The reaction mixture was extracted with ether, dried, filtered and concentrated to afford 20.8 g of (S)-1-(3-chlorophenyl)ethanol as a viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH3:8])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[S:6][C:5](/[C:7](=[N:11]/[OH:12])/[CH3:8])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C/C(=N\O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combined 1-(5-chlorothiophen-2-yl)ethanone (100 g, 622 mmol), hydroxylamine hydrochloride (47.6 g, 685 mmol, 1.1 eq) and sodium acetate (56.2 g, 685 mmol, 1.1 eq) in 1 L of ethanol and 300 mL of water. The reaction was heated to reflux. After 3 h, the reaction was cooled to rt and concentrated. The residue was slurried in 500 mL of water overnight, filtered and dried to afford the crude solid. Purified by extraction of the solid with hot dichloromethane, cooling to rt and filtering to remove unreacted starting material. The solid was slurried in hot dichloromethane several times to extract the solid enriched in the first eluting (E-oxime) compound (100% DCM) after concentration. The highly crystalline material was purified by column chromatography using 100% dichloromethane to afford (E)-1-(5-chlorothiophen-2-yl)ethanone oxime. NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.21 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 2.12 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([Sn](C)(C)C)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.Br[C:24]1[C:25]([N:44]2[CH2:48][CH2:47][CH2:46][C:45]2=[O:49])=[CH:26][C:27]2[O:31][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[C:29]([C:39]([NH:41][CH3:42])=[O:40])[C:28]=2[CH:43]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:24]5[C:25]([N:44]6[CH2:48][CH2:47][CH2:46][C:45]6=[O:49])=[CH:26][C:27]6[O:31][C:30]([C:32]7[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=7)=[C:29]([C:39]([NH:41][CH3:42])=[O:40])[C:28]=6[CH:43]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (60 mg, 0.14 mmol), 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide (50 mg, 0.11 mmol) in DMF (4 mL), Pd(PPh3)4 was added. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was filtered through a Celit pad. The filtrate was concentrated in vacuo. The resulting residue was suspended in water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-HPLC to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide (20 mg, yield: 29.2%). 1H-NMR (CDCl3, 400 MHz) δ 7.97 (s, 1H), 7.89˜7.93 (m, 2H), 7.44 (s, 1H), 7.40˜7.42 (m, 2H), 7.11˜7.19 (m, 4H), 7.05 (d, J=8.8 Hz, 1H), 6.77˜6.82 (m, 1H), 5.92 (s, 2H), 5.85 (br s, 1H), 3.83 (t, J=7.2 Hz, 2H), 2.95 (d, J=4.8 Hz, 3H), 2.26 (t, J=8.4 Hz, 2H), 2.00˜2.06 (m, 2H). MS (M+H)+: 591.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:8]2=[O:20])(=[O:4])=[O:3].CO>O>[OH:20][CH:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[C:10](=[O:14])[N:9]1[CH2:15][C:16]([F:19])([F:17])[F:18]
Reactant: CS(=O)(=O)c1ccc2c(c1)C(=O)N(CC(F)(F)F)C2=O
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc2c(c1)C(O)N(CC(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.9 %

Procedure:
3.4 g of 5-methanesulfonyl-2-(2,2,2-trifluoro-ethyl)-isoindole-1,3-dione were dissolved using 240 ml of MeOH. 0.63 g of KBH4 were then added in small portions at ambient temperature. The reaction mixture was stirred for 20 h at ambient temperature and subsequently poured into 1 l of water at 0° C. The aqueous layer was then extracted three times using 300 ml of CH2Cl2 each time. Then, the aqueous layer was extracted four times using 300 ml of EA each time. Each organic layer was dried separately over Na2SO4. The solvents were removed in vacuo. The EA layer yielded 1.4 g pure product as a pale yellow oil. The CH2Cl2 layer was chromatographed on silica gel using EA/HEP 1:2 yielding another 1.5 g of product (Rf (EA/HEP 1:2)=0.035; MS (DCI): 310 (M+1)+)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([N:14]([CH2:17][CH3:18])[C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (4-cyano-5-diethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M94) (0.35 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (209 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][O:14][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCS2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Yield: 76.8 %

Procedure:
0.25 g of (RS)-2-(4,4-dimethyl-thiochroman-6-yl)-heptanol dissolved in 15 ml THF were treated with 250 mg of triphenylphosphine, 150 mg of methyl 4-hydroxybenzoate and 0.15 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 50 ml of ether and washed with two portions of 15 ml of water and one portion of 15 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 280 mg of (RS)-methyl 4-[2-(4,4-dimethyl-thiochroman-6-yl)-heptyloxy]-benzoate as a pale yellow oil. 1H NMR (CDCl3): 7.95 (d, J=8.9 Hz, 2H), 7.21 (d, J=1.9 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.91 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d, J=8.9 Hz, 2H), 4.10-4.00 (m, 2H), 3.87 (s, 3H), 3.05-2.90 (m, 3H), 2.00-1.80 (m, 3H), 1.70-1.60 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.35-1.15 (m, 6H), 0.90-0.80 (m, 3H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].O1[CH2:10][CH2:9][CH2:8][CH2:7]1>[Ag]=O>[C:3]([C:2]1([C:1]#[N:5])[CH2:10][CH:9]1[CH:8]=[CH2:7])#[N:4]
Reactant: C1CCOC1
Reactant: N#CCC#N
Agent: O=[Ag]
Product: C=CC1CC1(C#N)C#N

Procedure:
A 3-liter glass vessel was charged with 250 g of 1,3-butadiene and 500 ml of n-hexane, and with vigorous stirring, 500 g of bromine was added dropwise at -15 to -25° C. over 6 hours to give 310 g of 1,4-dibromobutene-2. Furthermore, a 3-liter glass vessel was charged with 800 ml of tetrahydrofuran, 92 g of malononitrile, 325 g of silver oxide and 300 g of the 1,4-dibromobutene-2. These compounds were reacted by the method described in Journal of the American Chemical Society, 88 (9), 1979 (1966) to give 51 g of 1,1-dicyano-2-vinylcyclopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[O:10][CH3:11].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:16]2[C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]3[C:12]2=[O:22])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CBr)ccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a solution of 4-chloro-3-methoxybenzyl bromide (7.00 g) in anhydrous dimethylformamide (50 mL) was added potassium phthalimide (6.03 g), and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give N-(4-chloro-3-methoxybenzyl)phthalimide as white powders (5.88 g).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:44])[CH2:42][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 51.9 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol), 2-methylpropanal (17 μl, 0.186 mmol), acetic acid (11 μl, 0.181 mmol), and sodium triacetoxyborohydride (53 mg, 0.248 mmol) were processed as described in Example 27 to provide the title compound (50 mg, 52%). 1H NMR (CDCl3) δ 8.72 (s, 2H), 7.78 (s, 2H), 7.29-7.06 (m, 10H), 5.20 (s, 4H), 4.77 (br s, 2H), 3.83 (br s, 2H), 2.88 (dd, 2H), 2.70 (m, 2H), 2.42 (m, 4H), 2.15 (d, 2H), 0.83 (d, 6H); MS (ESI+) m/z 622 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[C:14]2[CH:15]=[CH:16][C:17](I)=[CH:18][C:13]=2[O:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[I:21]C1C=CC2OC=C(CCN)C=2C=1>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([I:21])[CH:17]=[CH:18][C:13]=2[O:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1coc2ccc(I)cc12
Reactant: CC(C)(C)OC(=O)NCCc1coc2cc(I)ccc12
Product: CC(C)(C)OC(=O)NCCc1coc2ccc(I)cc12

Procedure:
Synthesized as described for tert-butyl[2-(6-iodo-1-benzofuran-3-yl)ethyl]carbamate using 2-(5-iodo-1-benzofuran-3-yl)ethanamine. 1H-NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.84 (t, 1H), 3.43 (q, 2H), 4.62 (bs, 1H), 7.25 (d, 1H), 7.43 (s, 1H), 7.56 (dd, 1H), 7.88 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][CH2:15][CH3:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN
Product: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Ethylamino-3-nitro-benzoic acid methyl ester (4.0 g) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (5.0 g) in ethylamine (2.0 M in THF, 50 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH3:19])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH3:19])=[CH:12][N:11]=1
Reactant: COC(=O)CO
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Hydroxy-acetic acid methyl ester (3.96 g, 47.0 mmol) was dissolved in 50 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (2.01 g, 53.2 mmol) was added thereto at room temperature. After stirring for 30 minutes, 2-chloro-5-methyl-3-nitro-pyridine (5.39 g, 31.3 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid was recrystallized from dichloromethane and ether to obtain (5-methyl-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow solid (5.47 g, 77%).
Reaction SMILES: Cl.Cl[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>ClCCl>[CH2:10]([N:13]([CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)[CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: ClCC1CCCCN1
Agent: Cl
Solvent: ClCCl
Product: CCCN(CCC)CC1CCCCN1

Procedure:
A mixture of 170.1 g (1.0 mole) of 2-(chloromethyl)piperidine hydrochloride (M. Rink and H. G. Liem, Arch. Pharm. 292, 165-169 (1959)), 506 g (5.0 mole) of dipropylamine and 1.7 1 of dichloromethane were boiled under reflux for 3 hours, then evaporated in vacuo, and the residue was made alkaline with potassium hydroxide solution with external ice cooling. Exhaustive extraction with t-butyl methyl ether was carried out, and the combined extracts were washed twice with 100 ml of water each time, dried over sodium sulphate, and the solvent was removed by distillation in vacuo. The residue was fractionally distilled under water pump vacuum. Colourless oil of boiling point 108-114° C. (12 mm Hg ). Yield: 108.6 g (55% of theory).