Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:11]2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1c[nH]c2cc(OC)ccc12
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(OC)ccc12
Temperature: 40 °C
Reaction time: 0.3 h
Yield: 100.3 %

Procedure:
0.384 g (12 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 2.4 g (11.7 mmol) of 6-methoxy-3-methoxycarbonyl-1H-indole in 60 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hours, 1.98 g (12 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 5 hours, the reaction mixture is poured into 200 cm3 of water and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3.9 g of a brown residue which is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate (65/35 by volume)]. After concentrating the fractions under reduced pressure, 2.5 g of 6-methoxy-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 162° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].S(Cl)(Cl)=O.[CH3:15][CH:16](O)[CH3:17]>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH:16]([CH3:17])[CH3:15])=[O:9]
Reactant: CC(C)O
Reactant: Nc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1ccccc1N

Procedure:
1.0 g (7.3 mmol) anthranilic acid are dissolved in 5 ml propan-2-ol, combined with 795 μl (10.9 mmol) thionyl chloride and refluxed for 3 days. Then thionyl chloride is eliminated in vacuo, the residue is taken up in 50 ml dist. water and extracted three times with 30 ml of ethyl acetate. The organic phase is washed with 20 ml of a saturated aqueous NaHCO3 solution, dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: C[O-].[Na+].CO.[Na].Cl[C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1.[CH3:29][S:30](C)=O>>[CH3:29][S:30][C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CS(C)=O
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 13 °C

Procedure:
To a mixture of sodium methoxide (made from 100 ml (2.47 m) of methanol and 1.50 g (0.652 m) of sodium metal) which had been cooled to 13° C. was added 7.0 ml (0.126 m) of methylmercaptain. The mixture was allowed to warm to room temperature and then 20.0 g of 6-chloro-2-(diphenoxymethyl)pyridine and 150 ml of dimethylsulfoxide was added thereto. The mixture was heated to 90° C. and after 4 days at this temperature, the reaction mixture was cooled to room temperature and poured into 300 ml of ice. The solution was extracted with methylene chloride and the extract was dried over magnesium sulfate and the solvent stripped off under reduced pressure. The residue was further purified using preparative high pressure liquid chromatography with a 2:98 mixture of ethylacetate and hexane. The oil thus obtained crystallized in n-hexane and was purified by recrystallization from n-hexane leaving the above named compound as a white solid in a yield of 49 g (98 percent pure). The product melted at 58°-59° C. and its structure was confirmed by its NMR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 70.42, 5.19 and 4.20 percent, respectively, as compared with the theoretical contents of 70.59, 5.26 and 4.33 percent, respectively, as calculated for the above named compound (Compound 3).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][N:28]=1)[CH3:26])(=O)=O>O1CCCC1.CS(C)=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=3)[CH3:26])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(C)OS(C)(=O)=O)nc1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (263 mg, 1.1 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (44.2 mg, 60 wt % in mineral oil, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. A solution of the crude methyl 6-(1-(methylsulfonyloxy)ethyl)nicotinate prepared above in DMSO (6 mL) was added. The mixture was heated to 60° C. for 48 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1-(4′-(trifluoromethyl) biphenyl-4-yloxy)ethyl)nicotinic acid (60 mg). 1H NMR (400 MHz, CD3OD, 5): 8.98 (m, 1H), 8.19-8.21 (m, 1H), 7.54-7.61 (m, 4H), 7.42-7.44 (m, 3H), 6.86-6.89 (m, 1H), 5.42-4.43 (q, 1H), 1.58 (d, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:7]1[N:8]([CH3:11])[C:9]2[C:5]([N:6]=1)=[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Solvent: CC#N
Product: Cn1c(Br)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 60 °C
Yield: 85.2 %

Procedure:
To a suspension of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.08 g, 20.0 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (5.34 g, 30.0 mmol). The mixture was heated at 60° C. for 4 h. Cooled to rt, the contents were concentrated on a rotary evaporator. The remaining slurry was diluted with DCM and washed with a mixture of diluted Na2CO3 and NaHSO3 (2×), dried (Na2SO4), filtered and concentrated. The slightly orange solid was triturated with hot acetonitrile (˜70 mL). After cooled to room temperature (rt), the solid was collected with filtration and washed with acetonitrile. The filtrate was concentrated (to ˜30 mL) to yield a second crop. The product was dried in air then under vacuum to give 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.67 g, 85%). LCMS: M+H+=332.0, 334.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]([F:11])([F:10])[C:7](=O)[CH3:8]>ClCCl>[CH3:8][C:7]1([C:6]([F:11])([F:10])[F:5])[NH:1][CH2:2][CH2:3][O:4]1
Reactant: NCCO
Reactant: CC(=O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(F)(F)F)NCCO1
Temperature: -30 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
A solution of 2-aminoethanol (10.15 g, 10.0 ml, 166 mmol, Eq: 1.00) in dichloromethane (250 ml) was cooled to −30° C. and stirred while 1,1,1-trifluoropropan-2-one (20.1 g, 16.1 ml, 179 mmol, Eq: 1.08), followed by molecular sieves (4 Å, powder <5 micron, activated; 20.0 g, 166 mmol, Eq: 1.00) were added. The mixture was stirred at −30° C. for 3 h and then allowed to warm to room temperature and left stirring for overnight. The mixture was filtered, washed with dichloromethane, and concentrated to obtain 2-methyl-2-(trifluoromethyl)oxazolidine (39) (oil, 15.60 g, 101 mmol, 60.5% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[CH2:19](C1C=CC(F)=C(B(O)O)C=1)[CH3:20]>>[CH2:19]([C:7]1[CH:6]=[CH:5][C:4]([F:10])=[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:2]=1)[CH3:20]
Reactant: CCc1ccc(F)c(B(O)O)c1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: CCc1ccc(F)c(-c2nc(C(=O)O)cs2)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (5-ethyl-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)=[N:4][N:3]=1.Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>>[C:29]([C:28]1[CH:27]=[C:26]([CH:33]=[CH:32][CH:31]=1)[CH2:25][S:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[N:4][N:3]=1)#[N:30]
Reactant: O=C(CCc1ccccc1)Nc1cc(-c2nnc(S)o2)ccn1
Reactant: N#Cc1cccc(CBr)c1
Product: N#Cc1cccc(CSc2nnc(-c3ccnc(NC(=O)CCc4ccccc4)c3)o2)c1
Yield: 36 %

Procedure:
In the same manner as in Example 1 and using N-[4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]-3-phenylpropionamide instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 36%) was obtained as colorless crystals.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C.C(OCC)C>[C:2]([O:6][C:7](=[O:17])[C@@H:8]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)N1CCCCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of L-phenylalanine tert-butyl ester hydrochloride (3.05 g) in DMF (50 ml) were added potassium carbonate (5.38 g) and 1,5-dibromopentane (2.98 g), and the mixture was stirred at 80° C. for 2 hours, and then at room temperature for 22 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: methylene chloride-methanol) to give 1.24 g of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH:5]2[CH2:6][C:7](=O)[CH2:8]3)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH:5]2[CH2:6][C:7](=[N:20][OH:21])[CH2:8]3)[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CC2CCC(C1)N2C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC2CCC(C1)N2C1CC1
Temperature: 23 °C
Yield: 84 %

Procedure:
A mixture of 8-cyclopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS no: 60206-33-9) (17.86 g, 108.08 mmol) in ethanol (500 mL) with pyridine (13.05 mL, 162.1 mmol) and hydroxylamine hydrochloride (9.764 g, 140.51 mmol) was refluxed overnight. Cooled to 23° C., filtered off, washed with ethanol and ether and dried in vacuum to give a white solid, which was suspended in 200 mL sat. Na2CO3 solution and extracted 3 times with dichloromethane, the combined organic layers were dried over Na2SO4, filtered off and evaporated totally, dried in high vacuum to give the title compound as white crystals (16.3 g, 84%); MS: m/e=181.2 (M+H+).
Reaction SMILES: OO.C=CCCCC.C(=O)([O-])[O-:10].[Na+].[Na+].[F:15][C:16]([F:42])([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)[CH:17]([F:19])[F:18]>CO>[F:42][C:16]([F:15])([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40](=[O:10])[NH2:41])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)[CH:17]([F:19])[F:18]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: C=CCCCC
Solvent: CO
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.58 ml of hydrogen peroxide (30%), 0.16 ml of 1-hexene, 11 mg of sodium carbonate and 2 ml of methanol are added to 50 mg (0.12 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine and the reaction mixture is stirred for 14 h at RT. The product is isolated by filtration, washed with methanol/water (9:1) and dried to give N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine; m.p. 224°-225°, FAB-MS: 408 (M+ +H), 290.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH2:26][N:27]([CH3:29])C)[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O[C@@H](C1C([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=C2C(=CC=1C)[N+]([O-])=C(C)C=C2)COC(=O)C(C)(C)C)(C)(C)C.CN>>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[C:15]1[C:16]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH2:26][NH:27][CH3:29])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(CN(C)C)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: CN
Product: CNCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1

Procedure:
Following the procedure used to prepare compound (S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate of Example 9, except that (S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide, and methylamine solution was used instead of N,N-dimethylamine solution. LCMS-ESI+ (m/z): 497.3, 499.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([NH2:9])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([N:9]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 5-Methoxy-2-nitro-phenylamine (5.0 g, 0.030 mol) and Triethylamine (10.0 mL, 0.0717 mol) in Methylene chloride (100 mL, 2 mol) at 0° C. was added dropwise Methanesulfonyl chloride (5.1 mL, 0.065 mol). The mixture was stirred for 18 hours. The mixture was poured into 1N Hydrochloric Acid (200 mL). The aqueous was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The oil was purified by silica gel chromatography using 20%→100% Ethyl Acetate:Hexane solvent gradient. N-(5-Methoxy-2-nitro-phenyl)-N-(methylsulfonyl)methanesulfonamide isolated as a yellow solid (7.75 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1/[C:9](=[N:21]/[NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH3:10]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccccc1)c1c(O)cccc1O
Temperature: 120 °C
Yield: 56.3 %

Procedure:
1-(2,6-Dihydroxyphenyl)ethanone (100 mg, 0.657 mmol) and benzohydrazide (89 mg, 0.657 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (100 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 7.59 (m, 2H), 7.49 (m, 1H), 7.39 (m, 2H), 7.11 (t, 1H, J=8.0 Hz), 6.45 (m, 2H), 2.35 (s, 3H). ESI-MS: 271.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19]Cl)[CH:3]=1.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>C(Cl)Cl>[CH2:21]([N:24]([CH2:19][CH2:18][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]
Reactant: ClCCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: CCCNCCC
Solvent: ClCCl
Product: CCCN(CCC)CCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 120 °C
Reaction time: 39 h

Procedure:
To 604 mg of the crude 4-chloro-2-(3-chloropropyl)-1-(2-phenylethoxy)benzene, was added 5 ml of di-n-propylamine and the resulting mixture was stirred at 120° C. for 39 hours. After diluting with methylene chloride, the mixture was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:n-hexane =1:5) to give 0.50 g of N,N-di-n-propyl-3-[5-chloro-2-(2-phenylethoxy)phenyl]propylamine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:23][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: BrC(Br)(Br)Br
Reactant: CCCC(CCCCCCO)c1ccc(CC(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCCCCCBr)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 7-(4-isobutylphenyl)-1-decanol and carbon tetrabromide in tetrahydrofuran was added portionwise triphenylphosphine. The mixture was stirred at room temperature for 2 hours and insoluble materials were filtered off. The filtrate was concentrated and n-hexane was added thereto, then the mixture was filtered again and the filtrate was concentrated. The residue was chromatographed on a silica gel column (n-hexane as eluent) to give the object compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:18]\[C:17]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([O:24][CH3:25])[C:16]=3[O:15][CH3:14])/[C:10](=[O:11])/[C:12](=[CH:18]/[C:17]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([O:24][CH3:25])[C:16]=3[O:15][CH3:14])/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: COc1ccc(C=O)c(OC)c1OC
Product: COc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OC)c(OC)c3OC)C2=O)c(OC)c1OC

Procedure:
Calone is reacted with 2,3,4-trimethoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(2,3,4-tri-methoxyphenyl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C(N(CC)CC)C.[C:19]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32]Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:19]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCCCOCCl)c1ccccc1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Nc1nc2c(ncn2COCCCOC(=O)c2ccccc2)c(=O)[nH]1
Yield: 21.2 %

Procedure:
A solution of trimethylsilylated guanine in benzene (25 ml) prepared as in Example 6 (from 2.0 g of guanine) containing triethylamine was heated at reflux and 3-benzoyloxypropoxymethyl chloride (2.96 g) dissolved in benzene (15 ml) was added over a 3 hour period. The reaction mixture was heated at reflux under nitrogen overnight. The solvent was removed under reduced pressure, and 95% ethanol and methanol were added to the residual oil. The mixture was heated on a steam bath for several minutes and the solvent then evaporated under reduced pressure. Chloroform (200 ml) was added and the resulting solid removed by filtration. The solid was dissolved in a minimal amount of DHF, filtered (to remove any guanine present) and reprecipitated by the addition of water. Recrystallization from methanol (with charcoaling) gave 9-(3-benzoyloxypropoxymethyl)guanine (0.94 g) as a pale yellow solid, m.p. 198°-201° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:19]([Mg]Cl)[CH3:20]>C1COCC1>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:19][CH3:20])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-N-(1,4-dioxaspiro[4.5]decan-8-ylmethylene)-2-methylpropane-2-sulfinamide (as prepared in of Example 11 Step A, 3.66 g, 13.4 mmol) in dry THF (100 mL) was placed under an argon atmosphere and treated with ethylmagnesium chloride dropwise. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled to −10° C. and cautiously quenched by the addition of saturated ammonium chloride solution. After dilution with water and ether extraction, the organic layer was concentrated in vacuo. Purification of the residue by flash chrom (silica gel, ethyl acetate) afforded the titled compound as a solid. 1H NMR (CHLOROFORM-d) δ: 3.80-4.00 (m, 4H), 2.85-3.15 (series of m, 2H), 1.71 (series of m, 11H), 1.20-1.25 (s, 9H), 0.97 (t, J=7.5 Hz, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cc(Cl)ccc3Cl)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.061 g, 56%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.139 g, 0.29 mmol) and methylamine (0.090 g, 2.9 mmol). mp 179-181° C.