Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[F:42][C:22]([F:21])([F:43])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1
Reactant: CCCCCCCCCCCCO
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 10 °C

Procedure:
n-Dodecanol(2.5 grams; 0.134mol), toluene (80 ml) and triethylamine (5 ml) were placed into a 300 ml, 3-necked glass reaction flask equipped with stirrer, thermometer, reflux condenser, and nitrogen line. 2-[4-(5-trifluoromethyl-2-pyridinyloxy)phenoxy]propanoic acid chloride (4.45 grams; 0.0125 mol) in toluene (30 ml) was added dropwise to the reaction mixture with stirring at a temperature of about 10° C. The temperature of the reaction mixture was allowed to rise to room temperature and stirred overnight.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[CH:7]2>C(Cl)Cl.O=[Mn]=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N+:10]([O-:1])=[CH:9][CH:8]=[CH:7]2
Reactant: COc1cc2ncccc2cc1Cl
Reactant: OO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc2c(ccc[n+]2[O-])cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 mL round bottom flask, 6-chloro-7-methoxyquinoline was dissolved in DCM (25.8 mL) and MTO (0.051 g, 0.207 mmol) was added. The reaction mixture was capped and vented with a needle, then placed in an ice bath to cool. Once cool, hydrogen peroxide (0.633 mL, 10.33 mmol) was added drop-wise. When the addition was complete, the reaction mixture was removed from cooling, warmed to room temperature and stirred overnight (18 h). MnO2 (10 mg, 0.115 mmol) was added and the reaction mixture was stirred for an additional 2 h. The reaction mixture was filtered through celite, washing with DCM, then concentrated in vacuo to yield 6-chloro-7-methyoxyquinoline 1-oxide (1.036 g) MS [M+H+]=210.3.
Reaction SMILES: C([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5]CC)C.S(=O)(=O)(O)O.II.[I:35](O)(=O)=O>C(O)(=O)C.O>[I:35][C:21]1[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:19][C:18]2[NH:17][C:16](=[O:26])[C:15](=[O:27])[N:14]3[CH:9]([P:4]([OH:5])(=[O:8])[OH:3])[CH2:10][CH2:11][C:12]=1[C:13]=23
Reactant: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(C(F)(F)F)c(I)c3c2n(c1=O)C(P(=O)(O)O)CC3
Temperature: 80 °C
Reaction time: 15 h
Yield: 31.7 %

Procedure:
406 mg of 9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester in 2 ml of glacial acetic acid is mixed with 0.05 ml of water, 0.025 ml of concentrated sulfuric acid, 178 mg of iodine and 70 mg of iodic acid and stirred for 15 hours at 80° C. bath temperature. After concentration by evaporation, it is mixed with water and the product is suctioned off. 60 mg of 8-iodo-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid of melting point 307° C. (with decomposition) is obtained.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:17][C:18]([O:20]CC)=O)[C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].C(N(CC)CC)C>CO>[O:3]=[C:2]1[NH:1][C:18](=[O:20])[CH2:17][N:4]1[C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Solvent: CCN(CC)CC
Solvent: CO
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution containing the product from Example 36B (6.8 g, 20.9 mmol) in methanol (30 mL) was treated with triethylamine (5.6 mL, 40.2 mmol), stirred at 50° C. for 2 hours, and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (2.53 g, 47% yield).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:15][C:13](=[O:14])[CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: OB(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A mixture of 4-mercaptophenylboronic acid (1.0 g, 90%, 5.84 mmol), 2-bromoacetamide (1.8 g, 13 mmol) and K2CO3 (2.70 g, 19.5 mmol) in CH3CN (20 mL) was stirred at ambient temperature overnight. After CH3CN was removed, water was added to the residue, and the solid was collected via filtration and washed with water to give 0.6 g (49%) of {4-[(2-amino-2-oxoethyl)thio]phenyl}boronic acid as a white solid. The boronic acid was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 2H), 7.68 (d, 2H, J=8.2 Hz), 7.55 (bs, 1H), 7.24 (d, 2H, J=8.2 Hz), 7.15 (bs, 1H), 3.61 (s, 2H); LRMS (APCI), m/z 210 (M−H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([Cl:12])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(#N)C>[Cl:12][C:5]1[CH:4]=[C:3]([CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:8]=[CH:7][C:6]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(CBr)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(CN2CCOCC2)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
A mixture of 1-(4-(bromomethyl)-2-chlorophenyl)ethanone (1.65 g, 6.65 mmol) (preparation 16) and acetonitrile (25 ml) was prepared at room temperature and stirred under nitrogen. Potassium carbonate (1.10 g 7.98 mmol) was then added followed by morpholine (0.695 ml, 7.98 mmol) and the mixture stirred at room temperature. After 2 h, TLC indicated the presence of both product and starting material. The mixture was then heated under nitrogen to 40° C. for 16 h, then allowed to cool to room temperature, filtered to remove excess carbonate and filtrate concentrated under reduced pressure. The mixture was then diluted in DCM (30 ml), washed with water (2×10 ml), filtered through a phase separator and the filtrate concentrated under reduced pressure. The crude mixture was purified by column chromatography (40-100% EtOAc/hexane) to afford 1-(2-chloro-4-(morpholinomethyl)phenyl)ethanone as a yellow oil (1.08 g, 4.25 mmol, 64%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:12](=[O:47])[C@H:13]([CH2:33][CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)[NH:14][C:15](=[O:32])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:17]C(OC(C)(C)C)=O.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C([SiH](CC)CC)C>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:12](=[O:47])[C@H:13]([CH2:33][CH2:34][CH2:35][NH2:36])[NH:14][C:15](=[O:32])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Sc1ccc2ccccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Sc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Boc-phenylalanyl-Nδ-Cbz-ornithinyl 2-naphthyl thioether (C) (30 mg) and a mixture of trifluoroacetic acid-triethylsilane (3:1) (10 ml) was stirred at 25° C. for 1 hr and concentrated in vacuo. The crude material was purified by HPLC to afford desired product (10 mg) as a white solid: HPLC (method A, retention time=46.26 min); 1H NMR (400 MHz, D2O) δ1.69 (m, 2H), 1.77 (m, 1H), 1.87 (m, 1H), 2.84 (t, J=8.4, 2H), 3.02 (m, 2H), 3.09 (dd, J=14.4; 7.2 Hz, 1H), 3.22 (dd, J=14.0 5.2 Hz, 1H), 4.15 (t, J=8.0 Hz, 1H), 7.16 (m, 2H), 7.34 (m, 3H), 7.48 (m, 1H), 7.60 (m, 3H), 7.93 (t, J=7.2, 1H), and 7.97 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
(5R)-5-(Azidomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in acetonitrile:water (100:10 ml). Triphenylphosphine (5.42 g, 20.7 mM) was added. The reaction mixture was degassed and stirred at room temperature for 48 hours. The light yellow liquid was concentrated and the residue was purified by flash chromatography eluting with ethyl acetate then 6% methanol in ethyl acetate. Relevant fractions were combined to give the desired product as a light yellow solid (4.54 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1.[NH2:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48])[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: COc1cc(CN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (i) (234 mg) and (s)-3-aminohexan-1-ol (X mg). The sub-title compound (70 mg) was obtained as a colourless amorphous solid; LC-MS: m/z 528.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCN1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCN1C(=O)NCCN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 98.3 %

Procedure:
A solution of 1.68 g (4.59 mmol) of 1-[[2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine (Ia-25) and 1.05 g (5.5 mmol) of p-toluenesulfonic acid monohydrate in 75 ml of toluene was refluxed for 25 hr. using a Dean-Stark trap containing 10 g of Molecular Sieves-4A. By proceeding as in Example 67, 1.57 g of the objective compound (Ia-29) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:34])[C:25]([CH2:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:10]=3.C(=O)([O-])O.[Na+]>C(O)(=O)C.Br>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:34])[C:25]([CH2:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=3
Reactant: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Yield: 78.7 %

Procedure:
9-bromo-2-t-butoxycarbonylmethyloxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (57 mg) produced in Example 103 was dissolved in acetic acid (0.5 ml) and 48% HBr (0.5 ml), and the solution was stirred at 60° C. for 1 hour and allowed to cool. Saturated aqueous solution of sodium hydrogencarbonate was added to pH 7, and the crystals precipitated were recovered by filtration, washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (40 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.[CH3:24][O:25][C:26]([CH2:28]P(OC)(OC)=O)=[O:27]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[C:21](/[CH3:22])=[CH:28]/[C:26]([O:25][CH3:24])=[O:27])=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)/C=C(\C)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
According to the method described for Reference Example 22, 4'-(5-methyl-2-phenyl-4-oxazolylmethoxy)acetophenone was allowed to react with trimethyl phosphonoacetate gave methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-butenoate. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.125°-126° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[OH-].[K+].[CH3:14]I>CS(C)=O.C(Cl)(Cl)Cl>[CH3:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3]
Reactant: O=C1CCc2ccccc2N1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 3,4-dihydrocarbostyril (20 g) in DMSO (100 ml) is added to a suspension of KOH (31.4 g) in DMSO (50 ml). Methyl iodide (39.7 g) in DMSO (25 ml) is added to the reaction mixture and the mixture is stirred under an atmosphere of N2 at RT. After 2 hours a second portion of methyl iodide (20 g) is added and after 3 hours a third portion of methyl iodide (20 g) is added and stirring continued for 4.5 hours. The reaction mixture is diluted with chloroform (200 ml), quenched with sat'd aq. NH4Cl, separated, extracted with chloroform, washed with H2O and dried. The organic extracts are filtered and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][O:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([N:14]([O:13][CH3:12])[CH3:24])=[O:23])=[CH:22][CH:21]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: CON(C)C(=O)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C

Procedure:
Cool a slurry of aluminum chloride (87 g, 650 mmol) in methylene chloride (100 mL) with an ice bath. Add 4-chlorobutyryl chloride (51 g, 360 mL) dropwise over 0.5 hours. Add N-methoxy-N-methyl-benzeneacetamide (53 g, 300 mmol) over 0.5 hours. Allow the resultant solution to warm to room temperature. Then heat at reflux for 6 hours. Cool the solution to room temperature. Pour the solution into ice (1 L) and add methylene chloride (1 L). Separate the organic phase. Extract the aqueous phase with methylene chloride (2×500 mL). Dry the combined organics over anhydrous magnesium sulfate and concentrate to provide a solid which contains a ca. 1:1 mixture of the title compound and the meta isomer.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([C:15]4[CH:20]=[CH:19][C:18]5[O:21][CH2:22][O:23][C:17]=5[CH:16]=4)=[N:7][C:8](=[O:14])[NH:9]3)=[CH:4][C:3]=2[O:2]1.[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([C:15]4[CH:20]=[CH:19][C:18]5[O:21][CH2:22][O:23][C:17]=5[CH:16]=4)=[N:7][C:8]([O:14][CH2:27][CH:28]4[CH2:30][CH2:29]4)=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2c(cc1-c1nc(OCC3CC3)nc3cc4c(cc13)OCO4)OCO2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 16.5 %

Procedure:
To a suspension of 6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-quinazolin-2-one (310 mg, 1.00 mmol) in DMF (7 mL) was added NaH (97%, 32 mg, 1.33 mmol). The mixture was stirred at 25° C. for 45 min, then (bromomethyl)cyclopropane (0.2 mL, 2.0 mmol) was added. The resulting mixture was then heated at 100° C. for 6 h, cooled to rt, poured into ice-water (50 mL) and stirred for 30 min. The resulting precipitate was collected by filtration and the solid was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous MgSO4, and the solvent was removed in vacuo. This crude product was separated by chromatography in silica gel. Elution with hexane:acetone (65:35) gave 6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(cyclopropylmethoxy)-quinazoline as yellow solid (60 mg); mp 175-182° C.; 1H NMR (CDCl3) 7.31 (s, 1H), 7.21-7.25 (m, 3H), 7.14 (s, 1H), 6.93-6.96 (d, J=8.4, 1H), 6.09 (s, 2H), 6.06 (s, 2H), 4.29-4.31 (t, J=7.2, 2H), 3.2 (s, 1H); 0.63 (s, 2H), 0.41 (s, 2H); C20H16N2O5; C, 65.93; H, 4.43; N, 7.69. Further elution with the same solvents gave 1-cyclopropylmethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one as pale yellow solid (75 mg); mp 255-260° C.; 1H NMR (CDCl3) 7.18-7.36 (m, 3H), 6.82-7.02 (m, 3H), 6.11 (s, 2H), 6.06 (s, 2H), 4.22 (d, J=6.8, 2H), 1.18-1.40 (m, 1H), 0.41-0.78 (m, 4H); C20H16N2O5; C, 65.93; H, 4.43; N, 7.69.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:15][CH2:16][CH2:17][CH2:18][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCc1ccc(Oc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a 22 L flask was added 4-phenoxyphenol (900 g), 1,3-dibrompropane (5858 g), powered potassium carbonate (1335 g), and methyl ethyl ketone (9 L). The mixture was stirred for 30 minutes at 22° C. The off-white slurry was heated to a gentle reflux (˜83° C.) and held at that temperature for 16 hours. The off white slurry was cooled to 25° C. and vacuum filtered, washing the cake of inorganic salts with methyl ethyl ketone (4 L). The filtrate was concentrated on a rotary evaporator while increasing the temperature to 90° C. under house vacuum. After the condensation had stopped, the oil was held at 90° C. under vacuum for an additional two hours to ensure the remaining 1,3-dibrompropane below 8% by GC analysis. The residue was dissolved in 3 L of methyl alcohol, and the white slurry was cooled slowly to about 0–5° C. and held at that temperature overnight. The product was filtered, washed with cold methyl alcohol (6 L), and dried at 30° C. for about 20 hours to afford about 1234 g of compound (a) in 84% yield (99.4% pure by GC). 1H-NMR (CDCl3): 7.3(2H, m), 7.1(2H, m), 7.0(2H, m), 6.9(2H, m), 4.1(2H, m); 3.6(2H, m); 2.3(2H, m).
Reaction SMILES: [CH2:1]([N:4]([C:9]([O:11]C)=O)[C:5](=O)[CH2:6][NH2:7])[C:2]#[CH:3].[OH-:13].[Na+].Cl>CO>[CH2:1]([N:4]1[CH2:5][C:6](=[O:13])[NH:7][C:9]1=[O:11])[C:2]#[CH:3]
Reactant: C#CCN(C(=O)CN)C(=O)OC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C#CCN1CC(=O)NC1=O
Temperature: 70 °C

Procedure:
2.0 g of N-propargyl-N-methoxycarbonylglycinamide were added to the mixture of 5 ml of methanol and 2.5 ml of 20% aqueous solution of sodium hydroxide and maintained at 70° C. for an hour. After cooled down to room temperature; the reaction mixture was neutralized with concentrated hydrochloric acid followed by concentrating and drying the same by an evaporation under reduced pressure. Then it was extracted with acetonitrile and sodium chloride was removed off from the extract by filtration. The solvent was evaporated off from the filtrate to obtain 1.4 g of 1-propargyl-2,4-dioxoimidazolidine (melting point: 124°-125° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)=[CH:3][CH:2]=1.S(Cl)([Cl:15])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Cl:15])=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccncc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCCCCCc1ccncc1
Yield: 93.4 %

Procedure:
A solution of 5-(4-pyridinyl)-1-pentanol (3.7 g, 0.0225 mol) in 50 mL of chloroform is treated with thionyl chloride (5.4 g, 0.0449 mol) in 25 mL of chloroform. The resulting solution is neutralized with a saturated solution of sodium bicarbonate and extracted with chloroform. The organic phase is dried (sodium sulfate) and evaporated in vacuo to give 3.86 g of 5-(4-pyridinyl)-1-pentylchloride as a brown oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17](/[CH:18]=[N:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(/C=N/c2ccc(C(F)(F)F)cc2)c1
Yield: 100.2 %

Procedure:
A mixture of 4-trifluoromethyl-phenylamine (10.0 g, 62.06 mmol) and 3-Nitro-benzaldehyde (9.3 g, 62.06 mmol) in toluene was heated to reflux for 5 h with a Dean-stark trap. After evaporation of the toluene, the reaction mixture was heated for another 1 h at this temperature to afford 18.3 g of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-(4-trifluoromethyl-phenyl)-amine. The mixture was used in next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH:32]([CH3:34])[CH3:33])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCNC4)c1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCN(C(=O)/C=C/CN(C)C(C)C)C4)c1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-ethynylphenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 43A (100 mg, 0.344 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (93 mg, 0.48 mmol) to yield 82 mg (55%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH:20]=4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C1(CC(O)=[O:40])C2C(=CC=CC=2)CC=1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([C:17](=[O:40])[CH2:18][C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH:20]=4)[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1=CCc2ccccc21
Reactant: C1=C(CCN2CCN(c3cccc4c3OCCO4)CC2)c2ccccc2C1
Agent: Cl
Product: O=C(CC1=CCc2ccccc21)N1CCN(c2cccc3c2OCCO3)CC1
Yield: 30 %

Procedure:
4-(benzodioxan-5-yl)-1-[2-(ind-1-en-1-yl)-ethyl]-piperazine and its hydrochloride, m.p. (K): 254°-256° C., by reduction of 4-(benzodioxan-5-yl)-1-[2-(ind-1-en-1-yl)-acetyl]-piperazine (yield: 30%), which was itself prepared in a yield of 66% from 2-(ind-1-en-1-yl)acetic acid [m.p. (K): 92°-94° C.]and N-(benzodioxan-5-yl)piperazine.