Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:47]([O:46][CH2:45][CH2:44][N:27]1[C:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:24]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:25]2[S:30][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][C:26]1=2)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(OCc3ccccc3)cc1OCc1ccccc1)n2CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.12 g, 2.03 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 97 mg, 2.43 mmol) under ice-cooling and the mixture was stirred for 10 min. (2-Bromoethoxymethyl)benzene (0.53 ml, 3.24 mmol) was added and the mixture was stirred at room temperature for 4 hr. Ethyl acetate (25 ml) was added to the reaction mixture, and the organic layer was washed successively with water (20 ml×3) and saturated brine (10 ml), and dried over sodium sulfate. After filtration and concentration, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-2:1) to give methyl 4-(2-benzyloxyethyl)-5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.21 g, yield 87%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16])(=O)=O.[I-:26].[Na+]>CC(C)=O.C(Cl)Cl>[F:16][C:15]([F:18])([F:17])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][I:26]
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2C(F)(F)F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1CI
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A 200 mL round bottomed flask was charge under dry nitrogen with 35.08 g of 2-(trifluoromethyl)-6-nitrobenzyl tosylate dissolved in 100 mL of dry acetone. To this was added slowly with cooling 28.06 g of anhydrous sodium iodide dissolved in 75 mL of dry acetone. This reaction mixture was stirred overnight at room temperature. The mixture was stripped of acetone under vacuum redissolved in methylene chloride and filtered. The filtrate was extracted with 50 mL of distilled water, dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. By this procedure 29.92 g (97% yield) of product was obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:37])[NH:32][CH:33]1[CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CC(N(C)C)=O.O>[C:26]([O:30][C:31](=[O:37])[NH:32][CH:33]1[CH2:36][N:35]([C:14]2[CH:13]=[C:12]3[C:17]([C:18](=[O:19])[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10](=[O:25])[N:11]3[CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:20])[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)C1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.20 g, 0.55 mmol) in DMA (3.0 mL) was reacted with azetidin-3-yl-carbamic acid tert-butyl ester (0.286 g, 1.66 mmol), triethylamine (0.76 mL, 5.5 mmol) and heated to 80° C. for 2 days. The mixture was then cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, 3:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate) to provide 0.13 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:4][CH2:3]1.[C:53]1([S:59](O)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>COC(C)(C)C>[C:53]1([S:59]([O:18][C@H:16]2[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]3[N:11]=[C:10]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]5[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])=[CH:29][N:28]=5)[CH2:25][CH2:26]4)[C:9]([C@@H:40]([F:51])[C:41]4[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=4)=[C:8]([CH:5]4[CH2:4][CH2:3][C:2]([F:1])([F:52])[CH2:7][CH2:6]4)[C:17]2=3)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](O)CC(C)(C)C4)CC2)nc1
Solvent: COC(C)(C)C
Product: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OS(=O)(=O)c3ccccc3)CC(C)(C)C4)CC2)nc1
Temperature: 40 °C
Yield: 83.5 %

Procedure:
To a solution of 30.0 mg (0.0408 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 16, in 0.4 ml of tert-butyl methyl ether, 0.013 ml (0.041 mmol) of 3.16 M benzenesulfonic acid aqueous solution was added dropwise with stirring at 40° C. Then, the reaction mixture was cooled to room temperature and stirred for 30 minutes. The precipitated solid was obtained by filtration, washed with tert-butyl methyl ether and then dried under reduced pressure at 60° C. to provide 29.8 mg of the title compound as a white powder (yield: 82%).
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[CH:16]=[O:17])=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.P([O-])(O)(O)=[O:26].[Na+].OO.Cl([O-])=O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>C(#N)C.O>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16]([OH:26])=[O:17])=[C:12]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: CC#N
Solvent: O
Product: O=C(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a mixture of (E)-3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-propenal (50.0 g, 157.5 mmol) in acetonitrile (650 ml) and sodium dihydrogenphosphate (30.5 g, 220.5 mmol) in water (100 ml) is added hydrogen peroxide (18.8 g, 165.4 mmol) and a solution of sodium chlorite (25.0 g, 220.5 mmol) in water (120 ml) at 0° C. The reaction mixture is stirred in an ice bath for 120 min. Sodium thiosulfate pentahydrate (2.5 g, 10 mmol) and then 2M hydrochloric acid is added to adjust the pH to 2-3. After dilution with ethyl acetate (200 ml), the organic phase is separated and the pH of the aq. phase adjusted to 3-4 by addition of 2M sodium hydroxide. The reaction mixture is partitioned between ethyl acetate and water. The organic phases are separated, dried over magnesium sulphate and evaporated to afford (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid. MS (ES): [M−H]− 332, Mp. 173-174° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (250 mg, 1.24 mmol) was coupled to aniline (64)(241 mg, 1.24 mmol) using Method C to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[I-:14].[Na+].C(N)CCN>C(O)CCCC>[I:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: NCCCN
Agent: [Na+]
Solvent: CCCCCO
Product: Ic1ccc(-c2ccccc2)cc1

Procedure:
30 g of 4-bromobiphenyl is dissolved in 40 mL of n-pentanol. 2 equivalents of sodium iodide and 10 mole % of 1,3-propanediamine are added to the 4-bromobiphenyl solution. The reaction mixture is refluxed at 130° C. for sixteen (16) hours to produce 4-iodobiphenyl, as shown in reaction scheme (5).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A solution of 2.82 g of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone and 100 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator. A solution of 4.51 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.7 g (79%) of (R)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown-green oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][CH:13]([NH:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)=[C:20]([NH2:35])[N:19]=[CH:18][N:17]=3)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[O:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:16]([NH:15][CH:13]3[CH2:14][C:10]4([CH2:9][NH:8][CH2:11]4)[CH2:12]3)=[N:17][CH:18]=[N:19][C:20]=2[NH2:35])=[CH:27][CH:26]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(Nc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)C2)C1
Agent: Cl
Solvent: CO
Product: Nc1ncnc(NC2CC3(CNC3)C2)c1-c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 38.5 %

Procedure:
In a round bottom flask containing 6-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (167.23 mg; 0.35 mmol; 1.00 eq.) in methanol (5.00 ml) was added hydrogen chloride (1.80 ml; 3.53 mmol; 10.00 eq.). The reaction was stirred for 16 h before it was concentrated and purified by HPLC. The fractions containing the desired product were lyophilized to afford the title compound as a white solid (50.3 mg, 34%). HPLC purity: 95%. MS: m/z=374[M+H]+. 1H NMR (CD3OD) δ 8.25 (s, 1H), 7.10-7.44 (m, 8H), 4.60 (m, 1H), 4.20 (s, 2H), 4.01 (s, 2H), 2.69 (m, 2H), 2.32 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:11]=[CH:10][O:9][N:8]=1.C(N(CC)CC)C>C(OCC)C>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:11]=[CH:10][O:9][N:8]=1)=[O:4]
Reactant: Nc1ccon1
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ccon1
Reaction time: 3 h

Procedure:
To a stirred solution of bromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at −40° C. is added, dropwise over 20 minutes, a solution of 3-aminoisoxazol (5.0 ml, 67.0 mmol) and triethylamine (8.5 ml, 61.4 mmol) in diethylether (20 ml). Additional diethylether (50 ml) is added and stirring continued for 3 hours. The reaction mixture is filtered and the solution then washed with 1 M sodium carbonate solution, 1 M hydrochloric acid and brine. Concentration followed by purification by flash silica column chromatography (ethyl acetate/iso-hexane 4:7) gives the title compound as a white solid.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=O.Cl.[NH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C.CCCCCC.O1CCCC1>[Br:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)[C@H](Br)Cc1ccccc1)C(=O)OCC
Reaction time: 20 h

Procedure:
Combine (R)-2-bromo-3-phenylpropionic acid (3.44 g, 15 mmol), diethyl aminomalonate hydrochloride (4.23 g, 20 mmol), and N-methylmorpholine (5.5 mL, 50 mmol) in dichloromethane (50 mL). Add 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloric acid salt (3.83 g, 20 mmol) and 1-hydroxybenztriazole hydrate (2.70 g, 20 mmol). Add tetrahydrofuran (10 mL). After 20 hours, concentrate in vacuo and partition the concentrated reaction mixture between an aqueous 5% sulfuric acid solution and methyl t-butyl ether. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1/4 ethyl acetate/hexane, 1/3 ethyl acetate/hexane, and then 2.5/1 ethyl acetate/hexane to give diethyl 2-((R)-2-bromo-3-phenylpropionylamino)malonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1cncc(NCC2CC2)n1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of 2,6-dichloropyrazine (2.99 g), 1-cyclopropylmethanamine (2.14 g), potassium carbonate (4.14 g) and DMA (20 mL) was stirred at 80° C. for 23 hr. Water (15 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. This was used without purification for the next reaction.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([Mg]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH:8]1([CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: ON1CCOCC1
Reactant: Cl[Mg]C1CCCCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1C1CCCCC1
Reaction time: 1 h
Yield: 24 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclohexylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 50% diethyl ether in hexanes to give the title compound (0.220 g, 24%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>>[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:12]2[C:8]3=[N:9][C:10]4[C:5]([C:6](=[O:21])[N:7]3[C:14]3[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]2=3)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=4)=[O:31])=[CH:28][CH:27]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1
Product: Cc1ccc2c(=O)n3c4cc(C)c(C)cc4n(C(=O)c4ccc(OC(C)C)cc4)c3nc2c1

Procedure:
6-(4-Isopropoxybenzoyl)-3,8,9-trimethylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3,8,9-trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and 4-isopropoxybenzoyl chloride.
Reaction SMILES: CO/[N:3]=[C:4]1\[CH:5]([CH2:17][O:18][CH3:19])[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]\1>CO.[Ni]>[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][CH:5]1[CH2:17][O:18][CH3:19]
Reactant: COCC1CN(C(=O)OC(C)(C)C)CC/C1=N/OC
Agent: [Ni]
Solvent: CO
Product: COCC1CN(C(=O)OC(C)(C)C)CCC1N
Reaction time: 16 h

Procedure:
1,1-dimethylethyl (4Z)-4-[(methyloxy)imino]-3-[(methyloxy)methyl]-1-piperidinecarboxylate D32 (1.2 g) was dissolved in methanol (40 ml), raney-nickel (0.6 g) was added under nitrogen. The reaction mixture was then hydrogenated at atmospheric pressure for 16 hours. The raney-nickel was filtered off and the solution was evaporated in vacuo to afford a yellow oil of desired product D33 in 0.7 g. LCMS [M+H] 245.2 [M-56+H] 189.1@1.36 min (5 min run)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N+:18]([O-])([OH:20])=[O:19]>C(Cl)Cl>[CH3:17][O:16][C:12]1[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[C:3]([O:2][CH3:1])[C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)COc1c(OC)cccc1OC
Solvent: ClCCl
Product: CCOC(=O)COc1c(OC)cc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2,6-dimethoxyphenol (1.54 g, 10 mmol) and ethyl bromoacetate (2.00 g, 12 mmol) in 15 mL of anhydrous DMF, was added 2.76 g (20 mmol) of K2CO3. The reaction mixture was stirred at 30° C. for 20 hours. The mixture was concentrated in vacuo to remove volatiles. The resulting residue was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacou to give 2.2 g (91.6%) of ethyl 2-(2,6-dimethoxyphenoxy)acetate. The obtained ester (1.2 g, 5 mmol) was dissolved in a suspension of Silica Gel (2.0 g) in 20 mL of DCM. To this was dropwise added of a solution of concentrated HNO3 (20 mL) in 20 mL of DCM at rt. After being stirred at room temperature for 1 hour, it was transferred into a separatory funnel and then brown bottom layer was discarded into 100 g of ice. The remaining top organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacou to give 1.4 g (98%) of ethyl 2-(2,6-dimethoxy-4-nitrophenoxy)acetate as a brown solid. The obtained nitrophenoxy ester (1.34 g, 4.7 mmol) was dissolved in anhydrous THF (20 mL). To this, was slowly added of 1M DIBAL solution (10.3 mL, 10.3 mmol) in toluene with ice bath cooling. After 1 hour at rt, the reaction was quenched by addition of 1N-NaOH solution, and then extracted with EtOAc. The obtained organic layer was dried over anhydrous sodium sulfate, and passed through Silica Gel pad. The resulting filtrate was concentrated in vacuo to afford 2-(2,6-dimethoxy-4-nitrophenoxy)ethanol (1.01 g, 88%) as a pale yellow solid; MS (ESI) m/z 326 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)([OH:6])[CH2:4][OH:5].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:18][C:2]([F:1])([F:17])[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)([OH:6])[CH2:4][O:5][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CCOc1ccc(C(O)(CO)C(F)(F)F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(C(O)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
1,1,1-Trifluoro-2-(3-fluoro-4-ethoxyphenyl)propan-2,3-diol (0.4 g), prepared as described in Example 8 (ii), 3-phenoxybenzyl bromide (0.39 g), 40% sodium hydroxide solution (5cm3), dichloromethane (5 cm3) and tetra-n-butylammonium hydrogen sulphate (50 mg) were mixed, and stirred at room temperature under an atmosphere of nitrogen for 41/2 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was separated and the aqueous layer washed with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 1,1,1-trifluoro-2-(3-fluoro-4-ethoxyphenyl)-3-(3-phenoxybenzyloxy) propan-2-ol as an oil (0.67 g). The product was purified by column chromatography on a silica gel support, using n-hexane containing 15% by volume ethyl acetate as eluent.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc(Br)cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-bromophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 335, 337 (MH+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C=O)C>[N:26]1([CH2:2][C:3]2[N+:12]([O-:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]4[O:25][CH2:24][O:23][C:8]=4[CH:9]=3)[N:4]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: c1c[nH]cn1
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Solvent: CN(C)C=O
Product: [O-][n+]1c(Cn2ccnc2)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (192 mg, 0.53 mmol), in dry DMF (3 mL), was added imidazole (142 mg, 2.1 mmol). The mixture was stirred at 85° C. for 1.5 h and left at rt for 15 h. DMF was removed and the mixture was poured into ice-water. The precipitated solid was extracted with EtOAc. The organic layer was washed with water, brine and dried over anhydrous MgSO4. It was filtered and the solvent was removed to yield the title compound as off white solid (100 mg); mp 212-217° C. 1H NMR (CDCl3) 7.76 (s, 1H), 7.00-7.21 (m, 5H), 6.80 (s 1H), 6.13 (s, 2H), 6.08 (s, 2H), 5.63 (s, 2H).