Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:24]=[C:25](O)[CH:26]=1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[CH:24]=[C:25]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:26]=1)[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (570 mg, 2.0 mmol) was added drop wise to a solution of (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (546 mg, 1.69 mmol) and pyridine (0.41 mL, 5.0 mmol) in DCM (10 mL) at 0° C. The temperature was maintained at 0° C. for 15 mins before warming to room temperature and the mixture stirred for 18 hrs. The reaction was diluted with DCM, washed with H2O, Na2CO3, dil. HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography (EtOAc:petroleum ether), yield 695 mg (96%). 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.66 (d, 2H), 7.54 (t, 1H), 7.39 (t, 1H), 7.28 (t, 1H), 4.19 (q, 2H), 3.73 (s, 2H), 1.28 (t, 3H).
Reaction SMILES: CC1(C)O[C@H](CON)CO1.FC1C(NC2C=CC(I)=CC=2F)=C(C=CC=1F)C(O)=O.[OH:31][C@H:32]([CH2:55][OH:56])[CH2:33][O:34][NH:35][C:36](=[O:54])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[C:38]=1[NH:45][C:46]1[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=1[F:53]>CO>[OH:31][C@@H:32]([CH2:55][OH:56])[CH2:33][O:34][NH:35][C:36](=[O:54])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[C:38]=1[NH:45][C:46]1[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=1[F:53]
Reactant: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CC1(C)OC[C@@H](CON)O1
Agent: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CO
Product: O=C(NOC[C@@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
Prepared from (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid by the procedure described above for N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide: m.p. 116-118° C. (Form II of Compound C); and m.p. 116-118° C. (Form I of Compound C); [α]=+1.77° (c=1.13, methanol). Analysis: Calcd. For: C16H14F3I1N2O4: C, 39.85; H, 2.93; N, 5.81; F, 11.82; I, 26.32. Found: C, 40.01; H, 2.73; N, 5.84; F, 11.45; I, 26.42.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13]Br)=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15].[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]>O1CCOCC1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][N:19]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][CH3:18])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15]
Reactant: CN1C(=O)COc2cc(CCBr)ccc21
Reactant: CCCNCCC
Solvent: C1COCCO1
Product: CCCN(CCC)CCc1ccc2c(c1)OCC(=O)N2C
Reaction time: 96 h

Procedure:
5.4 g of 4-methyl-7-(2-bromoethyl)2,3-dihydro 3-oxo 1,4-benzoxazine, dissolved beforehand in 120 cm3 of dioxane and 6 cm3 of (0.044 mol) of dipropyl-amine, are introduced into a 250 cm3 round-necked flask equipped with a reflux condendser. The mixture is heated to reflux with magnetic stirring for 4 days. After cooling, the reaction mixture is filtered and the filtrate is then evaporated on a water bath under vacuum. The residue is ground with distilled water and extracted with ethyl acetate. The organic phase is recovered and evaporated to dryness and the residue is taken up with 5% HCl solution. The acidic aqueous phase is washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with ethyl acetate and the organic phase is washed with distilled water and then dried over potassium carbonate. The solvent is evaporated off on a water bath under vacuum. The residue is taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The residue is ground in toluene or ether, then drained and dried. The product is recrystallized in anhydrous acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=O.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1)[CH2:10]/[C:11](/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[N:32]\[OH:33]
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(2,5-dichlorophenyl)-3-(4-(methylsulfonyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 3% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=479.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH:5](=O)/[CH:6]=[CH:7]/[CH2:8][CH3:9]>>[CH3:1][N:2]([CH3:4])[N:3]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH3:9]
Reactant: CN(C)N
Reactant: CC/C=C/C=O
Product: CC/C=C/C=NN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
N,N-Dimethylhydrazine (42.0 mL 0.55 mol) was added dropwise to trans-2-pentenal (42.06 g, 0.50 mol) at such a rate that the reaction temperature could be maintained at about 0° C. The mixture was then stirred for 1 h at ambient temperature, and the organic phase separated and dried (K2CO3). Distillation (bp 84°-86° C., 25 mm Hg; lit bp 60° C., 15 mm Hg) through a 10 cm Vigreaux column gave trans-2-pentenal N,N-dimethylhydrazone (12) (51.3 g, 81%): n20 1.5104; IR (neat) 2960, 2870, 2850, 2820, 2780, 1565, 1470, 1460, 1445, 1265, 1135, 1030, 970 cm-1 ; 1H NMR (CDCl3) δ0.98 (t, 3 H, J=7.4 Hz), 2.16-2.05 (m, 2 H), 2.76 (s, 6 H), 5.82 (dt, 1 H, J= 15.6, 6.3 Hz), 6.14 (dd, 1 H, J=15.6, 8.8 Hz) 6.97 (d, 1 H, J=8.8 Hz).
Reaction SMILES: [H-].[Na+].C(O[C:6]([CH:8]([C:14](=[O:23])[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])C.C(O)(=O)C.O>C1(C)C=CC=CC=1.C(O)C>[O:7]=[C:6]1[CH:17]2[CH:16]([CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH2:15][C:14](=[O:23])[CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(=O)CC1CCCC(=O)C1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)CC2CCCC(=O)C2C1=O
Reaction time: 0.9 h

Procedure:
Sodium hydride in oil (60%, 24 g, 0.6 mole) was washed portionwise with petroleum spirit (60°-80°; dried over CaH2 ; 250 ml) in an atmosphere of nitrogen. The sodium hydride was then covered with toluene (Na dried; 150 ml) and the mixture heated to vigorous reflux while being stirred mechanically. A solution of the diester (11) (30 mmoles) in toluene (Na dried, 60 ml), containing superdry ethanol (10 drops) was added during 6 min and reflux continued for a further 54 min. After cooling the mixture in ice, the excess sodium hydride was decomposed by the slow addition of glacial acetic acid (45 ml) followed by water (100 ml). The aqueous layer was removed, the toluene layer washed with water (50 ml) and the combined aqueous layers were extracted with toluene (25 ml). The combined toluene layers were then extracted with a freshly prepared solution of sodium bicarbonate (24 g) in water (360 ml). Extraction was repeated twice more with sodium bicarbonate (12 g) in water (180ml). Filtration, followed by acidification with concentrated hydrochloric acid, of the bicarbonate extracts yielded 2.01 g (26.6%) of crude (12). Crystallisation from hexane (charcoal) gave a cream product m.p. 90.5°-93.5°.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][NH2:25]>C(Cl)(Cl)Cl>[CH3:24][NH:25][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: ClC(Cl)Cl
Product: CCCOc1ccccc1-c1nc2nc(NC)ncc2c(=O)[nH]1

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.40 g) was treated with a solution of methylamine in industrial methylated spirit (33%; 30 ml) in a pressure vessel for 9 hours at 90° C. The reaction mixture was evaporated under reduced pressure to yield a cream solid which was dissolved in chloroform. The organic solution was washed with water, dried (magnesium sulphate) and evaporated under reduced pressure to yield a cream solid. Elution from silica with chloroform:methanol (25:1) yielded a crude product which was recrystallized twice from ethanol to yield the title compound, 0.31 g, m.p. 235-236° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[H-].[Na+].[CH3:32]I>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH3:32])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reaction time: 1 h

Procedure:
A solution of 7.20 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH3:13])=[CH:8][C:7]=1[CH3:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][C:7]=1[CH3:21]
Reactant: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
A solution of crude [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester (25.8 g, 77 mmol) in CH2Cl2 (600 ml) was treated at 0° C. with TFA (198 ml) and stirred at RT for 30 min. The reaction was evaporated, treated with chilled aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 16.2 g of crude (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester. Purification by flash chromatography with a gradient of n-heptane:EtOAc 9:1 to 4:1 yielded 12.7 g of (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester as an orange oil, MS: 210 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].O.C(O)(=O)C>C(O)C>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1N
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1Oc1c(C(=O)O)[nH]c2ccccc12

Procedure:
1.6 g of methyl-3-[o-aminophenoxy]-indole-2-carboxylate was dissolved in 10 ml each of ethanol and water and refluxed for 10 min. The clear solution was acidified with acetic acid. The white precipitate was filtered and recrystallized from acetonitrile to give analytical material, mp. 217°-18°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCCC(CNC(=O)OCc2ccccc2)C1

Procedure:
A solution of [3-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (6 g, 16.6 mmol) in TFA (30 mL) was stirred for 1.5 h. The solution was concentrated using benzene to azeotrope, diluted with EtOAc, washed (1.0 N NaOH), dried (Na2SO4), filtered, and concentrated to afford (4.2 g, 97%) as a crude solid. Mass Spectrum (ES+) (m/z) 263.1 [M+1].
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:8]([OH:10])=[C:9]2[S:1][CH:2]=[CH:3][C:4]2=[N:5][CH:6]=1
Reactant: BrBr
Reactant: Oc1ccnc2ccsc12
Solvent: CC(=O)O
Product: Oc1c(Br)cnc2ccsc12
Temperature: 110 °C
Yield: 115.2 %

Procedure:
To a solution of thieno[3,2-b]pyridin-7-ol (1, 2.55 g, 16.87 mmol) in acetic acid (50 mL) was added bromine (1.7 mL, 32.72 mmol). The mixture was heated at 110° C. for 1 h, cooled and the resultant precipitate was separated by filtration, to afford the title compound 270 (4.47 g, crude) as a dark brown powder, which was used in next step without further purification. M/S (m/z): 231.9(M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][C:4]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=4)=[N:5][C:6]=23)=[O:13])[CH:30]=[CH:29][CH:28]=1)(=[O:32])(=[O:33])[NH2:34]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)O)cnn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.25) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 476.5 [(M+H)+]; mp 270-272° C.
Reaction SMILES: [Br:1][CH:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.FC(F)(F)[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].[Cl-].[NH4+]>>[Br:1][CH:2]1[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1.[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([C:15]3[CH:14]=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][OH:18])[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: BrC1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Product: OCc1ccccc1C1CCC2(CC1)OCCO2

Procedure:
When the bridging group is carbonyl, the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane is first prepared. The precursor 8-bromo-1,4-dioxaspiro[4.5]decane is prepared by the method of E. I. Snyder (JOC, 36, 403 (1971)). The Grignard reagent is in turn reacted with an appropriately substituted or unsubstituted benzaldehyde, for example, 3-trifluoromethylbenzaldehyde and then treated with aqueous ammonium chloride, yielding [(1,4-dioxaspiro[4.5]decan-8-yl)(phenyl)]methanol. The so-prepared alcohol is treated with sodium hydride in toluene, and then is reacted with phenylmethyl bromide, yielding phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(phenyl)]methyl ether. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, as previously described, affording the corresponding phenylmethyl [(cyclohexanon-4-yl)(phenyl)]methyl ether. The ether is then reacted with cyanoguanidine, as previously described, yielding the appropriate 2,4-diamino-6-[(phenylmethoxy)(phenyl)methyl]-5,6,7,8-tetrahydroquinazoline. The tetrahydroquinazoline is then cleaved with hydrogen gas in the presence of 5% palladium on charcoal, yielding the corresponding [(2,4-diamino-5,6,7,8-tetrahydroquinazolin-6-yl)(phenyl)]methanol. Using the method of D. Swern (Tetrahedron, 34, 1651-1660 (1978)), the methanol is oxidized with oxalyl chloride and dimethyl sulfoxide in methylene chloride, yielding the targeted 2,4-diamino-6-phenylcarbonyl-5,6,7,8-tetrahydroquinazoline. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25](O)(=O)[CH3:26].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCNC3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.3 g of 4-Isopropyl-N—((S)-4-pyrrolidin-3-yl-phenyl)-benzenesulfonamide (0.87 mmol) were dissolved in 20 ml dichloromethane. After addition of 0.07 ml of acetic acid, 0.073 ml of acetaldehyde (1.31 mmol) and 0.277 g of sodium triacetoxyborohydride (1.31 mmol), the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, the residue dissolved in water and the pH adjusted to pH 8-9 with aqueous sodium hydroxide solution. The aqueous phase was extracted three times with diethyl ether, the combined organic phases dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography (chromabond column) with dichloromethane, dichloromethane/methanol 4% as eluent to yield 64 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(O)C.O1CCCC1.[CH3:30][C:31]1([CH3:44])[O:35][CH:34]([C:36]2[CH:37]=[CH:38][C:39]([CH:42]=[O:43])=[N:40][CH:41]=2)[CH2:33][O:32]1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:30][C:31]1([CH3:44])[O:35][CH:34]([C:36]2[CH:37]=[CH:38][C:39]([C:42](=[O:43])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:4]3[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:40][CH:41]=2)[CH2:33][O:32]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Reactant: CC1(C)OCC(c2ccc(C=O)nc2)O1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C3COC(C)(C)O3)cn2)cc1F
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of 4-[3-fluoro-4-(methylsulfanyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (430 mg) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) were added 5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-2-carbaldehyde (290 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (41.0 mg) and triethylamine (84 μL), and the mixture was stirred with heating under reflux under argon atmosphere for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (510 mg, yield 71%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 516 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[F:22]C1C=CC(CC(C(O)=O)C(O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: O=C(O)C(Cc1ccc(F)cc1)C(=O)O
Product: Fc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(4-fluorobenzyl)malonic acid (Intermediate 4: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([Sn:13](Cl)([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[CH2:22]([Sn:13]([N:1]=[N+:2]=[N-:3])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC[Sn](Cl)(CCCCCCCC)CCCCCCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Temperature: 8 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In 30 ml of pure water was dissolved 10.19 g of sodium azide and the solution was cooled to 8° C. Then, 50.0 g of trioctyltin chloride was added dropwise over a period of 10 minutes and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was then extracted with 88 ml of methylene chloride and further with 25 ml of the same solvent, and the extract was washed with 25 ml of 10% aqueous sodium chloride solution and concentrated to provide 50.05 g of trioctyltin azide.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:13])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.[Cl:14][C:15]1[C:16](=[O:26])[N:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:18]=[CH:19][C:20]=1Cl>>[Cl:14][C:15]1[C:16](=[O:26])[N:17]([C:22]([CH3:24])([CH3:23])[CH3:25])[N:18]=[CH:19][C:20]=1[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH3:13])[CH3:3])=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Product: CN(C)c1ccc(CNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 9 were prepared in the synthetic manner and after-treatment similar to those in Example 2 except that the benzylamine dihydrochlorides with Y1, Y2, Y3 and R3 as identified in Table 9 were used instead of the starting 4-dimethylaminobenzylamine dihydrochloride used in Example 2, and the 4,5-di(chloro or bromo)-2-alkyl-3(2H)pyridazinones with R1 and R2 as identified in Table 8 were used instead of the starting 4,5-dichloro-2-t-butyl-3(2H)pyridazinone. In the NMR data, only the characteristic absorptions are given in Table 9.