Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=N)[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=1)([CH3:16])[CH2:9][CH2:8]2)(=O)C.Cl.C[O:35]CCO>>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:35])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=1)([CH3:16])[CH2:9][CH2:8]2
Reactant: CC(=O)Oc1cc2c(cc1C)OC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)CC2
Reactant: COCCO
Agent: Cl
Product: Cc1cc2c(cc1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
170 mg of 5-[4-(6-acetoxy-2,7-dimethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one (prepared as described in Example 5) were added to a mixture of 0.2 ml of 2N hydrochloric acid and 2 ml of ethylene glycol monomethyl ether, and the mixture was reacted at 95°-97° C. for 6 hours. It was then processed and purified as described in Example 1(a), except that the crude product, in the form of an oil, was subjected to column chromatography through silica gel, eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:6][C:11](=[O:12])[N:13]([CH2:18][CH3:17])[CH2:14][CH3:15])[C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1cc(C(=O)N2CCC(n3c(=O)n(CC(=O)N(CC)CC)c4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of 2-chloro-N,N-diethyl-acetamide. The crude reaction mixture was purified by preparative HPLC to afforded 6 mg of the title compound as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N:12]=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N+:12]([O-:27])=[CH:11][C:10]=2[CH:9]=1)(=[O:6])=[O:7]
Reactant: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2c[n+]1[O-]
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of N,N-dimethyl-N'-(6-methylfuro[3.2-c]pyridine-2-sulfonyl)formamidine (5.61 g, 21 mmol) in chloroform (65 ml) was added dropwise a solution of commercial 80% pure m-chloroperbenzoic acid (5.0 g, 23 mmol) in chloroform (45 ml). The reaction was stirred for 20 hours and then concentrated on a rotary evaporator to near dryness. The residue was digested in diethyl ether and the precipitated product filtered. This solid (6.06 g) was digested in ethyl acetate/chloroform/methanol and then cooled and pure product collected by filtration (5.76 g, 97% yield), m.p. 248°-249° C.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:18]([C:41]([F:44])([F:43])[F:42])=[N:19][N:20]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:45]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1>>[N:45]1([C:50]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[C:18]([C:41]([F:43])([F:42])[F:44])=[N:19][N:20]([C:22]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH:21]=5)[CH:15]=4)[N:10]=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Reactant: O=C(Cl)N1CCCC1
Product: O=C(N1CCCC1)N1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1

Procedure:
118 mg 4-piperazin-1-yl-6-(3-trifluoromethyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 188 and 33 μL 1-pyrrolidine carbonyl chloride were reacted in the same manner as in Example 193, to give 126 mg of the title compound as a colorless amorphous.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:21].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[CH:15]=[CH:14][C:13]4[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=4[C:7]=3[CH:18]=2)=[CH:24][CH:23]=1)(=[O:21])[CH3:19]
Reactant: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 4069.7 %

Procedure:
9-Bromomethyl-3-methyl benzo[f]quinazolin-1(2H)-one (1 g, 3.3 mmole) and 4-aminoacetophenone (0.89 g, 6.6 mole) (Aldrich) were dissolved in dimethylformamide (15 ml). The solution was stirred under nitrogen at 100° C. for 30 min. Sodium bicarbonate (0.55 g, 6.6 mmole) was added and stirring was continued for a further 30 min. Dimethylformamide was removed in vacuo, the residue triturated with water and the solid collected by filtration. The dried solid was subjected to chromatography on silica (methanol/methylene chloride (1:19)). Fractions containing product were concentrated until solid began to precipitate. The solution was chilled at 5° C. for 12 hours, then the solid filtered off and dried under high vacuum to yield the title compound (0. 48 g,41%). Mp>235° C. 1H NMR (DMSO-d6, 300 MHz) δ: 2.37 (s, 3H, CH3); 2.43 (s, 3H, CH3); 4.59 (d, J=6 Hz, 2H, CH2); 6.65 (d, J=9 Hz, 2H, Ar); 7.37 (t, J=6 Hz, 1H, ArNH); 7.59 (d, J=9 Hz, 1H, Ar); 7.61 (dd, J=8, 2 Hz, 1H, Ar); 7.69 (d, J=9 Hz, 2H, Ar); 8.00 (d, J=8 Hz, 1H, Ar); 8.21 (d, J=9 Hz, 1H, Ar); 9.85 (s, 1H, Ar); 12.52 (s, 1H, NH). Anal Calculated for C22H19N3O2.1/2 H2O: C,72.11; H,5.50; N,11.47. Found: C,72.26; H,5.46; N,11.35.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CN(C=O)C>[Cl:12][C:13]1[N:21]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)[C:19]([F:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(Cl)c(C(=O)O)cc2F)CC1
Temperature: 80 °C

Procedure:
Ethyl isonipecotate was added to a DMF solution of 2,6-dichloro-5-fluoronicotinic acid, and the mixture was stirred at 80° C. to obtain 2-chloro-6-[4-(ethoxycarbonyl)piperidin-1-yl]-5-fluoronicotinic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([C:15]2([CH3:22])[O:21][CH:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH3:22])[CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Product: COC(=O)C(O)C(C)(Oc1ccc(Br)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
51.9 g (0.3 mol) of 4-bromophenol and 19.2 g (0.1 mol) of methyl 3-phenyl-2,3-epoxybutyrate are stirred at 100° C. for 8 h and at room temperature for 12 h. After removal of the excess phenol by distillation, the residue is purified by flash chromatography (silica gel, n-hexane/ethyl acetate 9:1) to result in 7.2 g of a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:27]=[CH:26][C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[O:3]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:6]2[C:5]3[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=3[O:3][C:2]2=[O:1])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve the compound obtained in Example 2 (0.5 g) in absolute ethanol (6.5 ml) and add tetrahydrofuran (2 ml). Subsequently, cool the reaction mixture using an ice bath and add 2N sodium hydroxide (0.7 ml). Stir magnetically for 18 hours at ambient temperature. Remove the absolute ethanol/tetrahydrofuran mixture by evaporation under reduced pressure. Take up the resulting residue in water and extract twice with 50 ml of ether each time. Acidify the aqueous phase with a 6N hydrochloric acid solution until a pH of 1 is obtained, then extract twice with 50 ml of ether each time. Dry the organic phase over magnesium sulphate and remove the ether by evaporation under reduced pressure.
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL flask was added guanosine (2.0 g, 7.06 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.14 mmol). N,N-dimethylformamide (25 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (14 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and palmitoyl chloride (2.8 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot 2-methoxyethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:22])[CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCNc2ccc(Cl)cc2N1c1ccccc1
Agent: [K+]
Solvent: CI
Product: CN1CCC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
20.4 g 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is stirred for 2 hours on a water bath with 12.8 g methyl iodide and 10 g anhydrous potassium carbonate. The inorganic material is removed by filtration under suction and the filtrate is diluted with 200 ml water. The crystalline precipitate is filtered under suction, washed with water, and recrystallized from alcohol. The yield is 20 g of the m.p.=143° C.-144° C. (93% of the theory).
Reaction SMILES: Cl[O-:2].[Na+].[C:4]([C:7]1[C:8]([CH3:23])=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[S:13](=[O:19])(=[O:18])[CH2:12][C:11]([CH3:21])([CH3:20])[C:10]2=[O:22])(=[O:6])C>O1CCOCC1.O>[C:4]([C:7]1[C:8]([CH3:23])=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[S:13](=[O:19])(=[O:18])[CH2:12][C:11]([CH3:20])([CH3:21])[C:10]2=[O:22])([OH:6])=[O:2]
Reactant: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Reactant: [O-]Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CC(C)(C)C2=O
Temperature: 30 °C
Yield: 84 %

Procedure:
17.8 Grams (about 15 mmol) of a 6.4 wt % sodium hypochlorite aqueous solution was placed in a 100-ml three-necked round-bottomed flask, and cooled to 15~20° C., and then a solution of 1.26 g (4.26 mmol) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in 8 ml of dioxane was gradually added. The mixture was stirred at 15~20° C. with external cooling for 30 minutes, and then stirred at room temperature (temperature-increased to about 30° C.) for 3 hours. The reaction mixture was diluted with about 50 ml of water and washed with chloroform twice. A sodium sulfate aqueous solution was added to an aqueous layer to decompose excess hypochlorite, and then the aqueous solution was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution to give a white solid. The solid was extracted with ethyl acetate, and an organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.06 g (yield 84%) of 6-carboxy-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in the form of a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=3)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Product: CC(=O)c1ccc(OCc2cccc(Sc3cc(C#N)ccn3)c2)c(C)c1O
Yield: 51.9 %

Procedure:
Using the method of Preparation 166 using 2-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.46 g, 6.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.00 g, 6.02 mmol) affords the title compound (1.22 g, 52%). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:20][C:16]=2[N:17]=[CH:18][N:19]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[C:15]3[C:22]([CH3:23])=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1N
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C

Procedure:
Prepared from 4-fluoro-2-iso-propoxyaniline and methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate in an analogous fashion to that given in general route 1. Yield (0.25 g, 53%)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:15][CH2:16][CH3:17]
Reactant: [H][H]
Reactant: CCCC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC1CNCCC1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-n-propylpiperidine (3.3 g, 14.16 mmole) and 20% palladium hydroxide (0.25 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) for 24 hr at 30° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-n-propylpiperidine as oil. Yield 1.8 g (90%), C8H17NO, m/z 144 (M+1), PMR (CDCl3): 0.92 (3H, t, CH3, j=8 Hz), 1.2-1.52 (5H, m, 2×CH2 & H3), 1.72 (1H, m, H5), 1.94 (2H, m, H5, & OH, D2O exchangeable), 2.22 (1H, m, H2), 2.62 (1H, m, H6), 3.12 (1H, m, H2), 3.3 (1H, m, H6), 3.5 (1H, bs, NH, D2O exchangeable), 3.98 (1H, m, H4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:26]([Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 51.8 %

Procedure:
Step B To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K2CO3 (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70° C. for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane as a light yellow oil (1.0 g, 52%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][O:17][C:18](=[O:20])[N:19]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>O1CCOCC1.O>[O:17]1[C:18](=[O:20])[N:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])=[O:21])=[CH:10][CH:11]=2)[NH:16]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 3 (0.60 g, 2.0 mmol) was dissolved in a mixture of 1,4-dioxane/H2O (10 mL, 1/1, v/v). Aq. NaOH (2.0 mL, 2N) was added and the mixture was stirred for 3 h at RT. The reaction mixture was neutralized with Dowex H+ and filtered. The filtrate was concentrated under reduced pressure and the resulting white solid was dried under vacuum. Yield 0.51 g (93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I-].C[N+]1C=CN([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1OC
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N(C)c4ccccc4)cc3oc2=O)cc1OC
Yield: 13.5 %

Procedure:
The title compound (30 mg, 13% yield, oil) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[O:10][C:9]([CH2:13][OH:14])([CH2:11][OH:12])[C@@H:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:6]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>CN(C)C=O>[CH2:1]([O:4][CH:5]1[O:10][C:9]([CH2:11][O:12][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)([CH2:13][O:14][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C@@H:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:6]1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC1OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1OC(COCc2ccc(OC)cc2)(COCc2ccc(OC)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
The starting diol [((3S,4S,5R)-6-allyloxy-3,4,5-tris-benzyloxy-2-hydroxymethyl-tetrahydro-pyran-2-yl)-methanol (I-1b: 10 g, 19.208 mmol) was dissolved in N,N-dimethylformamide (70 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.69 g, 42.3 mmol) was added and the reaction was allowed to stir at 0° C. for 1 hour before the addition of 1-bromomethyl-4-methoxy-benzene (5.96 mL, 40.3 mmol). The reaction was then heated to 60° C. overnight. The mixture was cooled down to room temperature and the reaction was quenched with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction was then chromatographed over silica gel (eluting with a gradient of 0 to 80% ethyl acetate in heptane) yielding 7.55 g (52% yield) of product (I-1c). MS 778.8 (M+NH4+; positive mode).
Reaction SMILES: CC[N:3](CCCC(NC1C=C(/C=C/C2C=CC=CC=2Cl)N=C2C=C(Cl)C=CC=12)C)CC.Cl[C:33]1[C:34]2[CH2:42][CH2:41][N:40](C3C=CC=CN=3)[CH2:39][C:35]=2[N:36]=[CH:37][N:38]=1>>[N:36]1[C:35]2[CH:39]=[N:40][CH:41]=[CH:42][C:34]=2[C:33]([NH2:3])=[N:38][CH:37]=1
Reactant: Clc1ncnc2c1CCN(c1ccccn1)C2
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Product: Nc1ncnc2cnccc12

Procedure:
Appropriate 7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7- yl)pyrido[3,4-d]pyrimidin-4-amine derivatives are prepared starting from 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline. The nitroquinoline derivate is reacted with appropriate alkylating agent to give the N-substituted nitroquinoline, which is reduced using standard procedures known in the art to yield 7-aminoquinoline derivative. The resulting aminoquinoline derivated is then condensed with the appropriate 4-chloro-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine to give the desired 7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine derivative. As a representative example, preparation of the N-morpholionethyl derivative is depicted in Scheme 6.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:56]4[CH2:57][CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:56]4[CH2:57][CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 62.9 %

Procedure:
A solution of 0.148 g of (Cis)-2-butyl-6-(hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4yl]methyl]-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for 4 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 to 9:1 chloroform-methanol to give 0.065 g of the desired product as a solid. FAB mass spec 562 (M+H).