Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round-bottomed flask was charged with 2,4-dichloro-5-fluoropyrimidine (2.5 g, 15 mmol), ethyl 2-aminobenzoate (4.9 g, 30 mmol), N,N-diisopropylethylamine (5.2 mL, 3.9 g, 30 mmol) and isopropanol (50 mL). The flask was fitted with a reflux condenser and the mixture was heated to reflux and stirred for 18 h. After cooling the reaction mixture to room temperature a precipitate appeared. The solid was collected and washed sparingly with isopropanol then copiously with ethyl ether to afford the title compound as a white solid; yield, 1.8 g (41%). MS: M(C13H13ClFN3O2)=295.70 (M+H)+=296.0 and 298.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([N:17]([CH3:42])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:27])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2sc(NC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In N,N-dimethylformamide (10 ml), 1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (147 mg) was dissolved. After the addition of 60% oily sodium hydride (22 mg), the resulting mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.023 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 90 minutes. To the residue obtained by concentrating the reaction mixture under reduced pressure, ethyl acetate was added. The resulting mixture was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (43 mg) was obtained.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:37])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[C:31]1([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][C:16]([F:37])([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=3)[CH2:21][CH2:20]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCN(CCC(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Oc1cccc(C2(F)CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Yield: 64 %

Procedure:
A solution of 4-(3-benzyloxyphenyl)-1-(3,3-diphenyl-propyl)-4-fluoropiperidine hydrochloride (40 mg, 0.08 mmol) in methanol (5 mL) was treated with palladium on carbon (10 mg, 10% Pd, 50% H2O) and the mixture rapidly stirred under 1 atmosphere of hydrogen gas for 8 hours. After this time the hydrogen was replaced by nitrogen and the reaction mixture filtered through a celite pad. The pad was washed with additional methanol (10 mL) and the filtrate concentrated under reduced pressure. Trituration of the residue with a 1:1 mixture of 2-butanone/ethyl acetate (10 mL) and subsequent filtration and drying afforded a 64% yield of 1-(3,3-diphenylpropyl)-4-fluoro-4-(3-hydroxyphenyl)piperidine hydrochloride as an off-white solid.
Reaction SMILES: [K].[C:2]([C:4](=[N:8][OH:9])[C:5]([NH2:7])=[O:6])#[N:3].C1(C)C=CC(S(O[CH2:20][CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)(=O)=O)=CC=1>C(#N)C>[C:2]([C:4](=[N:8][O:9][CH2:20][CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:5]([NH2:7])=[O:6])#[N:3]
Reactant: N#CC(=NO)C(N)=O
Reactant: Cc1ccc(S(=O)(=O)OCCn2cncn2)cc1
Agent: [K]
Solvent: CC#N
Product: N#CC(=NOCCn1cncn1)C(N)=O

Procedure:
15.1 g (0.1 mol) of the potassium salt of 2-cyano-2-oximinoacetamide and 28.3 g (0.106 mol) of 1-(2-(p-toluenesulphonyloxy)-ethyl)-1,2,4-triazole in 100 ml of acetonitrile are heated at 80° C. for 10 hours. The solid product is separated off, and the acetonitrile solution is evaporated down in vacuo. The residue is recrystallized from boiling diethyl ketone. 13.4 g of 2-cyano-2-[2-(1,2,4-triazol-1-yl)-ethyl-oximino]-acetamide of melting point 137° C. are obtained: this is 64% of theory.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].CN1CCOCC1>C(Cl)Cl>[C:26]1([O:25][C:23]([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:21][CH2:20]2)=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)Oc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol) and phenyl chloroformate (40 mg, 0.26 mmol) in CH2Cl2 (3 mL) at 25° C. is added N-methyl morpholine (0.07 mL, 0.60 mmol). After being stirred at 25° C. for 3 h, the mixture is diluted with CH2Cl2 (10 mL), and washed with saturated sodium bicarbonate (1 mL) and water (2×5 mL). The organic layer is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid phenyl ester (69 mg, 81%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]([F:31])([F:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:18]([CH3:19])[O:17]2)=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[F:8][C:9]([F:30])([F:31])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)([OH:17])[CH:18]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH3:19])=[CH:12][CH:11]=1
Reactant: c1nc[nH]n1
Reactant: CC1OC1(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
1,2,4-1H-triazole was added to a stirred suspension of sodium hydride (0.86 g, 50% dispersion, washed with petroleum ether to remove oil) in dry dimethylformamide (40 cm3). After stirring for 1.5 hours, the oxirane (formed in (b) above) dissolved in dimethylformamide (5 cm3) was added slowly. The mixture was heated at 100° C. for 2 days, then cooled and poured into water, neutralised with dilute hydrochloric acid and the product extracted into ether, which was dried (MgSO4) and concentrated by evaporation of the solvent.
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][C:11]([Cl:17])=[C:10]([CH3:18])[C:9]=1[Br:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:19][C:9]1[C:8]([C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=2)=[C:13]([C:14](=[O:16])[CH3:15])[CH:12]=[C:11]([Cl:17])[C:10]=1[CH3:18]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
To a solution of sodium hydrogenecarbonate (2.8 g, 34 mmol) in water (70 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (6.7 g, 17 mmol) in toluene (70 mL) followed by (3,5-difluorophenyl)boronic acid (2.9 g, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.98 g, 0.85 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered, concentrated and purified on silica gel (eluting with 0-15% of ethyl acetate in hexanes) to give the desired product (5.6 g). LCMS calculated for C15H11BrClF2O (M+H)+: m/z=359.0. found: 359.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:29])([F:19])[F:28])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cn1
Temperature: 130 °C
Yield: 95 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-Trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol), followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130° C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([S:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1

Procedure:
A suspension of 3′-mercaptoacetophenone (Reference compound No. 4-1, 0.50 g, 3.3 mmol), potassium carbonate (0.55 g, 4.0 mmol) and 4-fluoronitrobenzene (0.42 mL, 4.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 8.5 hours. Water (30 mL) was added to the reaction mixture, extracted with mixed solvent (30 mL) which consists of hexane and ethyl acetate (3:1). The organic layer was washed with brine (30 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title reference compound (1.2 g) quantitatively as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C([O-])(=[O:19])C.[K+].[OH-].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:16][C@H:4]([CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2][OH:19]
Reactant: CC(=O)[O-]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Yield: 94 %

Procedure:
For the verification of the optical purity the compound obtained is hydrogenated on pre-hydrogenated platinum dioxide to (3R,7R)-1-chloro-3,7,11-trimethyldodecane; boiling point at 0.07 mm; 90°; αD =-1.2° (4.08% in CHCl3), which is converted by heating with dry potassium acetate in dimethylformamide (4 hours at 170°). This ester is purified by adsorption on silicagel (elution agent: n-hexane/ether 4+1), then further reacted to (3R,7R)-3,7,11-trimethyl-1-dodecanol by stirring with 4-N aqurous caustic potash (30 min. at room temperature). The mixture is extracted, washed neutral, dried, concentrated, distilled in the bulb-tube (115°, 0.20 Torr) and there is obtained (3R,7R)-3,7,11-trimethyl-1-dodecanol in 94% yield (based on (3R,7R)-1-chloro-3,7,11-trimethyldodecane employed). The product has an optical rotation value of [α]D20 =+3.7° (4.14% in n-octane) and is accordingly identical with authentic material.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[S:7]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18]C)=[O:17])[CH2:8]1>O.CO>[S:7]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([OH:18])=[O:17])[CH2:8]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCSC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC1CCSC1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A solution of potassium carbonate (7.4 g) in water (72 mL) is added, dropwise, to a stirred solution of methyl 3-(tetrahydrothiophen-3-oxy)-4-methoxybenzoate (11.8 g) in methanol (200 mL) at room temperature. After the addition is complete, the solution is stirred and heated at 60°-70° C. for 5 hours and allowed to stand at room temperature overnight. The solution is evaporated, the residue is dissolved in water, acidified with glacial acetic acid and the precipitate formed is collected and dried, to give 3-(tetrahydrothiophen-3-oxy)-4-methoxybenzoic acid (7.4 g). m.p. 177°-179° C. [Elemental analysis: C,55.3; H,5.5; calculated: C,56.7; H,5.55%].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[CH:16][CH:15]=3.C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:16]([N+:1]([O-:4])=[O:2])[CH:15]=3
Reactant: CC1(C)C(=O)Oc2ccc3ccc(Cn4cncn4)cc3c21
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)C(=O)Oc2ccc3cc([N+](=O)[O-])c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Nitric acid (72% by weight, 0.045 ml) was added dropwise to a stirred, ice-cooled mixture of 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone (0.44 g) and acetic anhydride (6 ml). The mixture was stirred at room temperature for 18 h, then added to a stirred mixture of aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography. Elution with ethyl acetate:pentane, 3:1 v/v, gave 1,1-dimethyl-7-nitro-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 183°-185° after recrystallisation from ethyl acetate. (Example 13).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[CH2:14][O:15]C(=O)C2C=CC=CC=2)=[CH:4][N:3]=1.CN>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:14][OH:15])[CH2:24][OH:25])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c2n1
Agent: CN
Product: Nc1ncc2ncn(COC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.844 g (1.88 mM) of 2-amino-9-[(2-benzoyloxyl-1-(benzoyloxymethyl)ethoxy)methyl]-9H-purine and 100 ml of a 40% aqueous methylamine solution was stirred at room temperature for 30 minutes. The mixture was flash evaporated to a yellow oil which was then washed with water. The aqueous layer was then extracted twice with methylene chloride. The aqueous layer containing the product was then flash evaporated to a light yellow oil. Recrystallization of the oil in hot acetonitrile yielded the title compound as an analytically pure ivory solid, mpt. 148°-151°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][C:49]=1[CH3:56]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:52][C:51]4[CH:54]=[CH:55][C:48]([F:47])=[C:49]([CH3:56])[CH:50]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1cc(CN)ccc1F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(F)c(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-fluoro-3-methylbenzylamine (Matrix) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([CH:22]=[CH2:23])=[CH:15]4)=[N:9][N:10]=2)[N:7]=1>[Pd].C(O)C>[CH2:22]([C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:11][C:8]1[N:6]3[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=1)=[CH:21][CH:20]=2)[CH3:23]
Reactant: C=Cc1cnc2ccc(Cc3nnc4ccc(C)nn34)cc2c1
Agent: [Pd]
Solvent: CCO
Product: CCc1cnc2ccc(Cc3nnc4ccc(C)nn34)cc2c1
Yield: 74.5 %

Procedure:
A mixture of 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-vinyl-quinoline (20 mg, 0.0664 mmol) and palladium on carbon (10% wt, 20 mg) in ethanol (1.5 mL) under a hydrogen atmosphere was stirred vigorously at ambient temperature for 4 hours. The mixture was then filtered through a pad of celite and the filtrate concentrated to provide the title compound (15 mg, 75% yield). Analytical data presented in Table 1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21](=[O:27])[CH:20]=[CH:19]2)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:42][CH2:43][NH:44][C:45](=[O:53])[O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]([CH2:42][CH2:43][NH:44][C:45](=[O:53])[O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:21](=[O:27])[CH:20]=[CH:19]2)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)CCOC(=O)NCCBr
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(ccc(=O)n2CCNC(=O)OCC[Si](C)(C)C)c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (0.4061 g, 0.812 mmol) in DMF (8.0 mL) was added potassium tert-butoxide (0.137 g, 1.22 mmol) and the mixture stirred for 30 minutes. A solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.327 g, 1.22 mmol) in DMF (1 mL) was added and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was cooled to 0° C., potassium tert-butoxide (0.200 g) was added and the resulting reaction mixture was stirred for 30 minutes. A solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.5 g) in DMF (1 mL) was added and the reaction mixture was warmed to room temperature overnight. Reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexanes) to give desired product a yellow foam (0.2725 g). Some O-alkylation side-product was also observed.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]I>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: O=C1CCN(Cc2ccccc2)C1
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
1-Benzyl-3-pyrrolidone [J. Org. Chem., 30., 740 (1965)] was allowed to react with methylmagnesium iodide to give 1-benzyl-3-hydroxy-3-methylpyrrolidine as an oil, b.p. 106° C./0.5 mmHg. This compound was treated with a mixture of acetonitrile and concentrated sulfuric acid under ice cooling to give 3-acetylamino-1-benzyl-3-methylpyrrolidine, m.p. 105°-106° C. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-acetylamino-3-methylpyrrolidine as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1.[CH3:25]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=Nc1cccnc1N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=Nc2cccnc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred suspension of 0.25 g (0.01 mole) of sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide was added, portionwise, 3.05 g (0.01 mole) of 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The mixture was warmed at about 60° C. for one hr. A solution of 1.42 g (0.01 mole) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over a 0.5 hr period and the reaction mixture stirred overnight at room temperature after which it was poured into 400 ml of water and stirred for 2 hr. The precipitated solid was recrystallized twice from isopropyl alcohol to give 2.0 g of product, m.p. 153°-6° C. Drying conditions prior to analyses were 1 hr at 82° C./0.1 mm Hg.