Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]1.CCN(CC)CC>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2N2CCC(CO)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 4-(3-chloro-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (39) (297 mg, 1 mmol) and piperidin-4-yl-methanol (35) (126.5 mg, 1.1 mmol) in DMSO (6 mL) was added Et3N (202 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give compound (40) (302 mg, 0.8 mmol, yield 80.32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:23])[C:12](=[O:15])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(=O)CC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(=O)CC2
Reaction time: 0.17 h

Procedure:
A solution of propyl (4-fluoro-7-oxo-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate in THF (0.17 M) was treated at −78° C. with a 1.0 M solution of NaHMDS in THF (1.2 eq.). After stirring for 10 min, MeI (2.0 eq.) was added. The cooling bath was removed and the mixture stirred for 1 hour, concentrated to dryness and the residue purified by chromatography on SiO2 (0-100% EtOAc/hexanes).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:52][O:51][CH2:50][CH2:49]1>>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([C:9]([N:8]2[CH2:49][CH2:50][O:51][CH2:52][CH2:6]2)=[O:40])[CH:15]=1
Reactant: C1COCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzamide (249 mg) described in Example 785 and morpholine (39 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (58 mg) was obtained.
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[C:18]([CH:17]1[CH2:4][CH:16]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C1CC1c1cccc(O)c1
Temperature: 15 °C
Yield: 99 %

Procedure:
To a 250 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 0.71 g (0.0178 moles) of 60% sodium hydroxide (oil suspension) and 50 mls of anhydrous DMSO. With stirring, under a nitrogen atmosphere, the trimethylsulfoxonium iodide (3.9 g, 0.0178 moles) was added in one portion, and the reaction was stirred at ambient temperature for 30 minutes. The mixture was then cooled to 15° C., and a solution of 3-hydroxychalcone (2.0 g, 0.0089 moles) was added dropwide in 10 mls of DMSO. The reaction was stirred for 1 hour at 15.10 C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 100 mls of 0.1N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 2.1 g of the tital compound, 2-benzoyl-1-(3-hydroxyphenyl)cyclopropane, as a thick yellow oil. 100% crude yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](=[O:32])([O-:31])[NH2:30].[CH:33]([OH:36])([CH3:35])[CH3:34]>>[C:14]([O:32][C:29](=[O:31])[NH:30][CH:34]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:33]([OH:36])[CH2:35][N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([C:21](=[O:22])[NH:20][CH:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24]1)([CH3:19])([CH3:13])[CH3:15]
Reactant: NC(=O)[O-]
Reactant: CC(C)O
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 70 °C

Procedure:
Piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. tert-Butyl[S-(R*, R*)]-(−)-(1-oxiranyl)-2-phenylethyl)carbamate (104.4 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (1%→20% methanol in methylene chloride) affording the desired product (166.7 mg) as an oil. ESMS: MH+ 642.6 (base).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[N:42]=[CH:41][N:40]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:39]=3)=[CH:35][CH:36]=2)[C:31]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[N:30]1>ClCCl>[CH:1]1([CH2:7][C:8]([NH:68][C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[C:34]([C:38]5[N:42]=[CH:41][N:40]([C:43]([C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)[C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[N:39]=5)[CH:33]=4)[N:29]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)[N:30]=3)[CH:63]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclohexylacetic acid (0.071 g, 0.498 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.105 g, 0.548 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. (Yield not calculated) ES-MS (m/z) 727 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:5].[CH3:13]OS(OC)(=O)=O>O1CCCC1>[CH3:3][C:4]([O:12][CH3:13])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:5]
Reactant: CC(C)=CCCC(C)(C)O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC=C(C)C
Reaction time: 16 h

Procedure:
To sodium hydride (93.5 g, 3.9 mol) suspended in tetrahydrofuran (300 mL) was added 2,6-dimethylhept-5-en-2-ol (500 g, 3.5 mol) in tetrahydrofuran (1000 mL). The mixture was heated at reflux until gas evolution was complete. Dimethylsulfate (274 mL, 2.9 mol) in tetrahydrofuran (226 mL) added to the cold (0~C.) mixture. After standing for 16 h, the mixture was heated at reflux for 7 hours. Aqueous workup yielded 2,6-dimethyl-2-methoxyhept-5-ene, bp40 65-68~C. (461.5 g); NMR(CDCl3) 1.2(s,6H), 1.4-1.6(m,2H), 1.6(s,3H), 1.7(s,3H), 1.9-2.1(m,2H), 3.2(s,3H), 5.1-5.2(m,1H); IR(neat) 2970, 2932, 1462, 1442, 1373, 1357, 1195, 1072 cm-1 ; MS(m/e) 41, 67, 73, 109, 124, 142.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]([NH:18][NH2:19])=[S:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28]>O1CCCC1.CCOCC>[CH3:14][C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:17][C:27](=[O:28])[NH:19][N:18]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:15]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)c1cc(C(=S)NN)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2n[nH]c(=O)s2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-benzene carbothioic acid, hydrazide (2.0 g, 0.0072 mole) in tetrahydrofuran (10 ml) is added triethylamine (0.39 g, 0.0039 mole) followed by carbonyl diimidazole (0.8 g, 0.0048 mole). The resulting mixture is stirred at 0° C. for one hour. Dilute with ether and extract product with 1M NaOH (2×). The combined aqueous layers are combined and made acidic with aqueous 6M HCl. The product is extracted with 1:1 ether/ethyl acetate. The combined organic extracts are washed with saturated aqueous NaCl and concentration in vacuo provides 1.4 g (2.2 g theor., 64%) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2(3H)-one after recrystallization from ethyl acetate/hexane: mp 229° C.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[NH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1>O>[N:8]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: C1=CCNCC1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CC=CCC1
Yield: 87.4 %

Procedure:
Monochloroacetic acid (8.5 g.) in water (10 ml.) was neutralised with sodium hydroxide (3.6 g.) in water (10 ml.). 1,2,5,6-Tetrahydropyridine (7.57 g.) was added. An exothermic reaction set in and after 30 minutes the pH of he dark red solution had changed from 9 to 8. After 24 hours the reaction mixture was evaporated, the residue was triturated with absolute ethanol ( 100 ml.) and filtered. The filtrate was evaporated, barium hydroxide (14 g.) in water (40 ml.) was added to the residue and evaporated repeatedly from water. The residue was redissolved in hot water, treated with CO2 gas, and filtered. The filtrate was evaporated to dryness and the residue, dissolved in hot absolute ethanol, (100 ml.) was acidified to pH 3-4 (2N H2SO4) and centrifuged to remove inorganic material. The supernatant liquor was evaporated to give 1,2,5,6-tetrahydropyridinyl acetic acid (11.1 g.) as an intractable dark brown gum.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][Sn](C)(C)C.[F-].[K+].O>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:11]
Reactant: C[Sn](C)(C)C
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: N#Cc1ccccc1
Product: CC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
A mixture of 2-chloronicotinic acid chloride (8.8 g, 49.5 mmol), tetramethyltin (5.5 mL, 40 mmol) and bis(benzonitrile)palladium(II) chloride (0.385 g) in 20 mL of hexamethylphosphoramide was stirred at room temperature for 20 hours. The mixture was stirred with 50 mL of 10% potassium fluoride and then poured into 50 mL of water. The mixture was extracted with diethyl ether (4×50 mL) and the combined extracts were washed with water, saturated sodium bicarbonate and sodium chloride, dried (Na2SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (3:1) to give 3-acetyl-2-chloropyridine (4.2 g, 27 mmol).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[C:17]([C:18]3[N:19]=[CH:20][N:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](O)=[O:27])[CH:22]=3)=[C:16]([CH3:32])[O:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1>>[CH:1]1([NH:5][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N:21]3[CH:22]=[C:18]([C:17]4[C:13]([C:9]5[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=5)=[N:14][O:15][C:16]=4[CH3:32])[N:19]=[CH:20]3)[CH:24]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CCC3)c2)cn1
Yield: 38 %

Procedure:
As described for Example 71c, cyclobutylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (44 mg, 38%) which was obtained as an off-white solid. MS: m/e=417.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCc1ccc(OCc2ccccc2)nc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(OCc3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Manufacturing Example 32-1-4 was added sodium hydride (5.50 g, 0.138 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. Thereafter, 2-benzyloxy-5-chloromethyl-pyridine (49.7 mg, 0.213 mmol) described in Manufacturing Example 191-1-2 was added to this mixture, which was stirred for 30 minutes at room temperature. This mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→ethyl acetate) to obtain the title compound (31.3 mg, 70.1%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,4-dichloroquinazoline (2 g, 10.05 mmol) in THF (50 ml) at 0° C. was added tert-butyl 4-aminopiperidine-1-carboxylate (2.2 g, 11.05 mmol), followed by TEA (2.8 ml, 20.1 mmol) and catalyst DMAP (3 mg). The reaction mixtures was then warmed up to room temperature and stirred for 20 hours. The product was extracted with EtOAc (×2). The organic layers were combined and washed with water, and brine, and dried (MgSO4) and concentrated under vacuum. The product was isolated after silica gel column chromatography using 20% EtOAc and 80% hexane as eluent.
Reaction SMILES: C(CCCOC1C=[CH:33][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:24]([C:25]#[N:26])=[CH:23][C:22]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[N:21]3)=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1)#N.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][CH2:43][CH2:44][CH:45]1[O:49][CH2:48][CH2:47][O:46]1.C[N:51]([CH:53]=[O:54])C>>[O:46]1[CH2:47][CH2:48][O:49][CH:45]1[CH2:44][CH2:43][CH2:42][O:54][C:53]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[C:24]([C:25]#[N:26])=[CH:23][C:22]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[N:21]3)=[CH:18][CH:19]=2)=[O:12])=[CH:33][N:51]=1
Reactant: N#CCCCOc1ccc(C(=O)Nc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cc1
Reactant: CN(C)C=O
Reactant: ClCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#Cc1cc(-c2cccnc2)nn1-c1ccc(NC(=O)c2ccc(OCCCC3OCCO3)nc2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-hydroxynicotinic acid methyl ester (prepared as describrd in Example 25) (10 mmol) in DMF (30 mL) was added cesium carbonate (10 mmol). After 30 minutes, 2-(3-chloropropyl)-1,3-dioxolane (10 mmol) was added and the reaction mixture was heated at 65° C. on an oil bath. After 2 days, the mixture was cooled to room temperature, volatiles were removed, the residue was taken up in water, and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. Chromatography of the residue over silica gel (eluent dichloromethane/ethyl acetate 9:1) gave the desired product as the faster eluting product (311 mg, 12%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C([O:15][C@@H:16]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][CH:17]1Cl)(=O)C>>[CH3:1][S:2][C:3]1[C:4]2[N:5]=[CH:6][N:7]([C@@H:17]3[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]3[OH:15])[C:8]=2[N:9]=[CH:10][N:11]=1.[C@@H:17]1([N:7]2[C:8]3[N:9]=[CH:10][N:11]=[C:3]([SH:2])[C:4]=3[N:5]=[CH:6]2)[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]1[OH:15]
Reactant: CSc1ncnc2nc[nH]c12
Reactant: CC(=O)OC[C@H]1OC(Cl)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: OC[C@H]1O[C@@H](n2cnc3c(S)ncnc32)[C@H](O)[C@@H]1O

Procedure:
6-Methylmercaptopurine riboside is synthesized by condensing 6-methylmercaptopurine with 2,3,5-tri-O-acetyl-D-ribo-furanosyl chloride using the catalyst mercuric chloride followed by deacetylation. Alternatively, 6-methylmercaptopurine riboside can be produced directly by methylation of 6-thioinosine (Fox, J. J. et al., J. Am. Chem. Soc. 80: 1669, 1958).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1.[H-].[Na+].P(O)(O)([O-])=O.[Na+].C(Cl)Cl.O1C[CH2:30][CH2:29][CH2:28]1>>[O:1]=[C:2]1[N:6]([CH2:30][C:29]#[CH:28])[C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)F
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCn1c(C(F)(F)F)c(C(=O)OCC)sc1=O

Procedure:
6.9 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-5-thiazole-carboxylate [prepared by the process of CA 92 110 998P]were dissolved in 70 ml of tetrahydrofuran at 0°±5° C. and then, 1.44 g of 50% sodium hydride in oil were added. Once the gaseous evolution ended, 15 ml of 2-bromopropyne were added and the mixture was refluxed for 48 hours. The mixture was poured on to an iced solution of monosodium phosphate and extraction was carried out with methylene chloride, then drying, filtering and concentrating under reduced pressure. The residue was chromatographed and elution with a hexane-ethyl acetate mixture (85-15) yielded 5.57 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH2:26])=[CH:16]1.CCN(C(C)C)C(C)C.O>CC(O)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=[C:2]([NH:26][CH2:25][CH2:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccn2)n1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: Clc1cc(NCCc2c[nH]c3ccccc23)nc(-c2ccccn2)n1

Procedure:
4,6-Dichloro-2-pyridin-2-yl-pyrimidine (Intermediate F) (1 eq, 8.85 mmol, 2.0 g) and 2-(1H-indol-3-yl)-ethylamine (1 eq, 8.85 mmol, 1.42 g) are dissolved in iPrOH (10 ml). DIPEA (2 eq, 17.7 mmol, 2.29 g) is added and the resulting mixture is heated using microwave radiation at 130° C. for 20 min. The reaction mixture is added to water and extracted with EtOAc. The combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue is crystallised from EtOAc giving the title compound [M+H]+=350.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:45])([F:44])[C:17]([F:43])([F:42])[C:18]([F:41])([F:40])/[CH:19]=[CH:20]/[C:21]([F:39])([F:38])[C:22]([F:37])([F:36])[C:23]([F:35])([F:34])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)=[CH:12][C:11]=1[N+:46]([O-])=O.C>O.CO.C1(C)C=CC=CC=1.C(=O)=O>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:35])[C:22]([F:36])([F:37])[C:21]([F:38])([F:39])[CH:20]=[CH:19][C:18]([F:40])([F:41])[C:17]([F:42])([F:43])[C:16]([F:44])([F:45])[C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([NH2:46])[CH:12]=2)=[CH:25][C:26]=1[NH2:31]
Reactant: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)C(F)(F)/C=C/C(F)(F)C(F)(F)C(F)(F)c2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: O=C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1cc(C(F)(F)C(F)(F)C(F)(F)C=CC(F)(F)C(F)(F)C(F)(F)c2ccc(O)c(N)c2)ccc1O
Yield: 54.2 %

Procedure:
Sodium dithionite (10 g) in 30 ml of water was added slowly with stirring at room temperature to a solution of 1.0 g (0.0017 mole) of trans-1,2-bis[3-(4-hydroxy-3-nitrophenyl)perfluoropropyl]ethylene (prepared as described in Example I) in 250 ml of methanol. The methanolic solution turned bright yellow and then slowly faded to water-white as reduction occurred. After addition of the sodium dithionite was completed, stirring was continued for an additional 30 minutes at which time water was added, resulting in a total solution volume of 750 ml. The resultant white slurry was extracted three times with 200 ml portions of ether and the combined ether extracts were washed repeatedly with water. The ether solution was then dried over anhydrous magnesium sulfate and stripped to dryness under reduced pressure to give a white residue. Most of this solid was soluble in 900 ml of hot toluene which was treated with charcoal and reduced in volume to 100 ml. Cooling in dry ice gave 0.5 g (55% yield) of the olefinic product as white platelets, mp 187°-188° C.