Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:8])(=O)/[CH:2]=[CH:3]\C([O-])=O.[N:9]1([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C1OC2C=CC(C(Cl)=O)=CC=2O1>CN(C)C=O>[C:1]([N:12]1[CH2:13][CH2:14][N:9]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:11]1)(=[O:8])[CH2:2][CH3:3]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N1CCN(c2ncccn2)CC1
Temperature: 130 °C

Procedure:
5.6 g of acid maleate of 2-(1-piperazinyl)pyrimidine are dissolved in 80 ml of dimethylformamide, then 5.6 ml of triethylamine and 3.8 g of 3,4-methylenedioxy benzoyl chloride are added. The mixture is heated for 12 hours at 130° C. then the solvent is evaporated to dryness in vacuo. The residue is taken up in a dilute solution of hydrochloric acid and washed with ether. The aqueous phase is rendered alkaline by a sodium carbonate solution and extracted with ethyl acetate. The solution is dried over sodium sulfate and the solvent is evaporated to dryness.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].[CH2:10]([C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[N:22][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClCCl>[CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[CH:19][C:18]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][N:22]=2)=[CH:29][CH:28]=1)=[O:5]
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC(=O)[C@@H](Cl)[C@@H](C)CC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of (S,S)-3-methyl-2-chloropentanoic acid, 16 g of p-(5-n-octylpyrimidin-2-yl)phenol, 11.6 of N,N-dicyclohexylcarbodiimide, 0.6 g of 4-N,N-dimethylaminopyridine and 300 ml of dichloromethane is stirred overnight at room temperature. After filtering off the precipitated urea derivative, the filtrate is washed with dilute hydrochloric acid and water, and the organic phase is worked up in the usual manner. p-(5-n-Octylpyrimidin-2-yl)-phenyl (S,S)-3-methyl-2-chloropentanoate is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24]/[N:25]=[C:26](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+].Cl>CN(C)C=O.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24]/[N:25]=[C:26](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (1.65 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (1.04 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 200 mg) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate (1.60 g, yield 64%) as crystals. Recrystallization from ethyl acetate-hexane gave pale yellow prisms. m.p. 67-69° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol) m.p. 154°-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 6H), 2.35 (s, 6H), 3.40 (m, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.11 (dt, 2H), 7.20 (s, 1H), 7.27 (d, 1H), 7.45 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(-n2ccc(NC(=O)c3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.17 g, 0.50 mmol) and 4-dimethylaminopyridine (0.01 g) in pyridine (10 mL) was added benzoyl chloride (0.07 mL, 0.60 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours, and water (100 mL) was added. The title compound was precipitated as a solid which was collected by filtration and washed with water and t-butylmethyl ether (0.17 g, 76%): mp 246-248° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.78 (t, J=5.7 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 7.95-7.90 (m, 2H), 7.66-7.47 (m, 3H), 7.35-7.18 (m, 6H), 6.94 (dd, J=7.8, 2.1 Hz, 1H), 4.39 (d, J=5.7 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 161.9, 161.0, 153.8, 150.3, 149.4, 139.8, 134.1, 132.9, 131.6, 129.0, 128.7, 128.4, 127.7, 127.2, 123.9, 104.2, 103.9, 43.1, 17.5; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3[NH:27][N:26]=[N:25][N:14]=3)=[CH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)sc2-c2ccc(F)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3nnn[nH]3)sc2-c2ccc(F)cc2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (3.1 g), sodium azide (1.3 g) and ammonium chloride (1.5 g) in N,N-dimethylformamide (30 ml) was stirred at 120° C. for 24 hours. The mixture was poured into ice-water, and the resulting mixture was acidified. The precipitates were collected and recrystallized from ethanol to give crystals of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(5-tetrazolyl)thiophene (0.9 g).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[C:35]([C:39]2[N:40]=[C:41]([CH3:44])[S:42][CH:43]=2)[CH:36]=[CH:37][CH:38]=1)=[C:31]=[O:32]>C1COCC1>[CH3:44][C:41]1[S:42][CH:43]=[C:39]([C:35]2[CH:34]=[C:33]([NH:30][C:31]([N:16]3[CH2:15][C:14]4[CH:13]=[N:12][C:11]5[NH:10][N:9]=[CH:8][C:20]=5[C:19]=4[CH2:18][CH2:17]3)=[O:32])[CH:38]=[CH:37][CH:36]=2)[N:40]=1
Reactant: Cc1nc(-c2cccc(N=C=O)c2)cs1
Reactant: c1nc2[nH]ncc2c2c1C[NH2+]CC2
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(NC(=O)N3CCc4c(cnc5[nH]ncc45)C3)c2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate (0.100 g, 0.25 mmol) in THF (5 mL) and Hunig's Base (0.26 mL, 1.50 mmol) was added 4-(3-isocyanatophenyl)-2-methylthiazole (0.0567 g, 0.25 mmol). The reaction was shaken at room temperature for 2 hours. The solvent was then removed under reduced pressure followed by addition of 1 M Na2CO3 (5 mL) and EtOAc (10 mL). The organic layer was separated, washed with water (3×10 mL) followed by adding water (10 mL). The EtOAC was then removed under reduced pressure. A white solid crashed out which was filtered, washed with water, dried under reduced pressure to give the pure desired product, N-(3-(2-methylthiazol-4-yl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a white solid (0.069 g, 71%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (1.95 g, 12.2 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.66 g, 13.5 mmol). The mixture was stirred at reflux for 2 h. The resulting suspension was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 50% MeOH/acetone (75 mL). The suspension was stirred at reflux for 5 min. The solid material was filtered and washed with acetone (2×25 mL). This allowed the isolation of compound O, 1.74 g (51%).
Reaction SMILES: CI.[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][NH:7]1)(=[O:5])[NH2:4].[C:21](=O)(O)[O-].[Na+]>CN(C)C=O>[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:8][N:7]1[CH3:21])(=[O:5])[NH2:4]
Reactant: O=C([O-])O
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.07 ml of methyl iodide was added, whilst ice-cooling, to a solution of 0.6 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (5) above] dissolved in 4.5 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 5 minutes and at room temperature for 20 minutes. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep Si 60, size B), and 252 mg of the title compound, melting at 113°-114° C., were obtained as crystals from the fractions eluted with a 9:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].C(N(CC)CC)C.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1>Cl.ClCCl>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])=[CH:18][CH:17]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A mixture of 2 g of L-alanine ethyl ester in hydrochloride form and 1.83 ml of triethylamine in 30 ml of dichloromethane is stirred at room temperature for 10 minutes. Next, 2.05 g of quinoline-4-carbaldehyde are added. The reaction medium is stirred at room temperature for 15 hours and then concentrated under reduced pressure. 35 ml of ethanol are then added; the solution is cooled to 0° C. and 0.49 g of sodium borohydride is then added portionwise. Stirring is continued for 15 hours at room temperature. The precipitate formed is filtered off; the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on a column (SiO2, CH2Cl2/MeOH, 95/5 by volume as eluent, Ar). 0.71 g of ethyl (S)-2-[(quinol-4-ylmethyl)amino]propanoate is obtained in the form of a pink oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([SH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](Br)[C:32]#[CH:33]>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19][CH2:33][C:32]#[CH:31])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(S)c2)c(Cl)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCSc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 16 h

Procedure:
2.0 g of 3-chloro-2-(4-chloro-3-mercaptophenyl)-5-trifluoromethylpyridine (prepared as in Example 33) and 2.1 g of potassium carbonate were introduced into 50 ml of anhydrous dimethylformamide amide at 23° C. After a dropwise addition of 0.73 g of propargyl bromide, the mixture was stirred for 16 h and then poured into 300 ml of water. After 30 minutes, the crystals which had formed were removed, washed with water and dried.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+].C([BH3-])#[N:20].[Na+]>CO.CCOC(C)=O>[CH3:13][O:12][C:10](=[S:11])[CH2:9][CH:8]([NH2:20])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=S)CC(=O)Cc1ccccc1
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=S)CC(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a solution of methyl phenylthioacetoacetate (1.00 g, 4.5 mmol) in MeOH (20 ml), ammonium formate (4.26 g, 6.75 mmol) and sodium cyanoborohydride (0.42 g, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc and partitioned into 1M HCl. The aqueous layer was then basified to pH=8.0 with NaOH. The desired product was extracted out with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated to yield 0.61 g yellow oil; MS (NH3 -CI/DDIP) Calc. for (M+H)+ : 226. Found: 226; 1H NMR (300 MHz, CDCl3)δ 7.39 (d, J=7, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=10, 1H), 3.74 (s, 3H), 3.39-3.31 (m, 1H), 3.13-3.07 (dd, J=13, J'=9, 1H), 2.91-2.83 (dd, J=12, J'=6, 1H), 2.65-2.58 (dd, J=12, J'=6, 1H), 2.46-2.38 (dd, J=16, J'=8, 1H).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][NH2:20]>C(Cl)Cl>[CH2:19]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][N:13]2[C:6](=[O:7])[NH:20]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC1CCCCN1
Solvent: ClCCl
Product: O=C1NCC2CCCCN12

Procedure:
A solution of CDI (830 mg, 5.1 mmol) and piperidin-2-ylmethanamine (520 mg, 4.6 mmol) in DCM (20 mL) was stirred at room temperature overnight. After the solvent was removed, the residue was directly used for the next step without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@H:23]3[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:19][C:20]=2[CH2:21][CH2:22]3)=[CH:9][CH:8]=1.[C:33]([O-])(=[S:35])[CH3:34].[K+]>>[C:33]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@H:23]3[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:19][C:20]=2[CH2:21][CH2:22]3)=[CH:9][CH:8]=1)(=[S:35])[CH3:34]
Reactant: CC([O-])=S
Reactant: C[C@]12C[C@H](c3ccc(OCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [K+]
Product: CC(=S)CCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Yield: 82.2 %

Procedure:
The operation is carried out as in Stage E of Example 8 starting with 1.18 g of the product obtained in Stage D and 460 mg of potassium thioacetate. 850 mg of expected product is obtained. M.p. #90° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][O:17][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Methyl (4S)-4-[(tert-butoxy)carbonylamino]-5-hydroxypentanoate (9.11 mmol, 2.25 g) was dissolved in 30 mL of methylene chloride. p-Toluenesulfonyl chloride (9.1 mmol, 1.7 g) and triethylamine (27.33 mmol, 3.8 mL) were added and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and crude was purified by column chromatography (SiO2, 4:1 n-hexanes/ethyl acetate to 7:3 n-hexanes/ethyl acetate) to yield the title compound (1.98 g, 54% yield). ES-MS: 402 (M+1).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][O:33]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:31]=[CH:30][C:20]([NH:21]C(=O)C2C=CC=CC=2)=[N:19][C:17]1=[O:18])C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:31]=[CH:30][C:20]([NH2:21])=[N:19][C:17]1=[O:18]
Reactant: O=C(Nc1ccn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)n1)c1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)n1

Procedure:
To a solution of nucleoside 57 (0.3 g, 0.55 mmol) in anhydrous methanol (22 cm3) were added 1,4-cyclohexadiene (5.0 cm3) and 10% palladium on carbon (0.314 g). The mixture was stirred under reflux for 18 h. Additional 10% palladium on carbon (0.380 g) and 1,4-cyclohexadiene (5.5 cm3) were added and the mixture was refluxed for 54 h. The reaction mixture was filtered through a pad of silica gel which was subsequently washed with methanol (1500 cm3). The combined filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (92.5:7.5, v/v) as eluent to give compound 57A as a white solid material (0.051 g, 36%). δH ((CD3)2SO) 7.73 (1H, d, J 7.7, 6-H), 7.12-7.20 (2H, br s, NH2), 5.74 (1H, d, J 7.7, 5-H), 5.61 (1H, br s, 3′-OH), 5.39 (1H, s, 1′-H), 5.12 (1H, m, 5′-OH), 4.08 (1H, s, 2′-H), 3.80 (1H, d, J 7.7, 1″-Ha), 3.81 (1H, s, 3′-H), 3.74 (2H, m, 5′-Ha, 5′-Hb), 3.63 (1H, d, J 7.7, 1″-Hb). δC ((CD3)2SO) 165.66 (C-4), 154.58 (C-2), 139.68 (C-6), 93.19 (C-5), 88.42, 86.73 (C-1′, C-4′), 78.87, 70.85, 68.32, 56.04 (C-2′, C-1″, C-3′, C-5′). FAB-MS m/z 256 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:16]1
Reactant: C1CNCCN1
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCOc1ccc(C2CCCC(N3CCNCC3)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone (80 mg) and piperazine (24 mg) were dissolved in dichloroethane (5 ml) and stirred at ambient temperature for 1 hr under argon. Tetramethylammonium triacetoxyborohydride (79 mg) was added and stirring continued under argon. After 16 hr, additional portions of piperazine (24 mg) and tetramethylammonium triacetoxyborohydride (79 mg) were added and stirring continued. After a further 6 hr, glacial acetic acid was added dropwise until a solution was obtained, and stirring continued at ambient temperature. After a further 16 hr, the reaction mixture was partitioned between sodium hydrogen carbonate (20 ml of a saturated solution) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography chromatography (SiO2, dichloromethane/methanol, 9:1 v/v) to furnish the title compound as an off white solid (52 mg, 53%) and mixture of diastereoisomers; m/z (ES+) 365 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[N:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:39][CH3:40])[CH:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:38][O:37][C:35]1[N:36]=[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:32]=[C:33]([O:39][CH3:40])[N:34]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: COc1cc(Cl)nc(OC)n1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)nc(OC)n1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of 3.70 g (0.00924 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 1.61 g (0.00924 mol) of 6-chloro-2,4-dimethoxypyrimidine, 1.29 ml (0.00924 mol) of triethylamine and 125 ml of ethylene glycol is heated at 100° C. for 6 hours. After cooling, the precipitated solid is collected on a sintered glass funnel and dried in the air over the weekend. The solid is chromatographed on silica gel, eluting with 6% methanol/methylene chloride, to give 2.15 g (43%) of 1-(2,6-dimethoxy-4-pyrimidinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 260°-262° C., after crystallization from methanol/methylene chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH2:10]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN
Solvent: CCO
Product: CNc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33% solution in ethanol, 84.43 mmol) and warmed to 80° C. for 3 days. After this time the reaction is concentrated and the remaining solid is treated with 1M HCl (50 ml) and DCM. The layers are separated and the aqueous phase is basified using 1N NaOH (to pH-11). The product was extracted into DCM (2×) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g). 1H-NMR (400 MHz, DMSO-d6): 2.75 ppm (d, 3H), 6.44 ppm (d, 1H), 6.72 ppm (bs, 1H), 7.51 ppm (dd, 1H), 8.05 ppm (s, 1H)