Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:16]#[C:17][Si](C)(C)C)[CH:7]=[CH:8][C:9]=1[CH2:10][O:11][C:12]1([CH3:15])[CH2:14][CH2:13]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:16]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2([CH3:15])[CH2:13][CH2:14]2)=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)#[CH:17]
Reactant: CC(C)c1cc(C#C[Si](C)(C)C)ccc1COC1(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(COC2(C)CC2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane (Intermediate 165, 110.0 mg, 0.37 mmol) in methanol (6 mL) was treated with potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature. The crude alkyne (84 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13]C(OC(C)(C)C)=O)=[CH:8][CH:9]=1)=[O:4].C(OC(=O)NCC#C)(C)(C)C.COC(C1SC(Br)=CC=1)=O>C(#N)C.CCOC(C)=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Agent: C#CCNC(=O)OC(C)(C)C
Agent: COC(=O)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(CCCN)s1
Temperature: 25 °C

Procedure:
5-(3-tert-Butoxycarbonylamino-prop-1 ynyl)-thiophene-2-carboxylic acid methyl ester, A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetonitrile under nitrogen was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH:1]([C:4]1[C:5]([CH:10]=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccnc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)c1cccnc1C=O
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a vigorously stirred solution of (3-isopropyl-pyridin-2-yl)-methanol (26 g, 170 mmol) in CH2Cl2 (575 mL) was added MnO2 (105 g, 1.20 mol) under N2. The mixture was stirred for 18 h then filtered through a celite pad and concentrated in vacuo. Purification by column chromatography on silica gel (EtOAc/hexanes, 1:3) afforded 3-isopropyl-pyridine-2-carbaldehyde (15.65 g, 61%) as an orange oil. 1H NMR (CDCl3) δ 1.26 (d, 6H, J=7.0 Hz), 4.17 (sep, 1H, J=6.6 Hz) 7.45 (dd, 1H, J=7.9, 4.4 Hz), 7.84 (d, 1H, J=7.9 Hz), 8.56 (dd, 1H, J=4.4, 1.3 Hz), 10.2 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@@H:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[C@H:6]([C:19](OCC)=[O:20])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C@@H:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[C@H:6]([CH2:19][OH:20])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(C)=O)CC[C@H]1N1CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)N1CC[C@@H](N2CCc3ccccc32)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of trans-1-(1-acetyl-3-ethoxycarbonyl-piperidin-4-yl)indoline (780 mg) in ethanol (40 ml) was added sodium borohydride (5.7 g) in 3 portions at 30 min. intervals. After stirring at room temperature overnight, sodium borohydride (3.3 g) was added thereto and the resultant mixture was stirred for additional 4 hr. Then ethyl acetate (20 ml) and water (50 ml) were successively added carefully to the reaction mixture followed by extraction with ethyl acetate (50 ml) for three times. The organic phase was washed with water (100 ml) twice and brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give the title compound (250 mg) as a yellow powder (yield: 39%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH2:18][CH3:19])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=2)[C:5]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)[C:5]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)O

Procedure:
A mixture of 4.0 g of 6 and 0.4 g of sodium hydroxide in 50 ml of 50% ethanol was refluxed for 45 minutes, then concentrated to dryness. The residue was mixed with water, the mixture was acidified with hydrochloric acid and extracted with ether. The ether was evaporated from the extract and the residue was recrystallized from ether-hexane to give 8, as a white solid, m.p.: 98° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:39][C:40]1[CH:45]=[C:44]([S:46]([CH3:49])(=[O:48])=[O:47])[CH:43]=[CH:42][C:41]=1[N:50]1[C:54]2=[N:55][CH:56]=[N:57][C:58]([O:59][CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[C:53]2[CH:52]=[N:51]1.C(N(CC)CC)C>CN(C=O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:63]2[CH2:64][CH2:65][CH:60]([O:59][C:58]3[N:57]=[CH:56][N:55]=[C:54]4[N:50]([C:41]5[CH:42]=[CH:43][C:44]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:45][C:40]=5[F:39])[N:51]=[CH:52][C:53]=34)[CH2:61][CH2:62]2)=[O:10])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(OC(F)F)cc5)CC4)ncnc32)c(F)c1
Reaction time: 24 h
Yield: 12.1 %

Procedure:
4-Difluoromethoxy-benzoic acid (527 mg, 2.8 mmol) and HATU (1.06 g, 2.8 mmol) were stirred together in DMF at room temperature for 30 min. 1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (800 mg, 1.87 mmol) and triethylamine (785 μL, 5.61 mmol) were added next. The resulting mixture was allowed to stir for 24 hours. Progress of the reaction was monitored by TLC and LCMS. Removal of organic solvents in vacuo and purification by HPLC afforded Compound A193 as a beige solid (127 mg, 32%). Exact mass calculated for C25H22F2N5O5S 561.53, found 562.2 (MH+)
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=3)[C:20]#[N:21])[N:11]=2)=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=3)[C:20]#[N:21])[N:11]=2)=[CH:8][CH:9]=1)=[O:2]
Reactant: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(C#N)c3)no2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1C#N
Temperature: 60 °C
Yield: 101.8 %

Procedure:
5-(5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.086 g, 0.227 mmol) and p-toluenesulfonic acid monohydrate (0.043 g, 0.227 mmol) were added in acetone (10 ml) to give a colorless solution. The reaction mixture was heated at 60° C. for 2 hr. The solution was cooled, the reaction mixture was concentrated, the residue was purified via silica gel chromatography (12 g, 50% EtOAc:Heptane) to afford 5-(5-(4-formylphenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g, 0.231 mmol, 102% yield) as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:30].CCOCC>CO>[ClH:30].[ClH:30].[C:24]1([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[O:17])[CH2:19][CH2:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 2-(4-phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (6.67 g, 16.5 mmol) in MeOH (10 mL) was added 2M HCl in Et2O solution (16.5 mL, 32.9 mmol). The brown solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 15% (over 75 min) MeOH in water with 0.1% TFA). The pure sample was stirred in a 4M aq HCl solution (20 mL) overnight before being concentrated in vacuo. The resulting yellow oil was washed with heptane, concentrated in vacuo and dried in a vacuum oven overnight to give the morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate dihydrochloride salt (4.72 g, 76%) as a pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1>CO.[Pd]>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([F:18])[C:10]([F:19])=[C:9]([OH:8])[CH:14]=1)[CH3:17]
Reactant: CCOc1cc(F)c(F)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(O)c(F)c(F)c1
Yield: 74.9 %

Procedure:
A solution of 1-benzyloxy-5-ethoxy-2,3-difluoro-benzene (which may be prepared as described in Description 60) (546 mg, 2.07 mmol) in methanol (10 mL) was passed through a 10% Pd—C H-cube cartridge at 1 ml/min. The solution was passed through the H-cube a second time. Chromatography on silica (elution with DCM) gave 5-ethoxy-2,3-difluoro-phenol (D61) (270 mg);
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1OCc1cccc(Cl)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCc3cccc(Cl)c3)n2)c1

Procedure:
Example 28 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {2-[(3-chlorobenzyl)oxy]phenyl}boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:16][CH:17]([CH2:20][O:21][C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][OH:19])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.Cl>N1C=CC=CC=1>[C:1]([O:16][CH:17]([CH2:20][O:21][C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][OH:19])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=1)([O-:15])(=[O:45])=[O:44]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCC
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C

Procedure:
2,3 Dimyristoylglycerol (600 mg, 1.4 mmol) was dissolved in pyridine and the solution cooled to 0° C. The solution was stirred under a nitrogen atmosphere and p-toluenesulfonyl chloride (300 mg, 1.57 mmol) was added. The solution was allowed to warm to room temperature and was then stirred overnight at ambient temperature. To the solution was added hydrochloric acid (2.5M, 20 mL) and the solution was extracted three times with methylene chloride (25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude oil. The oil was purified by flash chromatography (50 g of silica gel, 60 Å) eluting with 5% ethyl acetate/hexane. The oil obtained by flash chromatography was dried under high vacuum at ambient temperature to give 2,3-Dimyristoylglycerol-tosylate(630 mg, 77% yield).
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH3:4][N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8].O>>[C:1](=[O:8])([OH:3])[OH:2].[CH3:4][N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]
Reactant: O=C=O
Agent: CN(CCO)CCO
Solvent: O
Product: O=C(O)O

Procedure:
Carbon dioxide was introduced into a mixture of 305.5 g of N-methyldiethanolamine (2.28 mol) and 47 g of water (1.68 mol) while the mixture was cooled with ice. 33.7 g of CO2 (0.74 mol) had been absorbed at this temperature after 3 days.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17](=[O:23])[CH:18](Cl)[C:19]([CH3:21])=O>CO.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:14][C:18]([C:17]([O:16][CH3:15])=[O:23])=[C:19]([CH3:21])[N:13]=2)=[CH:8][CH:7]=1
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccc(OCCCCl)cc2)nc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzenecarbothioamide ax71 (34.67 mmol, 1 eq, 7.96 g), and 2-chloroacetoacetic acid methyl ester (34.67 mmol, 1 eq, 5.2 g) in methanol is stirred at 70° C. for 2 hours. The reaction mixture is then poured into a sealed tube and stirred at 100° C. for 3 hours. The mixture is taken up in dichloromethane and washed with water then dried over magnesium sulfate. The solvent is removed under reduced pressure to give 11.8 g of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i105. The product is used as such in the next step.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH-].[K+]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2c(c1)OCCO2
Yield: 67.1 %

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carboxaldehyde (2.03 g, 12.4 mmol), was slurried in water (50 ml) at 80° C. Potassium permanganate (2.70 g, 17.1 mmol) as a solution in water (50 ml) was added over 1 hour. The mixture was then heated for a further 2 hours after which time the reaction mixture was basified with 10% aqueous potassium hydroxide. The resulting precipitate was removed by filtration and washed with water (2×50 ml). The combined filtrates were acidified with concentrated hydrochloric acid and the resulting solid isolated by filtration and dried under vacuum. This provided the desired compound as a white solid (1.50 g, 67%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:38])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[CH:54][N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[C:51](Cl)[N:50]=1>C(O)(C)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:38])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:51]2[N:50]=[C:49]([Cl:48])[N:57]=[C:56]3[C:52]=2[N:53]=[CH:54][N:55]3[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](N)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(Cl)nc7c6ncn7C6CCCCO6)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 25 °C

Procedure:
(2R,3R,4R,5R)-2-{6-[(trans-4-Aminocyclohexyl)amino]-2-chloro-9H-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 4) (7.9 g) was dissolved in isopropanol (200 ml) and stirred at room temperature under nitrogen. N,N-diisopropylethylamine (10 ml) was added followed by 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.92 g). The mixture was stirred at 60° C. under nitrogen for 18 h. The reaction mixture was allowed to cool to room temperature and evaporated down in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous extracted twice with ethyl acetate. The organic phases were combined, dried (MgSO4), and evaporated down in vacuo to give the title compound (10.35 g). Used without purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1>>[F:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-fluoropyrimidine. ESI-MS (m/z): 410, 471 [M+1]+.
Reaction SMILES: Cl.C(O)C.C([O:7][C:8](=[O:34])[CH2:9][C:10]1[S:11][C:12]2[C:13]([O:32]C)=[CH:14][C:15]3[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=3[C:17](O)([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:18]=2[CH:19]=1)C.[OH-].[Na+]>O>[CH3:26][N:23]1[CH2:22][CH2:21][C:20](=[C:17]2[C:16]3[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=3[CH2:14][C:13](=[O:32])[C:12]3[S:11][C:10]([CH2:9][C:8]([OH:34])=[O:7])=[CH:19][C:18]2=3)[CH2:25][CH2:24]1
Reactant: CCOC(=O)Cc1cc2c(s1)C(OC)=Cc1ccccc1C2(O)C1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCC(=C2c3ccccc3CC(=O)c3sc(CC(=O)O)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Hydrochloric acid (8 mL) was added to an ethanol (24 mL) solution of the compound obtained in Example 16 (2.0 g, 4.7 mmol), and the mixture was refluxed while heating overnight. The solvents were distilled off, water (20 mL) and sodium hydroxide (0.8 g, 20 mmol) were then added to the residue, and the mixture was stirred at room temperature overnight. The property of the solution is adjusted to a pH of 6.5 with hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 0.68 g (39%) of the captioned compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Sn]([N:31]=[N+:32]=[N-:33])(C)C>C1(C)C(C)=CC=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[NH:33][N:32]=[N:31][N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(C#N)ccc32)n1)c1ccccc1
Solvent: Cc1ccccc1C
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4nnn[nH]4)ccc32)n1)c1ccccc1
Yield: 26.6 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-cyanobenzimidazol-1-yl ]pyrimidine (20 mg) and trimethylstannylazide (18 mg) were heated (110° C.) in xylene for 15 hours. Upon cooling, the solution was evaporated to dryness and the residue was purified with preparatory thin-layer chromatography (SiO2, 5% MeOH/1% triethylamine in CH2Cl2) to yield 6 mg of the title compound Mass spectrum (ESI) 384.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1>>[O:27]1[C:26]2[CH:31]=[CH:32][C:23]([N:18]3[CH2:19][CH2:20][N:15]([C:5]4[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]5[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=5[C:6]=4[CH3:14])[CH2:16][CH2:17]3)=[CH:24][C:25]=2[O:30][CH2:29][CH2:28]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc4c(c3)OCCO4)CC2)c(C)c2c1OC(C)(C)C2
Yield: 22.5 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 6-bromo-2,3-dihydro-1,4-benzodioxine (484 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 143 mg (yield 15%). Melting point was 167 to 168° C. (hexane).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21](OC(=O)C)(=[O:23])C>C(O)=O>[CH2:14]([S:13][C:4]1[N:3]=[C:2]([NH:1][CH:21]=[O:23])[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nc(SCc2ccccc2)nn1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1nc(SCc2ccccc2)nn1-c1ccccc1

Procedure:
5-Amino-3-benzylthio-1-phenyl-1,2,4-triazole (45 g) was suspended in acetic anhydride (31 ml) and formic acid (16.09 ml), and the mixture was stirred for 1 hour at 80° C. The solvents were then removed, and the residue was recrystallised from ethyl acetate to give 35.4 g of the desired product, mp 94° C.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:12]=1
Reactant: OCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 32 h
Yield: 71.9 %

Procedure:
Methyl 4-hydroxy cinnamate (40 g, 225 mmol) was dissolved in 1-methyl-2-pyrrolidinone (NMP, 300 mL). 6-Chlorohexanol (269 mmol, 36.8 g), anhydrous K2CO3 (37.2 g, 269 mmol) and catalytic amount of KI were added. The batch was stirred at 90° C. for 32 hours. Water was added to the cooled solution, which was subsequently extracted with ethyl acetate (EtOAc, 3×200 mL). The combined organics were washed with 10% KOH (2×100 mL), brine solution and then dried over MgSO4. The concentrated product was then recrystallized from a 1:1 mixture of EtOAc/hexanes to give 45 g (72% yield) of an off-white solid.