Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[NH2:11].[C:12]1([S:18]([Cl:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[ClH:21].[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[NH:11][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2ncccc2s1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2ncccc2s1)c1ccccc1
Reaction time: 16 h
Yield: 25.2 %

Procedure:
To a suspension of compound 146-A (0.65 g, 2.91 mmol) in pyridine (30 mL), at rt, was added benzenesulfonyl chloride (0.751 mL, 5.83 mmol), and the reaction was stirred for 16 h. Additional benzenesulfonyl chloride (0.225 mL, 1.76 mmol) was added and the reaction mixture was stirred at rt for an additional 16 h. The solvent was evaporated in vacuo, the residue treated with 1N HCl and extracted several times with dichloromethane and ethyl acetate. The aqueous layer was filtered, dissolved in methanol, and the combined organic extracts were evaporated in vacuo. The resultant residue was purified by reverse phase HPLC, eluting with an MeCN—H2O gradient to afford compound 146-B as an orange solid (0.24 g, 20%). 1H-NMR (CD3CN): δ 6.92 (s, 1H), 7.2 8.0 (d of d, 1H), 7.46 (m, 2H), 7.56 (m, 1H), 7.85 (m, 2H), 8.27 (d, 1H), 8.35 (d, 1H); MS: m/z 291.09 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CO)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[CH:15]=1.CCN=C=NCCCN(C)C.[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37]([S:41]([NH:44][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][C:16]=12)=[O:24])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: CC(C)(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (170 mg, 0.49 mmol) in dry DCM (10 mL) was added EDCI (288 mg, 1.5 mmol) followed by DMAP (0.18 g, 1.4 mmol) and stirring was continued at 25° C. for 2 h. To the reaction mixture was added tert-butyl sulfonamide (67 mg, 0.49 mmol) and the stirring was continued at 25° C. for 72 h. Reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous KHSO4 solution followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by combiflash chromatography followed by re-crystalisaiton from EtOH to afford (R)-N-(tert-butylsulfonyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as white solid. MS (ESI): m/z 463.2 (M+H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:9][CH2:10][C:11]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Resorcinol (275 g) was dissolved in acetic acid (560 mL) at 50° C. to prepare a solution. Separately, ethyl 4-chloroacetoacetate (205 g) was dissolved in acetic acid (187 ml), and concentrated sulfuric acid (100 mL) was added at 8° C. The solution was added at 8° C. to the resorcinol solution prepared in advance, and the mixture was stirred at 25° C. for 1 hr and at 60° C. for 3 hr. Warm water (3.24 L) was added at 40° C., and the mixture was stirred at 25° C. for 2 hr. The precipitated solid was collected by filtration. The solid was washed with water and air-dried to give the title compound (255 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH:20]=[C:21]4[CH2:26][CH2:27][C:28](O)=[O:29])[N:12]=2)=[CH:4][CH:3]=1.[NH2:32][O:33][C:34]([O:37][CH3:38])([CH3:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:35][C:34]([O:37][CH3:38])([O:33][NH:32][C:28](=[O:29])[CH2:27][CH2:26][C:21]1[C:22]2[C:17](=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH3:31])[CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH:20]=1)[CH3:36]
Reactant: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC(=O)O)c(C)o2)cc1
Reactant: COC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(C)(C)ONC(=O)CCC1=CCCc2c(OCCc3nc(-c4ccc(C)cc4)oc3C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a dimethylformamide (5 ml) solution of the compound (208 mg) prepared in Example 2 and 2-aminooxy-2-methoxypropane (57.7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg) and triethylamine (83 μl ) were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with methylene chloride. The diluted solution was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to thereby obtain the title compound (239 mg) having the following physical data.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[F:16][C:17]([F:35])([F:34])[C:18]([C:24]1[CH:29]=[CH:28][C:27](F)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].N1(C(OC(C)(C)C)=O)CCNCC1>>[C:12]([O:11][C:9]([N:3]1[CH2:4][C@@H:5]([CH3:8])[N:6]([C:27]2[CH:28]=[CH:29][C:24]([C:18]([OH:23])([C:17]([F:35])([F:34])[F:16])[C:19]([F:20])([F:21])[F:22])=[CH:25][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:7][C@@H:2]1[CH3:1])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Similar reaction and treatment as Example 43-b) was conducted except that (2S,5R)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate obtained in Example 14-1-a-2-2) was used in place of 1,1,1,3,3,3-hexafluoro-2-(4-fluoro-3-nitrophenyl)propan-2-ol obtained in Example 43-a) and tert-butyl piperazine-1-carboxylate, and the title compound was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:22][CH2:23][CH2:24][NH2:25]>>[OH:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and 2-hydroxylethylamine (20 μL) by a procedure similar to example 10 and was isolated as white solid (12 mg, 80%). 1H NMR (CDCl3): 7.43 (ddd, J=8.4, 1.5 and 0.9 Hz, 1H), 7.35 (ddd, J=7.8, 3.3 and 1.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.84 (dd, J=8.4 and 1.5 Hz, 1H), 6.66 (ddd, J=7.2, 6.3 and 1.5 Hz, 1H), 3.91-3.89 (m, 2H), 3.83 (s, 3H), 3.69-3.65 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH:1](O)=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH:19]=1)[NH2:18]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH:19]=1)[NH:18][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A mixture of formic acid (7.64 g) and acetic anhydride (16.9 g) was stirred at 60° C. for 2 hr then a solution (100 mL) of 5-methoxy-2-nitroaniline (9.30 g) in tetrahydrofuran was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution (200 mL) of the residue in tetrahydrofuran was added a 1.0M solution (140 mL) of borane-tetrahydrofuran complex in tetrahydrofuran at 0° C., and the mixture was stirred with heating under reflux for 2 hr. Methanol was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. After stirring, 1N hydrochloric acid was added to adjust to pH=2. The reaction mixture was stirred with heating under reflux for 1 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title object compound (6.30 g, 62%) as a colorless oil.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]1[CH:41]=[CH:40][C:21]([CH2:22][O:23][C@H:24]2[C@@H:36]([OH:37])[C@@H:35](O)[C@H:34]([CH3:39])[O:33][C@@H:25]2[S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[S:7]([O:37][C@H:36]1[C@@H:35]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C@H:34]([CH3:39])[O:33][C@H:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:24]1[O:23][CH2:22][C:21]1[CH:40]=[CH:41][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:8])=[O:6]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](O)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Trifluoromethanesulfonic anhydride (1.8 mL, 10.8 mmol) is added at 0° C. to a solution of phenyl 6-deoxy-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-14) (1.01 g, 2.69 mmol) and pyridine (2.2 mL, 26.9 mmol) in 30 mL of CH2Cl2. The solution is stirred at 0° C. for 1 h and allowed to warm at room temperature over 3 h. The reaction mixture is cooled to 0° C. before quenching with TEA (1.0 mL, 7.2 mmol). The reaction mixture is diluted with 30 mL of CH2Cl2, washed with saturated NaHCO3 (30 mL), 1N HCl (30 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (8% EtOAc/petroleum ether) to give 1.36 g (79%) of phenyl 6-deoxy-3,4-di-O-(trifluoromethanesulfonyl)-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-15): Rf 0.49 (20% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.48 (d, 2H, ArH), 7.33-7.21 (m, SH, ArH), 6.91 (d, 2H, ArH), 5.34 (t, J=2.0 Hz, 1H, H-3), 4.93 (d, J=9.2 Hz, 1H, H-1), 4.77 (d, J=11.2 Hz, 1H, CH2), 4.65 (d, J=11.2 Hz, 1H, CH2), 4.55 (dd, J=2.0, 8.8 Hz, 1H, H-4), 4.19-3.96 (m, 1H, H-5), 3.90 (s, 3H, OCH3), 3.47 (dd, J=2.0, 9.2 Hz, 1H, H-2), 1.36 (d, J=5.8 Hz, 3H, H-6).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.Cl[Si](C)(C)C.[CH:26]1C=CC=C[CH:27]=1>>[CH3:26][CH2:27][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
Reactant: c1ccccc1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: C[Si](C)(C)Cl
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Reaction time: 2 h

Procedure:
Another method is reported by Bhakuni et al. (Bhakuni R. S; Jain D. C and Sharma, R P., Indian J. Chemistry, 34B, 529-30 (1995). Arteether was prepared by dissolving dihydroartemisinin in alcohol and benzene mixture and then adding chlorotrimethylsilane as acid catalyst. The reaction was stirred for 2 hrs. at room temperature. The reaction mixture was washed with 10% sodium acetate solution and workup as usual method. The other products formed during the reaction were removed by column chromatography, to obtain pure arteether.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:15][O:16][CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(I)cc1
Yield: 88 %

Procedure:
Paraiodophenol (25 g) was dissolved in DMF (100 ml), followed by the addition of potassium t-butoxide (25 g) and methoxymethyl chloride (13 ml), and the mixture was reacted at 60° C. overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The resulting residue was subjected to a silica gel short column, to give 4-methoxymethoxy-1-iodobenzene as an oil (26.5 g, yield; 88%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[SH:12].[CH2:13]([N:20]1[C:28]2[C:27](Cl)=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.O>[CH2:13]([N:20]1[C:28]2[C:27]([S:12][C:5]3[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=3[CH3:3])=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc(C)c(S)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(Sc2nc(N)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred suspension of NaH (48 mg, 2 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl-benzene-1-thiol (191 mg, 1.2 mmol) The mixture was and stirred at room temperature for 30 min under argon. The reaction mixture was then added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (103 mg, 0.4 mmol) in dry NMP (2.5 mL) and heated at 60° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:3) to give the product as a light yellow solid (131 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.ClCCCl.N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:36](=[O:37])[O:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a suspension of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (196.8 mg, 0.6201 mmol) in 1,2-dichloroethane (6.0 mL, 76 mmol) was added pyridine (0.15 mL, 1.8 mmol) and p-nitrophenyl chloroformate (0.1406 g, 0.6975 mmol). The reaction mixture was stirred at room temperature for 2 hours and then pyridine (0.15 mL, 1.8 mmol) and p-nitrophenyl chloroformate (131.9 mg, 0.6544 mmol) were added. After an additional hour at room temperature, the reaction mixture was evaporated in vacuo and purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-100% ethyl acetate in heptanes) to yield 114.8 mg (38%) of 4-nitrophenyl 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamate. LCMS (ESI): M+H=483.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.90 (d, J=8.9 Hz, 2H), 6.54 (d, J=5.8 Hz, 2H), 2.14-2.02 (m, 4H), 0.85 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.[Na]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: O=C1CCC(O)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: OC1CCC(N2C[C@@H]3COCCN3c3nc(Cl)ncc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
To (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol) and 4-hydroxycyclohexanone (126 mg, 1.103 mmol) in CH2Cl2 (8 mL) was added titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) dropwise to give an orange suspension. The reaction mixture was stirred at ambient temperature for 4 hours and then cooled to 0° C. Sodium triacetoxyhydroborate (514 mg, 2.427 mmol) was added in two portions. The reaction mixture was stirred for 1 hour and then quenched with aqueous saturated NH4Cl (1 mL). The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a colorless foam (30 mg, 8%). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O2, 325.14; found 325.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].B1C2CCCC1CCC2.C([O-])(C)(C)C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C1COCC1.CCCCC>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:7][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Reactant: O=C(CBr)c1ccccc1
Agent: B1C2CCCC1CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)C2CCC(CCC(=O)c3ccccc3)C1C2
Temperature: -78 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
1.36 g (−)-β-pinene (10 mmol) was dissolved in 5 ml THF. 21 ml of a 0.5-molar solution of 9-BBN in THF (10.5 mmol) was added to this solution at 0° C. The reaction mixture was slowly brought to room temperature and stirred for a further 3 hours. The resulting solution was cooled to −78° C., and a solution of 1.12 g potassium tert-butanolate (10 mmol) in 10 ml THF was then added to the cooled reaction solution. After a short time, 2 g α-bromacetophenone (10 mmol) was added in portions with constant stirring. The reaction mixture was slowly brought to room temperature and stirred for 4 hours at room temperature. The resulting product mixture had 50 ml n-pentane added to it, and washed three times in each case with 10 ml of a 3N sodium hydroxide solution and with 10 ml water. The organic phase was dried over magnesium sulfate. Solvent was removed from the filtrate at reduced pressure. The raw product was purified by column chromatography. 140 mg (10%) of the aforesaid product was obtained.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.Cl.NC1[N:21]=[CH:22][NH:23][C:24]=1[C:25]([NH2:27])=[O:26].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[N:21]3[CH:22]=[N:23][C:24]([C:25]([NH2:27])=[O:26])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2ccnc3c(C(N)=O)ncn23)cc1OC
Yield: 53.8 %

Procedure:
A stirred mixture of 15.0 g of 3-dimethylamino-3',4'-dimethoxyacrylophenone (prepared as described in Example 6) and 8.0 g of 4-amino-5-imidazolecarboxamide hydrochloride in 150 ml of glacial acetic acid was heated at reflux for 24 hours. The solvent was evaporated in vacuo to give an oil. The oil solidified on standing at room temperature, and this was treated with 200 ml of saturated sodium bicarbonate solution and then it was filtered to collect the crystals. The material was treated by boiling with 700 ml of ethanol and then was filtered. The solid was recrystallized from methanol-chloroform to give 7.9 g of the desired product, mp 262°-265° C.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=O)[CH:4]=[C:5](SC)[S:6]C.O.[NH2:14][NH2:15]>C(O)C>[C:2]([C:3]1[N:14]=[N:15][C:5](=[S:6])[CH:4]=1)([CH3:12])([CH3:11])[CH3:1]
Reactant: CSC(=CC(=O)C(C)(C)C)SC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1=CC(=S)N=N1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a stirred solution of 4,4-dimethyl-1,1-bis(methylthio)-1-penten-3-one (18.4 g) in ethanol, was added dropwise with stirring hydrazine hydrate (5.3 g), keeping the temperature below 25°. The reaction mixture was stirred briefly at room temperature, then refluxed for 2 hours. Evaporation of the solvent, and trituration with ether, afforded 3-t-butylpyrazole-5-thione (7.8 g, 20% yield), of melting point 147°-8°.