Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH3:2][C@H:3]1[C@@H:13]2[CH2:14][CH2:15][C@:16]3([CH3:20])[O:18][O:19][C@:12]42[C@H:6]([C@@H:7]([CH3:21])[C:8](O[C@@H:11]4[O:17]3)=[O:9])[CH2:5][CH2:4]1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.S(=O)(=O)(O)O>ClCCl>[CH3:21][C@H:7]1[C:8](=[O:9])[NH:1][CH:11]2[O:17][C@@:16]3([CH3:20])[O:18][O:19][C:12]42[C@H:6]1[CH2:5][CH2:4][CH:3]([CH3:2])[CH:13]4[CH2:14][CH2:15]3
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Reactant: N
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1CC[C@H]2[C@@H](C)C(=O)NC3O[C@]4(C)CCC1C32OO4
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a saturated solution of methanolic ammonia (12 ml) at room temperature was added artemisinin (1.128 g, 4 mmol). The solution was stirred for 1.5 hours and concentrated under reduced pressure to give a light yellow solid. The solid was dissolved in dichloromethane (180 ml), and 2,6-di-tert-butyl-4-methylphenol (BHT) (80 mg, 0.36 mmol), 15% sulphuric acid (0.8 ml), and silica gel (8.0 g) were added in succession. After stirring overnight at room temperature, the reaction mixture was filtered and the silica gel washed with dichloromethane. The combined organic solution and washes were concentrated under reduced pressure. Column chromatography of the residue on silica gel with acetone:dichloromethane (8:92) gave crystalline solid 11-azaartemisinin (510 mg, 45%): mp 143-145° C.; Rf=0.40 (acetone:CH2Cl2, 15:85); [α]25D=−40.9° (c 0.127, CH2Cl2); IR 3313, 3223, 2928, 2873, 1668 cm−1; CIMS (NH3) 299 (M+NH4+, 76), 282 (M+1,100); 1H NMR δ 0.93-1.01 (2H, m), 0.93 (3H, d, J=5.5 Hz), 1.07 (3H, d, J=7.2 Hz), 1.30 (3H, s), 1.25-1.42 (3H, m), 1.61-1.70 (2H, m), 1.71-1.77 (1H, m), 1.92 (2H, dm, J=10.2 Hz), 2.34 (1H, m), 3.17 (1H, pent, J=6.8 Hz), 5.33 (1H, s), 5.93 (1H, bs).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[C:21]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl>C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cccc(F)c4Cl)CC3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (41, 125 mg, 0.27 mmol) in CH2Cl2 (2 mL) was added HCl (2.0 N solution in Et2O, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to give (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride as a white solid (42, 93 mg, 86%): 1H NMR (300 MHz, DMSO-d6) δ 9.37 (br s, 2H), 7.42-7.21 (m, 3H), 5.31-5.13 (m, 1H), 4.74-4.57 (m, 1H), 4.25-4.14 (m, 2H), 3.44-3.14 (m, 4H, overlaps with H2O), 3.00-2.75 (m, 3H), 1.93-1.77 (m, 2H), 1.70-1.47 (m, 2H) missing N—H pyrazole; ESI MS m/z 363 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][CH3:13])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([O:23][CH2:24][C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][CH3:13])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCNc1cccc(N)c1C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzamide (3 g) in methylene chloride (100 ml) is added pyridine (3 ml), and thereto is added dropwise acetoxyacetyl chloride (2.0 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (2.5 g) having the following physical properties.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([CH3:48])([CH3:47])[C@H:12]3[C@:25]([CH3:28])([CH2:26][CH:27]=2)[CH:24]2[C@:15]([CH3:46])([C@@:16]4([CH3:45])[C@H:21]([CH2:22][CH2:23]2)[C@H:20]2[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]2([C:35]([O:37]CC2C=CC=CC=2)=[O:36])[CH2:18][CH2:17]4)[CH2:14][CH2:13]3)=[CH:6][CH:5]=1)=[O:3].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51]>>[CH3:45][C@:16]12[C@@:15]3([CH3:46])[CH:24]([C@:25]4([CH3:28])[C@@H:12]([CH2:13][CH2:14]3)[C:11]([CH3:47])([CH3:48])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:2](=[O:3])[NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[CH:5][CH:6]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22][C@@H:21]1[C@H:20]1[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]1([C:35]([OH:37])=[O:36])[CH2:18][CH2:17]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(N)(=O)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6ccc(C(=O)NS(C)(=O)=O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from the procedure described above for (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-benzyl 9-(4-(chlorocarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate using methanesulfonamide as the reactant sulfonamide. The title compound was isolated as a white solid (3.2 mg, 7%). LCMS: m/e 636.51 (M+H)+, 2.13 min (method 7). 1H NMR (500 MHz, DMSO-D6) δ ppm 0.88 (d, J=3.05 Hz, 6H), 0.94 (s, 6H), 0.98 (s, 3H), 1.11-1.62 (m, 15H), 1.63-1.72 (m, 5H), 1.77-1.88 (m, 2H), 2.03-2.17 (m, 2H), 2.24-2.35 (m, 1H), 2.97 (d, J=4.58 Hz, 1H), 3.57 (s, 3H), 4.58 (s, 1H), 4.71 (d, J=1.83 Hz, 1H), 5.23 (d, J=4.58 Hz, 1H), 7.17 (d, J=8.24 Hz, 2H), 7.86 (d, J=8.24 Hz, 2H), 12.03 (s, 1H), 12.10 (br. s., 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](S)=[N:8][C:7]=2[CH:12]=1>C(O)(=O)C.[Fe]>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:12]=1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2scnc2c1
Temperature: 110 °C

Procedure:
Into a solution of 5-(trifluoromethyl)-1,3-benzothiazole-2-thiol (500 mg, 2.13 mmol, 1.00 equiv) in acetic acid (15.0 mL) was added Fe (1.2 g, 10.00 equiv). The resulting solution was heated for 3 h at 110° C. in an oil bath. The solid was filtered out and washed with ethyl acetate. The filtrate was concentrated under reducing pressure, dissolved in 30 mL of ethyl acetate, washed with 50 mL of saturated sodium bicarbonate solution and 50 mL of brine respectively and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent provided 0.45 g (crude) of the title compound, which was used for next step without further purification. MS m/z [M+H]+ (ESI): 204
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:7]([OH:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[C@@H:3]([O:9][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[CH2:4][CH2:5][CH2:6][C:7]1=[O:8]
Reactant: CC1(C)C(=O)CCC[C@@H]1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)C(=O)CCC[C@@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
(3S)-2,2-dimethyl-3-hydroxycyclohexanone (3) (5.12 g, 36.0 mmoles) and dihydropyran (5.00 g., 59.0 mmoles) were dissolved in dry methylene dichloride (90 ml). The solution was cooled in an ice bath, and p-toluenesulfonic acid (50 mg) was added. The resulting mixture was stirred at room temperature for 2 hours. After the reaction, a saturated aqueous solution of sodium hydrogencarbonate was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The product was filtered, concentrated, and purified by distillation. Amount yielded 8.14 g (yield 99.9%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Nc1nnc(-c2cc(F)cc(F)c2)c(-c2ccccc2)n1
Yield: 47.3 %

Procedure:
6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (160 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,5-difluorophenylboronic acid (0.20 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[N:16]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[N:9]=1.N1CCCCC1CC1N=C2C=CC=CN2N=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[S:77][C:76]([CH3:78])=[N:75][C:74]=2[C:79](O)=[O:80])=[CH:69][CH:68]=1>CN(C=O)C>[F:66][C:67]1[CH:68]=[CH:69][C:70]([C:73]2[S:77][C:76]([CH3:78])=[N:75][C:74]=2[C:79]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[N:16]=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[O:80])=[CH:71][CH:72]=1
Reactant: C1CCC(Cc2nc3n(n2)CCCC3)NC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccn2nc(CC3CCCCN3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccn3n2)c(-c2ccc(F)cc2)s1

Procedure:
The mixture of 2-piperidin-2-ylmethyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridine and 2-piperidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a]pyridine, D34 (0.220 g) was treated with HATU (0.380 g), N,N-diisopropylethylamine (1.0 ml) and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (0.240 g) in dry DMF, according to the procedure described in Example 60. The crude product was chromatographed (silica gel, 4% methanol-diethyl ether) to afford 1-[5-(4-fluoro-phenyl)-2-methylthiazol-4-yl]-1-(2-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethylpiperidin-1-yl)-methanone as a colourless foam (0.070 g) (Mass spectrum (API+): found 436 (MH+): C23H22FN5OS requires 435). Continued elution (10% methanol-diethyl ether) afforded 1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethyl)-piperidin-1-yl]-methanone as a colourless foam (0.230 g) (Mass spectrum (API+): found 440 (MH+): C23H26FN5OS requires 439).
Reaction SMILES: CC([N:5]([C@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@@H](C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl((1S)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 66, 70 mg) in dichlorometane (2.5 mL) cooled down to 0° C. TFA (0.779 mL, 10.11 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 hours and then evaporated. The residue was diluted with dichloromethane (10 mL) and neutralized with a saturated aqueous solution of NaHCO3 (15 mL). The organic phase was separated, dried over sodium sulphate, filtered and evaporated to afford the title compound as a yellow pale oil (53.1 mg).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (24.1 mg, 69.4%), MS (ISP) m/z=435.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1SC.[N+:9]([CH2:12][C:13]([O:15]C)=[O:14])([O-:11])=[O:10]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:12]([N+:9]([O-:11])=[O:10])[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCN1C
Agent: [Cl-]
Agent: [Zn+2]
Product: CN1CCNC1=C(C(=O)O)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
19.5 g of 1A, 17.8 g of methyl nitroacetate and a small amount of zinc chloride were mixed and the mixture was heated to 100°-105°. After 30 minutes, the solid reaction mixture was washed with ether, then with hot methanol. The mixture was filtered to give the methyl ester of (1-methyl-2-imidazolidinylidene)nitroacetic acid (1B) as a tan solid, m.p.: 209°-210°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[C:25]([C:32](O)=[O:33])=[CH:24]2>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:25]1[C:26]([CH3:31])=[N:27][C:28]2[C:23]([CH:24]=1)=[CH:22][C:21]([F:20])=[CH:30][CH:29]=2)=[O:33]
Reactant: Cc1nc2ccc(F)cc2cc1C(=O)O
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc2cc(F)ccc2nc1C

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-fluoro-2-methyl-quinoline-3-carboxylic acid. MS: 447.4 (M+H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:12][CH2:13][C:14]#[N:15].[H-].[Na+]>CN(C=O)C>[C:14]([CH2:13][CH2:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])#[N:15]
Reactant: N#CCCBr
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCn1cnc2c(N)ncnc21
Yield: 75 %

Procedure:
As shown in Scheme 4, alkylation of adenine 10 with 3-bromopropionitrile in the presence of NaH in DMF gave N9-(cyanoethyl)adenine 15 in 75% yield. Reaction of 15 with methyl iodoacetate and lithium 2,2,6,6-tetramethylpiperidine (Li TMP) in THF afforded a mixture of N7-alkylated product 16 (60% yield) and N9-isomer 17 (20% yield). Reduction of the ester group in 16 with NaBH4 in wet THF13 gave N7-(hydroxyethyl)adenine 18 in 55% yield. Conversion of 18 to phosphonate 19 (60% yield) was accomplished by use of diethyl (p-toluenesulfonyloxymethane)phosphonate and sodium tert-butoxide in DMF.14 Treatment of compound 19 with Me3SiBr15 then afforded phosphonic acid 20 in 45% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])=[CH:10][CH:11]=2)[O:6][C:5](=[O:26])[CH:4]=1.Cl.[OH-:28].[Na+]>>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:9]1[CH:10]=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:26])=[O:28])=[CH:2][O:6][C:7]=2[CH:8]=1)(=[O:15])=[O:16])([O-:25])=[O:24]
Reactant: O=c1cc(CCl)c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2o1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1coc2cc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-[4-(chloromethyl)-2-oxo-2H-chromen-7-yl]-2-nitrobenzenesulfonamide (14.3 g, 36.2 mmol) and 1 M aqueous sodium hydroxide solution (120 mL) was stirred at room temperature for 24 hr. The reaction mixture was acidified with 1 M hydrochloric acid, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (13.6 g, quant.) as pale-brown crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:14]2[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:21])[C:17]([OH:35])=[C:16]([OH:36])[N:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:7][C:8]1([C:14]2[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:21])[C:17]([OH:35])=[C:16]([OH:36])[N:15]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1(c2nc(O)c(O)c(C(=O)NCc3ccc(F)cc3S(C)(=O)=O)n2)CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(C2(N)CCOCC2)nc(O)c1O

Procedure:
A solution of tert-butyl-4-[4-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-5,6-dihydroxypyrimidin-2-yl]tetrahydro-2H-pyran-4-yl-carbamate (C-31) in dichloromethane was treated with an excess of trifluoroacetic acid for 3 hours at room temperature. The acid in excess was removed in vacuo to obtain the crude title compound (C-32) as a pale yellow solid, after trituration with ethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:15]=1)[O:7][CH2:8][CH2:9][C:10]([CH:13]=O)=[C:11]2Cl.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:24][C:23]([C:22]([O:26][CH3:27])=[O:25])=[CH:13][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:15]=1
Reactant: O=CC1=C(Cl)c2ccc(Br)cc2OCC1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 50 °C
Yield: 78 %

Procedure:
(Z)-8-Bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde 9 was dissolved in 10 mL DMF and treated sequentially with potassium carbonate (2.20 g, 16.6 mmol) and methyl thioglycolate (0.83 mL). The whole was heated at 50° C. overnight, cooled to room temperature, diluted with water and extracted with ethylacetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (20-50% ethylacetate in hexanes) to give 2.20 g (78% yield) 10 as a colorless solid. 1H NMR (DMSO-d6, 500 MHz) 7.70 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.31-7.28 (m, 2H), 4.32 (t, J=5.0 Hz, 2H), 3.84 (s, 3H), 3.21 (t, J=5.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C1(C)C(C)=CC=CC=1>[OH:12][C:13]1[C:6]2[C:7](=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=2)[N:8]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Cc1ccc(N)c(C)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc2c(C)nc(C)cc2c1O
Temperature: 25 °C
Yield: 29.2 %

Procedure:
A mixture of 2,6-dimethyl-3-aminopyridine (0.85 g) and diethyl ethoxymethylenemalonate (1.53 g) is heated at 135° C. in xylene (30 mL) for 2 h allowing for removal of ethanol. After the solvent is removed, the mixture is suspended in diphenyl ether (15 mL). The mixture is then heated to reflux with removal of ethanol for 30 min. The reaction mixture is cooled to room temperature and hexanes (20 mL) is added. The resulting precipitate is filtered, washed with diethyl ether (2×10 mL) and dried to give 0.5 g (30%) of the title compound as a brown solid. Physical chracteristics: MS (ESI+) m/z 247 (M+H)+; 1H NMR (DMSO) δ 8.67, 7.97,4.38, 2.85,2.67, 1.40.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[N:26][CH:25]=[CH:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13].[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[N:26][CH:25]=[CH:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13]
Reactant: O=C1c2cnccc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN2C(=O)c3cnccc3C2C1
Temperature: 90 °C

Procedure:
A mixture of 2-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-1,3,4,10b-tetrahydropyrido[4′,3′:3,4]pyrrolo[1,2-a]pyrazin-6(2H)-one (250 mg), trimethylboroxin (0.190 mL), potassium carbonate (189 mg) and Pd(PPh3)4 (103 mg) was heated to 90° C. under argon for 18 hours. The reaction mixture was partitioned between EtOAc and aqueous saturated sodium bicarbonate solution. The aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine, dried through a hydrophobic frit and evaporated to a brown oil. This was purified by chromatography eluting with 0-5% methanol in DCM over 12 column volumes. The clean fractions were combined and evaporated to a pale yellow gum. This was purified further to remove triphenylphosphine oxide by MDAP. The clean fraction was evaporated to give the title compound as a white solid (46 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1>O.C(O)C.[Fe](Cl)(Cl)Cl.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[CH:20][C:13]=12
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]ccc23)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Nc2ccnc3[nH]ccc23)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Variant B: A solution of 10 mg (60 μmol) of iron(III) chloride in 2.40 ml of water and then 38 mg (170 μmol) of powdered iron are added to a solution of 16 mg (60 μmol) of N-(2-chloro-4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 3.60 ml of ethanol. After 3 h of stirring at 80° C., the suspension is filtered through kieselguhr and the kieselguhr is washed with ethanol. The solvent is removed under reduced pressure and the residue is dissolved in a mixture of dichloromethane/methanol 10:1 and crudely purified by column filtration on silica gel. This gives 22 mg of a crude product which is directly reacted further without further purification.