Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B#B.[F:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>O1CCCC1>[F:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: O=C(O)COc1ccc(F)cc1
Agent: B#B
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCCOc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To 200 ml of 1 Molar diborane in tetrahydrofuran (chilled to 5°-10° C.) is added dropwise 17.0 g of 2-(p-fluorophenoxy)acetic acid in 100 ml of tetrahydrofuran. The mixture is stirred overnight and poured into 100 g of ice and 250 ml of chloroform. The organic layer is separated and the aqueous layer extracted with chloroform. The organic layer and extracts are combined, dried (MgSO4) and the solvent removed under vacuum. The residual pale yellow oil is distilled to give the product (14.8 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Cc1ccc(CBr)cc1
Product: COP(=O)(Cc1ccc(C)cc1)OC

Procedure:
Following the procedure of Compound 11, 4-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [ClH:1].Cl.C[CH:4]([C:23](=[O:25])[OH:24])[CH2:5][C@H:6]([C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[NH2:7].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1.[Li+].[OH-].Cl>>[ClH:1].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:7][C@@H:6]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[CH2:14][CH2:15]3)=[O:9])[CH2:5][CH2:4][C:23](=[O:25])[OH:24])=[O:36])[CH:33]=2)[CH:28]=[CH:27]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(C2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Prepared from 1-[(γ-methyl)-D-glutamyl]-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride and indole-6-carboxylic acid using methods substantially equivalent to General Coupling Method 1. Ester deprotection with 2 eq LiOH and final purification and HCl salt formation via prep HPLC.
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[CH2:6]([C:8]1[CH:9]=[CH:10]C(C=C)=[N:12][CH:13]=1)[CH3:7].BrN1C(=O)CCC1=O.[OH-].[Na+]>O>[CH2:9]([C:8]1[CH:6]=[CH:7][C:2]([CH:1]2[CH2:3][O:5]2)=[N:12][CH:13]=1)[CH3:10]
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(CC)cn1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C2CO2)nc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 750 mL tert-butanol and 2250 mL water, 200 g (1.488 mol) of 5-ethyl-2-vinyl-pyridine was dissolved and under stirring 324 g (1.786 mol) N-bromosuccinimide was added in 30 min. at 25-30° C. Stirring was continued for 1 hr, and 178.6 g (4.46 mol) of NaOH dissolved in 2250 mL water was added into it. Reaction mixture was stirred for 45 min. Product was extracted twice with 1100 mL methyl tert-butyl ether. Organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 206.13 g (92%) of 6.
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:18])[CH2:4]1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:18])[CH2:4]1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1CC(=O)N1CC(=O)CCc1ccccc1
Solvent: ClCCl
Product: CS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of 4-methylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (0.4 g, 1.5 mmol) in dichloromethane (40 ml) was cooled to -60° C. To this a solution of meta-chloroperbenzoic acid (m-CPBA, 0.52 g, 1.5 mmol) in dry dichloromethane (50 ml) was added dropwise over 10 minutes, maintaining the temperature between -50 and -60° C. The mixture was stirred at room temperature for 60 minutes, washed with dil. Na2SO3, dil. NaHCO3, H2O (×2) and dried (MgSO4). Evaporation under reduced pressure gave a residue which was purified by flash chromatography on silica gel using ethyl acetate then petroleum ether/ethyl acetate to give 4-methylsulphinyl-1-(4-phenyl-2-oxobutyl)azetidin-2-one as a waxy yellow solid (0.18 g, 43%). 1H NMR demonstrated that this was a 1:1 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Cl[Si](C)(C)C.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>CN(C=O)C.C(N(CC)CC)C>[OH:5][CH2:1][CH2:2][C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCO
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCO)c21
Temperature: 70 °C

Procedure:
Using Method I above, 3-butyn-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL DMF and 2 mL triethylamine, and to this solution was added chlorotrimethylsilane (0.13 mL, 1 mmol). The reaction was stirred at room temperature for 1 h, at which time (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) was added and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P)2PdCl2 (13 mg) and Cul (7 mg) were added and the reaction was heated at 70° C. for 14 h. The reaction mixture was then poured into 25 mL 1N HCl and the yellow precipitate was filtered off. The product was purified via flash column chromatography to obtain (Z)-1,3-dihydro-4-(4-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 35 mg, 30%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)(C)(C)C.[ClH:24]>O1CCOCC1.C(OCC)C>[ClH:24].[ClH:24].[ClH:24].[N:17]1([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[CH2:12][CH2:13]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(N2CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCCN1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of (3-[1,4′]bipiperidinyl-1′-yl-propyl)-carbamic acid tert-butyl ester (2.15 g, 6.6 mmol), dry dioxane (40 mL) and 6.5 N hydrogen chloride in dioxane (22 mL) was stirred at room temperature overnight, then diluted with diethyl ether and stirred at 0° C. for 1 h. The precipitated crystals were filtered off, washed with diethyl ether and dried to yield 2.03 g (92%) of the title compound as a beige solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][C:65]([OH:67])=[O:66].C(O)(=O)C>CO>[C:65]([CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:67])=[O:66]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.052 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 192) and 204 μl einer of a 15% aqueous solution of 4-oxobutanoic acid were combined in 2 ml of methanol and admixed with 23.4 mg (0.252 mmol) of borane-pyridine complex and 6 μl of acetic acid. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions, 38 mg (78% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25]C(=O)C)[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[CH:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25][S:34]([CH:31]5[CH2:33][CH2:32]5)(=[O:36])=[O:35])[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[CH:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-n3cccc3)c2)cn1

Procedure:
The compound was prepared from the compound of Example 87 using the procedures of Example 88 and cyclopropane sulfonyl chloride. 1H-NMR (300 MHz, DMSO-d6): δ 10.2 (s, 1H), 8.71 (s, 1H), 8.2 (s, 1H), 7.99 (m, 1H), 7.95 (s, 1H), 7.68-7.59 (m, 3H), 7.44-7.41 (m, 4H), 6.31 (m, 2H), 3.95 (s, 3H), 2.95 (m, 1H), 1.0 (m, 4H); LC-MS (ESI): Calculated mass: 458.54; Observed mass: 459.2 [M+H]+ (rt: 1.29 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]([N+:26]([O-])=O)([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C>[Zn]>[NH2:26][C:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[N:15]=1)([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCCCCCCOc1ccc2nc(C(C)(C(=O)OCC)[N+](=O)[O-])ccc2c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCCOc1ccc2nc(C(C)(N)C(=O)OCC)ccc2c1
Temperature: 10 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
Ethyl 2-(6-heptyloxyquinolin-2-yl)-2-nitropropanoate (325.0 mg, 0.0008366 mol) was dissolved in acetic acid (5 mL, 0.09 mol), and cooled to at 10° C., followed by zinc (547.1 mg, 0.008366 mol;) in very small portions to keep the temperature constant. The reaction mixture was then allowed to stir for additional for 5 hours, and filtered through a Celite pad. The excess is of solvents were removed under vacuum, and the residue was purified via HPLC (10-100% acetonitrile with 0.1% formic acid) to give a pure product (57.0 mg, 14%). 1H NMR (CHLOROFORM-d) δ: 8.05 (d, J=8.5 Hz, 1H), 7.94 (d, J=9.3 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.36 (dd, J=9.3, 2.5 Hz, 1H), 7.06 (d, J=2.5 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.07 (t, J=6.5 Hz, 2H), 1.77-1.93 (m, 5H), 1.44-1.57 (m, 2H), 1.28-1.44 (m, 6H), 1.22 (t, J=7.2 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H). MS (M+1): 359.30.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:68]=[CH:67][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([C:46]3[N:47]=[CH:48][N:49]4[CH:53]=[C:52]([Sn](CCCC)(CCCC)CCCC)[S:51][C:50]=34)=[O:45])[CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:52]3[S:51][C:50]4=[C:46]([C:44]([CH:41]5[CH2:40][CH2:39][N:38]([C:36]([O:35][CH2:34][C:33]6[CH:67]=[CH:68][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH2:43][CH2:42]5)=[O:45])[N:47]=[CH:48][N:49]4[CH:53]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)C5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)CC5)c4s3)[C@H](C)[C@H]12
Yield: 59.1 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.16 g) was prepared in the same manner as in step a) of Example 1, except that 938 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.91 g of 7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5C=CN=CC=5)=[CH:26][C:25]=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C2[N:49]=[C:48]([CH3:50])[O:47][N:46]=2)=CC=1)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:49]=[C:48]([CH3:50])[O:47][N:46]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C#Cc1ccc(-c2noc(C)n2)cc1
Product: Cc1nc(-c2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)no1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 3-(4-ethynyl-phenyl)-5-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CCO>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:23][CH2:24]1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: C1COCCN1
Solvent: CCO
Product: O=C(CN1CCOCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 100 °C
Yield: 29.9 %

Procedure:
To a solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) in EtOH (5 mL), morpholine (63 μL, 0.706 mmol) was added and the reaction mixture was heated at 100° C. for 20 hrs. Upon completion, the solvent was removed in vacuo and the crude oily residue was purified by preparative LCMS to afford 2-morpholino-N-(3-(quinoxalin-2-yl)phenyl)acetamide (35 mg, 30% yield). LCMS calculated for C20H20N4O2 (M+H): 349.40. found 349. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.98 (1H, br.), 9.53 (1H, s), 8.55 (1H, m), 8.13-8.20 (2H, m), 8.05-8.08 (1H, m), 7.82-7.98 (3H, m), 7.55-7.60 (1H, m), 3.70 (4H, m), 3.20 (2H, s), 2.58 (4H, m).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([O:23][CH3:24])=[O:22]>C(OCC)(=O)C>[CH3:24][O:23][C:21]([C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[O:22]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)[C@@H]1CCCCN1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCCC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.333 g, 10.77 mmol) was added to (S)-methyl piperidine-2-carboxylate (2.93 g, 20.46 mmol) neat while stirring. The reaction was stirred 1 h at 90° C., cooled to room temperature and taken up in ethyl acetate (10 mL). The mixture was purified by SiO2 (330 g, 20-30% EA in Hexanes) to yield 3.4 g (98%) of the title compound as a yellow oil. [M+H] calc'd for C14H17N3O6, 324; found, 324.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH:14]=[O:15])=[C:11]([CH3:16])[C:10]=2[CH:17]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:14]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:18])=[CH:17][C:10]=3[C:11]=2[CH3:16])[OH:15])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCCN(C)c1ccc2oc(C=O)c(C)c2c1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COCCN(C)c1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of 5-[(2-methoxyethyl)(methyl)amino]-3-methyl-1-benzofuran-2-carbaldehyde (0.09 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (2 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.11 g, quantitative) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][O-:25].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[O-]
Reactant: COCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Agent: [Na+]
Solvent: CO
Product: COCCNc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Reaction time: 4 h
Yield: 44 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-methoxyethyl)aminopurine (68 mg, 0.18 mmol) was dissolved in 28% sodium methoxide in methanol (30 ml) and the solution was refluxed on heating under stirring for 4 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (26 mg, yield 44%).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Na].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2.[H-].[Na+]>CN(C)C=O.ClCCl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:18]=[CH:17]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triisopropylsilyl chloride (6.87 g) was added to the sodium salt prepared from 5bromoindole (6.35 g) and sodium hydride (1.71 g, 50% suspension in oil) in dimethylformamide (32 ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150 ml). The crude intermediate obtained by evaporation of the dichloromethane extract was column chromatographed (silica gel, 40°-60° C. petroleum ether) to give 5-bromo-1-triisopropylsilylindole isolated as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[O:41]=[S:37]1(=[O:40])[CH2:36][CH2:35][CH:34]([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:39][CH2:38]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCC(S(=O)(=O)c2ccccc2Br)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 4-((2-bromophenyl)sulfonyl)tetrahydro-2H-thiopyran 1,1-dioxide. MS (ESI): mass calcd. for C21H20FN3O4S2, 461.09; m/z found, 462.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.07-8.04 (m, 2H), 7.92 (m, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.49 (dd, J=7.5, 1.0, 1H), 7.38-7.31 (m, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.74 (s, 2H), 3.25-3.06 (m, 5H), 2.16-2.04 (m, 2H), 2.02-1.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15]O)[C@@H:12]([OH:13])[C@H:10]1[OH:11].S(Br)([Br:29])=O.S(Cl)(Cl)=O>>[Br:29][CH2:15][C@H:14]1[O:17][C@@H:9]([N:8]2[C:18]3[N:19]=[C:2]([Cl:1])[N:3]=[C:4]([NH:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:5]=3[N:6]=[CH:7]2)[C@H:10]([OH:11])[C@@H:12]1[OH:13]
Reactant: O=S(Br)Br
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=S(Cl)Cl
Product: O[C@@H]1[C@H](O)[C@@H](CBr)O[C@H]1n1cnc2c(NN3CCCCC3)nc(Cl)nc21
Yield: 9 %

Procedure:
This compound was prepared by general method C, described in more detail in Example 2. 2-Chloro-N-(1-piperidinyl)adenosine [WO 93/08206 (Novo Nordisk A/S)] (3.08 g, 8 mmol) was subjected to the same reaction conditions described above, except that thionyl bromide was substituted for thionyl chloride. The procedure provided the desired 5'-bromo-2-chloro-5'-deoxy-N-(1-piperidinyl)adenosine as a foam (0.19 g, 9%) after column chromatography, 1H-NMR (400 MHz, DMSO-d6) δ1.37 (2H, br, piperidine C--H), 1.62 (4H, m, piperidine C--H), 2.80 (4H, br, piperidine C--H), 3.72, 3.82 (2H, ABX, H-5'a and H-5'b), 4.10 (1H, dt, H-4'), 4.17 (1H, dt, H-3'), 4.68 (1H, q, H-2'), 5.50, 5.62 (1H, 2d, 2'- and 3'-OH), 5.88 (1H, d, H-1'), 8.38 (1H, s, H-8), 9.36 (1H, br, NH). HPLC retention time 11.06 min. (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 96.4% purity at 250 nm). C15H20N6BrClO3.1.3 H2O requires C, 38.2; H, 4.8; N, 17.8. Found: C, 38.7; H, 4.7; N, 17.3%.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:6]([O:20][CH3:21])[CH:5]=1.C[O:24][C:25]([C:27]1([NH2:36])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:26]>>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[C:3]([NH:36][C:27]1([C:25]([OH:26])=[O:24])[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35]1)=[O:22]
Reactant: COC(=O)c1ccc(OCCc2cccc(C)c2)c(OC)c1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Product: COc1cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)ccc1OCCc1cccc(C)c1

Procedure:
The compound of step 3 was hydrolyzed in analogy to example 2, the obtained carboxylic acid reacted with 2-amino-indane-2-carboxylic acid methyl ester in analogy to step 1 of example 15, and the obtained ester hydrolyzed in analogy to example 2.