Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([C:16](=O)[CH3:17])[CH2:12][CH2:11]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][CH:16]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH3:17])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CC(=O)C1CCOCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Nc1cc(Br)cnc1N)C1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.6 %

Procedure:
2,3-Diamino-5-bromopyridine (1.07 g) and 1-(tetrahydro-2H-pyran-4-yl)ethanone (0.80 g) were dissolved in methanol (20 ml), and acetic acid (0.98 ml) was added. After stirring at room temperature for a while, sodium cyanoborohydride (1.08 g) was added and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (developed with ethyl acetate-hexane) to give the title compound (334 mg).
Reaction SMILES: [NH2:1][C:2](=[N:22][OH:23])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([O:20][CH3:21])[CH:4]=1.[CH3:24][O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33](O)=O)[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]>>[CH3:21][O:20][C:5]1[CH:4]=[C:3]([C:2]2[N:1]=[C:33]([C:31]3[CH:30]=[CH:29][C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[C:27]([CH2:26][O:25][CH3:24])[CH:32]=3)[O:23][N:22]=2)[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: COc1cc(C(N)=NO)ccc1CN(C)CC(=O)OC(C)(C)C
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the procedure 7, starting from Intermediate 44 and Intermediate 3. It was isolated as a colorless gum. 1H NMR (CDCl3, 400 MHz) δ 8.43 (1H, s), 8.18 (1H, dd, J=7.9, 1.9 Hz), 7.80 (1H, dd, J=7.7, 1.5 Hz), 7.68 (1H, d, J=1.5 Hz), 7.55 (1H, d, J=7.8 Hz), 7.35-7.24 (4H, m), 7.13 (1H, d, J=7.4 Hz), 4.23 (2H, s), 3.95 (3H, s), 3.81 (2H, s), 3.33 (3H, s), 3.24 (2H, s), 2.44 (3H, s), 2.08 (3H, s), 1.49 (9H, s).
Reaction SMILES: C[CH:2]1[CH2:11][C:10](C)(C)[CH:9]2[C:4](=[CH:5][C:6]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:7][CH2:8]2)[NH:3]1.COC1C=C2C(CCCN2)=CC=1>>[C:16]([NH:15][CH2:14][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][CH2:2][NH:3]2)=[CH:8][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCC1=CCC2C(=C1)NC(C)CC2(C)C
Agent: COc1ccc2c(c1)NCCC2
Product: CC(=O)NCc1ccc2c(c1)NCCC2

Procedure:
2,4,4-trimethyl-7-acetamidomethyl-tetrahydroquinoline ps 7-methoxy-tetrahydroquinoline
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1.ClC1C=CC(C(O[NH2:32])=O)=CC=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:32])[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc[nH]1
Reactant: NOC(=O)c1ccc(Cl)cc1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred, ice/water cooled mixture of 1H-pyrrole-2-carboxylic acid methyl ester (425 mg, 3.40 mmol) in NMP (10 mL) was added a solution of potassium tert-pentoxide in toluene (2.30 mL, 3.90 mmol, 25 wt % solution); then the solid of O-4-chlorobenzoyl hydroxyamine (670 mg, prepared according to the literature: Parlanti, L Discordia, R. P.; Hynes, J. Jr.; Miller, M. M.; O'Grady, H. R.; Shi, Z. Org. Lett. 2007, 9(19) 3821-3824) was added in one portion; the cold bath was removed after addition completed, and the slurry was stirred at rt for 30 min. Subsequently, the reaction was quenched by addition of saturate sodium bicarbonate solution, then extracted with EtOAc, washed with brine; organic layers was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column purified to give the desired product (309 mg). 1H NMR (CDCl3, δ in ppm): 6.94 (t, 1H, J=2.3 Hz), 6.81 (dd, 1H, J=2.0 Hz, 4.0 Hz), 6.00 (dd, J=2.7 Hz, 4.3 Hz), 5.53 (br, s, 2H), 3.82 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=O>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc(F)cc3F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 23 %

Procedure:
4-[4-(2,4-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (66 mg, 23%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′,4′-difluoroacetophenone (available from Matrix Scientific) using the procedure described for the preparation of Example 18. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=1.4 Hz, 2H), 8.10-8.35 (m, 4H), 7.21-7.33 (m, 3H), 7.77 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.23-7.50 (m, 4H).
Reaction SMILES: [OH:1][C:2]12[O:32][CH:25]([CH:26]([O:30][CH3:31])[CH2:27][CH:28]1[CH3:29])[CH:24]([O:33][CH3:34])[CH2:23][CH:22]([CH3:35])[CH2:21][C:20]([CH3:36])=[CH:19][CH:18]([CH2:37][CH3:38])[C:17](=[O:39])[CH2:16][CH:15]([OH:40])[CH:14]([CH3:41])[CH:13]([C:42]([CH3:53])=[CH:43][CH:44]1[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]1)[O:12][C:11](=[O:54])[CH:10]1[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]1)[C:4](=[O:55])[C:3]2=[O:56].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[OH:1][C:2]12[O:32][CH:25]([CH:26]([O:30][CH3:31])[CH2:27][CH:28]1[CH3:29])[CH:24]([O:33][CH3:34])[CH2:23][CH:22]([CH3:35])[CH2:21][C:20]([CH3:36])=[CH:19][CH:18]([CH2:37][CH3:38])[C:17](=[O:39])[CH2:16][CH:15]([OH:40])[CH:14]([CH3:41])[CH:13]([C:42]([CH3:53])=[CH:43][CH:44]1[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]1)[O:12][C:11](=[O:54])[CH:10]1[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]1)[C:4](=[O:55])[CH:3]2[OH:56]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)C(O)CC1=O
Yield: 62.3 %

Procedure:
A solution of 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (FR-900520, EP 184162) (80 mg) and tri-n butyltin hydride (0.2 ml) in toluene (5ml) was heated at 70° C. for 2 hours. The cooled reaction mixture was then evaporated in vacuo and the residue purified by column chromatogragphy on silica eluting with ethyl acetate to give the title compound as a foam (50 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:7][CH:6]=2)=[O:9])[CH:15]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(O)cc2)c1
Agent: Cl
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(OCCN3CCCCC3)cc2)c1
Yield: 83.5 %

Procedure:
Synthesized from (4-hydroxyphenyl)[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]methanone (1.3 g) and 1-(2-chloroethyl)piperidine hydrochloride (970 mg) according to an analogous synthetic method to Example 383 described below, the title compound (yellow viscous oil) (1.4 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([C:13]([OH:15])=[O:14])=[C:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]2=O.O.[NH2:26][NH2:27]>C(O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:7]([C:13]([OH:15])=[O:14])[NH:26][N:27]=2)[CH:3]=1
Reactant: NN
Reactant: COc1ccc(-c2c(C(=O)O)oc3cc(O)c(Cl)cc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(-c3cc(Cl)c(O)cc3O)n[nH]c2C(=O)O)cc1
Temperature: 70 °C

Procedure:
6-Chloro-7-hydroxy-3-(4methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid (1 eq) was taken up in ethanol and hydrazine hydrate (3 eq) was added. To aid dissolution a few drops of NaHCO3 (aq) was added, and then all was heated at 70° C. under nitrogen for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to a brown oil. This was partitioned between 1MHCl(aq) and diethyl ether. The organic phases were combined, washed with 1MHCl(aq), dried over MgSO4, filtered and concentrated in vacuo to give 5-(5-chloro-2,4dihydroxy-phenyl)-4-(4-methoxy-phenyl)-2H-pyrazole-3-carboxylic acid as a yellow foam.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)([O-:16])=[O:15].[Cl-].[NH4+]>CN(C=O)C>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[CH:5][C:3]#[N:4])([O-:16])=[O:15]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CC=Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77 %

Procedure:
Sodium hydride, 60% disp. in mineral oil (0.265 g) was added in portions to a solution of Diethyl cyanomethylphosphonate (1.17 g, 6.6 mmol) in anhydrous DMF (20 mL, 0.2 mol) under stirring and ice cooling. A solution of 2-Nitrobenzaldehyde (1.00 g, 6.6 mmol) in DMF (5 mL) was then added dropwise over 10 min. After being stirred for 5 min, the reaction mixture was poured into ice water, neutralized with ammonium chloride, and extracted with ether. The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. A mixture of E and Z 3-(2-Nitro-phenyl)-acrylonitrile was isolated (892 mg, combined yield=77%.)
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[C:11]([C:19]1[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=1)[NH:12][C:13]2=[O:18].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([C:4]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[N:23]=[CH:24][C:19]([C:11]4[NH:12][C:13](=[O:18])[C:14]5[C:9]([CH:10]=4)=[C:8]([CH3:7])[CH:17]=[CH:16][CH:15]=5)=[CH:20][N:21]=3)[CH2:30][CH2:29]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc2c(=O)[nH]c(-c3cnc(N4CCNCC4)nc3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3cnc(N4CCN(C(=O)C5CC5)CC4)nc3)cc12
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
Cyclopropylcarbonyl chloride (9 μL, 2.28 mmol) was added to a stirred solution of 5-methyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-2H-isoquinolin-1-one (36 mg, 0.11 mmol) and N,N-diisopropylethylamine (23 μL, 0.132 mmol) in CH2Cl2 (2 mL) at −20° C. and allowed to stir for 10 min. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC-MS to afford 3-[2-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyrimidin-5-yl]-5-methyl-2H-isoquinolin-1-one as a white solid (19 mg, 45%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=3)[C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=3)[N:21]=2)[CH2:16]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=3)[C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=3)[N:21]=2)[CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of {(R)-1-[6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester trifluoroacetate (0.4 g, 0.57 mmol) in DCM (5 ml) and TFA (2.5 ml) is stirred at room temperature for 2 hours. The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:30][C:28]1[CH:27]=[CH:26][C:25]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:29]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)cc1OCc1ccccc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 2-benzyloxyl-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H17FN4O, 385. Found, 385.
Reaction SMILES: [I:1]I.[C@:3]12([CH2:13]S(O)(=O)=O)[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][C:4]2=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[I:1][CH2:13][C@:3]12[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][C:4]2=[O:5]
Reactant: II
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C2CC[C@@]1(CI)C(=O)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
120 mmol of iodine are added to a solution of 40 mmol of (1S)-camphor-10-sulfonic acid and 200 mmol of triphenylphosphine in 400 ml of toluene and the solution is refluxed for 15 hours. After cooling to room temperature, the solution is washed twice with 100 ml of water and dried. After removal of the solvent, the crude product is purified by means of chromatography and the product is obtained in a yield of 85%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2)cc1
Yield: 78 %

Procedure:
Bromobenzene (80 mg, 0.51 mmol) reacted with 4-chlorophenylboronic acid (103 mg, 0.66 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (318 mg, 1.50 mmol) in toluene at 100° C. to give the title compound (75 mg, 78%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.41-7.62 (m, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 139.95, 139.62, 133.33, 128.88, 128.86, 128.36, 127.56, 126.96. GC/MS(EI): m/z 188 (M+), 152
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C.CO>[CH:2]([C:3]1[N:29]([C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)([CH3:6])[CH3:1]
Reactant: CC(C)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methylpropanamide (71.4 mg, 0.820 mmol) and triethyloxonium tetrafluoroborate (154 mg, 0.812 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.5 mL) and added to a suspension of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (69.2 mg, 0.248 mmol) in ethanol (1.7 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C17H22N3O2S (M+H)+: m/z=332.1. Found: 332.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]2[C:15]3[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Product: CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)c1
Yield: 45 %

Procedure:
Method G1 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tertbutylbenzoyl chloride to afford the title compound as a white solid (29 mg, 45%).
Reaction SMILES: C[N:2]([CH3:7])[CH2:3][CH2:4][CH2:5]N.[C:8]([N:16]1[C:20]2[N:21]=[CH:22][C:23]3[C:24](OC4C=CC=CC=4)=[N:25][C:26]4[N:27]([N:29]=[CH:30][N:31]=4)[C:28]=3[C:19]=2[CH:18]=[N:17]1)(=O)[C:9]1C=CC=CC=1.N1(N2N3C4C5C=NNC=5N=CC=4C=NC3=NC2)CCCC1>>[CH2:8]([N:16]1[C:20]2[N:21]=[CH:22][C:23]3[C:24]([N:2]4[CH2:3][CH2:4][CH2:5][CH2:7]4)=[N:25][C:26]4[N:27]([N:29]=[CH:30][N:31]=4)[C:28]=3[C:19]=2[CH:18]=[N:17]1)[CH3:9]
Reactant: CN(C)CCCN
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Agent: C1=NC2=NCN(N3CCCC3)N2c2c1cnc1[nH]ncc21
Product: CCn1ncc2c1ncc1c(N3CCCC3)nc3ncnn3c12

Procedure:
By substituting pyrrolidine for 3-(dimethylamino)propylamine in the procedure of Example 1 (c), 8-ethyl-5-(1-pyrrolidinyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#N.[Li].[C-]#[C-].[Li+].[Li+].[CH3:14][Si:15]([C:18]#C)([CH3:17])[CH3:16].C([Li])CCC>C1COCC1.C(#N)C1C=CC=CC=1>[CH3:14][Si:15]([C:18]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cccnc1
Agent: [C-]#[C-]
Agent: [Li+]
Agent: [Li]
Solvent: N#Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccnc1
Reaction time: 20 h
Yield: 50 %

Procedure:
The procedure was identical to Example 1, with the exception that 3-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile and lithium trimethylacetylide (8.00 ml; 4.00 mmol; 0.5 M in THF) was used instead of the in situ derived lithium acetylide made from trimethylsilylacetylene and n-butyllithium. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 1.00 mmol (50% yield) of 3-(trimethylsilylethynyl)pyridine and no remaining 3-cyanopyridine in the reaction mixture.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:12]>>[C:1]1([CH2:7][C:8]([Cl:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)Cc1ccccc1
Product: O=C(Cl)Cc1ccccc1

Procedure:
Phenylacetyl chloride is prepared according to the method described in Example 8 using phenylacetic acid (2.13 g, 15.6 mmol) to give a pale yellow oil which is dissolved in chloroform (10 mL). This solution is refluxed for 12 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (2.75 g, 14.9 mmol) in chloroform (10 mL) under nitrogen. The reaction mixture is partitioned between 1M sodium hydroxide solution (100 mL) and dichloromethane (80 mL). The organic layer is separated and the aqueous is washed with more dichloromethane (2×50 mL). The combined dichloromethane extracts are dried over sodium sulfate, and the solvent is removed to leave the crude free ester. This is purified by column chromatography and converted to the hydrochloride salt as described in Example 9. The product is recrystallised from hot methanol to yield the title compound.
Reaction SMILES: [N:1]([C:4]1[N:12]=[C:11]([F:13])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:14]1[O:34][C@H:33]([CH2:35][O:36]CC2C=CC=CC=2)[C@@H:24]([O:25]CC2C=CC=CC=2)[C@@H:15]1[O:16]CC1C=CC=CC=1)=[N+]=[N-]>COCCO.[Pd](Cl)Cl>[C@@H:14]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:11]([F:13])=[N:12][C:4]=3[NH2:1])[O:34][C@H:33]([CH2:35][OH:36])[C@@H:24]([OH:25])[C@@H:15]1[OH:16]
Reactant: [N-]=[N+]=Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: COCCO
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 67.6 %

Procedure:
6-Azido-2-fluoro-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)purine (0.19 g) was dissolved in 2-methoxyethanol (20 mL) with palladium (II) chloride (PdCl2) (20 mg) and activated carbon and the mixture was hydrogenated at 55 pounds per square inch (psi) in a Parr shaker. The reaction was monitored by thin layer chromatography (TLC) until complete. The mixture was then filtered through celite and the filtrate was concentrated in vacuo. Three times, the residue was dissolved in ethanol and reconcentrated. Then the residue was recrystalized from ethanol/water to obtain 0.063 g of the title compound which was consistent in its structure with an authentic sample by IR and TLC.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:15])[C:11](Br)([CH3:13])[CH3:12])[CH3:8].[F:16][C:17]1[CH:18]=[C:19]([OH:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:15])[C:11]([O:26][C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=1)([CH3:13])[CH3:12])[CH3:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
Potassium carbonate (3.96 g, 29 mmol) and 2-bromo-2-methylpropanoic acid ethyl ester (4.47 g, 23 mmol; CAS Reg. No. 600-00-0) were added to a solution of 3-fluoro-4-nitrophenol (3 g, 19 mmol; CAS Reg. No. 394-41-2) in DMSO (50 ml). The mixture was stirred for 18 h at 100° C. 10% aqueous citric acid and EtOAc were added and the layers were separated. The organic layer was washed with brine and dried over MgSO4. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/heptane) to obtain the title compound (1.19 g, 4.4 mmol; 23%) as yellow oil.