Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:38][CH:37]=2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:7][CH:6]=2>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:40][CH:41]=2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][C:8]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C)c(OC)c3cc(OCc4ccccc4)ccc23)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C)c(-c2ccc(OCc3ccccc3)cc2)c(Oc2ccc(/C=C/C(=O)O)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
Synthesized in a manner similar to Example 46 (Step 7) using ethyl (2E)-3-{4-[(3-methyl-4-(methyloxy)-6-[(phenylmethyl)oxy]-2-{4-[(phenylmethyl)oxy]phenyl}-1-naphthalenyl)oxy]phenyl}-2-propenoate (257). 1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=9.1 Hz, 1H), 7.57 (d, J=16.0 Hz, 1H), 7.45-7.18 (m, 1H), 7.07 (dd, J=9.0, 2.5 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H) 6.53 (d, J=8.6 Hz, 2H), 6.53 (d, J=8.6 Hz, 2H), 6.16 (d, J=16.0 Hz, 1H), 5.16 (s, 2H), 4.95 (s, 2H), 3.81 (s, 3H), 2.12 (s, 3H). LRMS (ESI) m/z 621 (M−1)−. TLC (90:10; CHCl3/MeOH): Rf=0.44.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]2[NH:9][C:10]([C:15]3[C:16](=[O:31])[N:17]([NH:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:18]4[C:23]([C:24]=3[OH:25])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:11][S:12](=[O:14])(=[O:13])[C:7]=2[CH:6]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH:28]1([CH2:27][NH:26][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]([OH:25])=[C:15]([C:10]3[NH:9][C:8]4[CH:32]=[CH:33][C:5]([O:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:6][C:7]=4[S:12](=[O:14])(=[O:13])[N:11]=3)[C:16]2=[O:31])[CH2:30][CH2:29]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 120 °C
Yield: 28.5 %

Procedure:
To the product of Example 394 (15 mg, 0.032 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (12 μl, 0.156 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was purified by chromatography on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (5 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (d, J=7.72 Hz, 2 H) 1.01 (m, 1 H) 2.86 (d, J=5.52 Hz, 2 H) 2.97 (s, 3 H) 3.38 (t, J=5.33 Hz, 2 H) 4.18 (t, J=5.33 Hz, 2 H) 6.44 (s, 1 H) 7.32 (t, J=5.88 Hz, 1 H) 7.41 (m, 3 H) 7.67 (d, J=9.93 Hz, 1 H) 7.89 (t, J=7.91 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (d, J=8.46 Hz, 1 H) 14.08 (s, 1 H) 15.11 (s, 1 H). MS (ESI−) m/z 546 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)O)=[N:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1.O>[CH2:26]([O:33][C:2]1[C:7]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=[CH:4][N:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(C(O)c2nccnc2Cl)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2nccnc2OCc2ccccc2)cc1
Temperature: 120 °C

Procedure:
To a solution of n-butyllithium (1.57 mol/L solution in tetrahydrofuran, 2.0 mL) in tetrahydrofuran (23 mL) was added 2,2,6,6-tetramethylpyridine (0.57 mL) at −78° C. The temperature was raised to 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was cooled to −78° C., 2-chloropyrazine (0.22 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 4-methoxybezaldehyde (0.35 mL), and the mixture was stirred for additionally 1.5 hours. To the reaction-mixture were added concentrated hydrochloric acid (1.2 mL), ethanol (1.2 mL) and tetrahydrofuran (4.8 mL), and the temperature was raised to room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. After the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) to give 2-chloropyrazin-3-yl 4-methoxyphenyl methanol (0.31 g). To a suspension of the obtained 2-chloropyrazin-3-yl 4-methoxyphenyl methanol(0.13 g), sodium hydroxide (0.12 g) and potassium carbonate (0.072 g) in toluene (1 mL) were added benzyl alcohol (0.080 mL) and tris-[2-(2-methoxyethoxy)ethyl]amine (0.017 mL), and the mixture was stirred for 2,hours at 120° C. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give 2-benzyloxy-3-(4-methoxybenzyl)pyrazine (0.026 g). To a solution of the obtained 2-benzyloxy-3-(4-methoxybenzyl)-pyrazine (0.025 g) in ethanol (1 mL) was added 10% palladium carbon powder (0.0099 g), and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/3) to give 3-(4-methoxybenzyl)-1H-pyridin-2-one (0.0055 g).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([NH:26][C@@H:27]([CH2:31][NH2:32])[C:28]([OH:30])=[O:29])=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C1COCC1.[OH-].[Na+]>[CH:18]1[C:19]2[CH:20]([CH2:22][O:23][C:24]([NH:26][C@@H:27]([CH2:31][NH:32][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:28]([OH:30])=[O:29])=[O:25])[C:21]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CNC(=O)C1CCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentanecarbonyl chloride (81 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (142 mg, 54%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:29])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:43][OH:44]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:29])[CH2:16][C:17]([NH:43][OH:44])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC1CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC1CCCC1
Yield: 91.5 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (1.00 g, 2.53 mmol), carbonyldiimidazole (430 mg, 2.66 mmol) and hydroxylamine hydrochloride (230 mg, 3.29 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide as a white solid (950 mg, 91% yield): mp, 183.0-184.5° C.; 1H NMR (DMSO-d6) δ1.54-1.82 (m, 8H, C5H8), 2.82-2.86 (m, 2H, CH2), 3.70 (s, 3H, CH3), 4.13 (d, J=17.5 Hz, NCHH), 4.55 (d, J=17.5 Hz, 1H, NCHH), 4.73 (m, 1H, CH), 5.74 (t, J=7.6 Hz, 1H, NCH), 6.85-6.93 (m, 3H, Ar), 7.47-7.70 (m, 4H, Ar), 8.84 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ23.50, 32.11, 32.18, 46.20, 51.17, 55.53, 79.52, 112.21, 114.00, 119.14, 122.78, 123.43, 127.85, 131.31, 131.86, 132.27, 141.65, 146.87, 149.07, 166.04, 166.91; Anal Calcd for C23H26N2O5 0.7 H2O: C, 65.30; H, 6.53; N, 6.62. Found: C, 65.59; H, 6.38; N, 6.65; H2O, 2.94.
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH:4]([CH3:16])[N:3]1[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:27]=[C:28]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[C:29](C)(C)C.C(O)(=O)C(O)=O>CN(C=O)C.C1COCC1.N1CCC[C@H]1C(O)=O.[Cu]I>[CH3:1][CH:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[N:7](/[CH:27]=[C:28](/[C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)\[CH3:29])[C:6]=2[CH2:5][CH:4]([CH3:16])[N:3]1[CH3:17]
Reactant: CC(C)(C)C(=CBr)c1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C)N(C)C(C)C3
Agent: [Cu]I
Agent: O=C(O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C/C(=C\n1c2c(c3cc(C)ccc31)C(C)N(C)C(C)C2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,3,4,5-Tetrahydro-1,2,3,8-tetramethyl-1H-pyrido[4,3-b]indole (550 mg, 2 mmol) was dissolved in DMF. Copper (I) iodide L-proline (46 mg, 0.4 mmol) and potassium phosphate (848 mg, 4 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-bromo-3,3-dimethylbut-1-en-2-yl)pyridine (294 mg, 3.0 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. The free base was converted into oxalate salt by treatment of oxalic acid (1 equiv) in THF. Yield: 8 mg as the oxalate salt. 1H NMR (CD3OD, freebase) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.35 (s, 1H), 7.30 (s, 1H), 7.10 (m, 2H), 4.50 (m, 1H), 4.0 (m, 1H), 3.10 (m, 1H), 2.90 (s, 3H), 2.80 (m, 1H), 2.42 (s, 3H), 2.0 (s, 3H), 1.76 (d, 3H), 1.50 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>CCO.N1CCCCC1>[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: O=Cc1cccc(O)c1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1cccc(O)c1
Yield: 55 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in EtOH (10 mL) and 3-hydroxybenzaldehyde (559 mg, 1 eq.) and piperidine (10 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((3-hydroxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (800 mg, 55% yield).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F-].[K+].[NH:7]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:8]([C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23]Br)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH3:9]>>[NH:7]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:8]([C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23][O:3][C:1]([CH3:2])=[O:4])=[O:22])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH3:9]
Reactant: CC(=O)O
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Agent: [F-]
Agent: [K+]
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
Acetic acid (230 μl, 4.02 mmol), KF (0.234 g, 4.02 mmol), 13 (1.00 g, 2.01 mmol).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([S:3][CH2:1][CH3:2])=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: CCS
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCSC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 3 h
Yield: 50.6 %

Procedure:
0.7 g of ethyl mercaptan and 1.2 g of triethylamine were dissolved in 20 ml of N,N-dimethylacetamide. To the resulting solution, 3.5 g of 3-(2'-chloro 4'-trifluoromethylphenoxy)phenylacetyl chloride was dropwise added at 10° C. After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, 50 ml of water was added to the liquid reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation-removal of the ether under reduced pressure, thereby to obtain a crude product. The so-obtained crude product was subjected to purification by the silica gel column chromatography (elution was performed by using a mixed solvent of toluene and n-hexane). As a result, there was obtained 1.9 g of S-ethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylthioacetate.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].Br[C:11]1[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1>CS(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:11]1[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CN(C)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc(C=O)s1
Temperature: 90 °C

Procedure:
2-dimethylaminoethanethiol hydrochloride (1.85 g, 13.09 mmol) was suspended in dry DMSO and sodium hydride (60% dispersed in mineral oil, 1.10 g, 2.1 equivs) was added carefully. The reaction mixture was left stirring for 1 hour before 5-bromo-2-thiophenecarboxaldehyde (2.5 g, 1.56 ml, 13.09 mmol) was added. The reaction mixture was then heated to 90° C. under nitrogen.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>[Cu]Cl.CN(C)C=O>[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Brc1cccnc1
Reactant: Nc1cc[nH]n1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccn(-c2cccnc2)n1

Procedure:
In a typical reaction, copper(I) chloride, 3-aminopyrazole, potassium carbonate and N,N-dimethylformamide are introduced into a reaction vessel under a nitrogen atmosphere and 3-bromopyridine is gradually added. The mixture is heated at about 110° C. until most of the 3-bromopyridine has reacted. The mixture is allowed to cool and most of the solvent is removed under reduced pressure. The crude 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is conveniently isolated and purified by crystallization from water.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[O:13]1[CH2:18][CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CCOC(C)=O.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>[O:13]1[CH2:14][CH:15]=[C:16]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:17][CH2:18]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=c1[nH]nc(Cl)c2ccccc12
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(C2=CCOCC2)c2ccccc12
Temperature: 180 °C

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (150 mg, 0.831 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (174 mg, 0.831 mmol), Na2CO3 (164 mg, 2.49 mmol) and Pd(PPh3)4 (47.8 mg, 0.042 mmol) in DMF (3 mL) and H2O (1 mL) was heated at 180° C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (APCI) M/Z 229 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]([C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=2)=[CH:12][CH:11]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:10]2[CH:25]=[CH:24][C:13]([O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)=[CH:12][CH:11]=2)[CH2:3]1
Reactant: CC1CCCNC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: CC1CCCN(Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 29.5 %

Procedure:
Using a method similar to Example 345, using 3-methyl-piperidine (0.0420 g, 0.423 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.129 g, 0.610 mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (10:1→7:3 methylene chloride:methanol), 0.0400 g (29%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C19H24N3O2 326.1869, found 326.1841; 1H NMR (DMSO-d6): 8.66 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.5, 8.4 Hz), 8.06 (s br, 1H), 7.53 (s br, 1H), 7.38 (d, 2H, J=8.4 Hz), 7.17-7.09 (m, 3H), 3.38-3.28 (m, 2H), 2.83-2.70 (m, 2H), 1.95 (t, 1H, J=10.6 Hz), 1.74-1.41 (m, 5H), 0.97-0.79 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][O:22][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-hydroxymethylpyrrolidine (1.00 g) in tetrahydrofuran (20 ml) was dropwise added a 1.6 M solution of butyllithium in hexane (2 ml) at -40°~-30° C. in a nitrogen stream and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added ethyl bromoacetate (0.40 ml) at -40°~-30° C. and the reaction mixture was stirred at -40°~-30° C. for 30 minutes and then at ambient temperature for 3 hours. The mixture was poured into a mixture of water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with chloroform to give (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(ethoxycarbonylmethyloxymethyl)pyrrolidine (0.88 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39](=[O:53])[NH:40][CH2:41][CH2:42][C@H:43]([NH2:52])[C:44]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:45])([CH3:37])([CH3:36])[CH3:35].[C:54]([O:58][C:59](=[O:81])[C:60]1[CH:65]=[C:64]([C:66]2[CH:71]=[C:70]([S:72][CH2:73][CH2:74][C:75](O)=[O:76])[N:69]=[C:68]([NH2:78])[N:67]=2)[C:63]([CH3:79])=[CH:62][C:61]=1[CH3:80])([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[C:54]([O:58][C:59](=[O:81])[C:60]1[CH:65]=[C:64]([C:66]2[CH:71]=[C:70]([S:72][CH2:73][CH2:74][C:75](=[O:76])[NH:52][C@H:43]([C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[O:45])[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:53])[N:69]=[C:68]([NH2:78])[N:67]=2)[C:63]([CH3:79])=[CH:62][C:61]=1[CH3:80])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)N1CCOCC1
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)O)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-c2cc(SCCC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N3CCOCC3)nc(N)n2)cc1C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (58 mg, 0.149 mmol), and diisopropylethylamine (43 μl, 0.247 mmol) were added at room temperature to an N,N-dimethylformamide solution (1.0 ml) of ((S)-3-amino-4-morpholin-4-yl-4-oxobutyl)carbamic acid tert-butyl ester (44 mg) obtained in Step 2 above and 5-[2-amino-6-(2-carboxyethylsulfanyl)pyrimidin-4-yl]-2,4-dimethyl-benzoic acid tert-butyl ester (50.3 mg) obtained in Step 1 of Example 2-1. The reaction solution was stirred for 16 hours, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=30:1) to yield 5-(2-amino-6-{2-[(S)-3-tert-butoxycarbonylamino-1-(morpholine-4-carbonyl)propylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (84 mg) as a pale yellow oily material.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]([CH3:11])=[O:10])=[CH:6][C:5]([CH2:12]C)=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C([N+]([O-])=O)=CC(CC)=CC=1OCC1C=CC=CC=1.CC1C(N)=CC(CC)=CC=1OCC1C=CC=CC=1.C(N1C2C(=C(OCC3C=CC=CC=3)C=C(CC)C=2)C=N1)(=O)C>>[NH:8]([C:7]1[C:2]([CH3:1])=[C:3]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=[C:5]([CH3:12])[CH:6]=1)[C:9]([CH3:11])=[O:10]
Reactant: CCc1cc(NC(C)=O)c(C)c(OCc2ccccc2)c1
Agent: CCc1cc(N)c(C)c(OCc2ccccc2)c1
Agent: CCc1cc(OCc2ccccc2)c(C)c([N+](=O)[O-])c1
Agent: CCc1cc(OCc2ccccc2)c2cnn(C(C)=O)c2c1
Product: CC(=O)Nc1cc(C)cc(OCc2ccccc2)c1C

Procedure:
from (2-methyl-3-acetamino-5-ethyl-phenyl)-benzyl ether; m.p. 139°-140° C. (prepared via (2-methyl-3-nitro-5-ethyl-phenyl)-benzyl ether and (2-methyl-3-amino-5-ethyl-phenyl)-benzyl ether), 1-acetyl-4-benzyloxy-6-ethyl-indazole; m.p. 109,5°-110,5° C.