Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([CH3:32])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[O:8])[CH3:5].[OH-].[Na+]>O1CCCC1.CO>[CH3:32][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:25][CH:26]=1)=[O:8])([CH3:5])[C:3]([OH:33])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1OCc1ccc(OC(F)(F)F)cc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2c(c1OCc1ccc(OC(F)(F)F)cc1)CCCC2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
0.13 g 2-methyl-2-{[1-(4-trifluoromethoxy-benzyloxy)-5,6,7,8-tetrahydro-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester was dissolved in 5 ml of tetrahydrofuran and 0.5 ml of methanol. To this was added 0.42 ml of 2 M NaOH (aq), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, diluted with 5 ml of ethyl acetate and 5 ml of water and acidified to pH 3 with 1N HCl (aq). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to give 99 mg of 2-methyl-2-{[1-(4-trifluoromethoxy-benzyloxy)-5,6,7,8-tetrahydro-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CO)cs1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
2-{[4-(Hydroxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 10 and 4-bromobenzylbromide (4.75 g) were dissolved in N,N-dimethylformamide (50 mL), potassium tert-butoxide (2.33 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (4.5 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:12]>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][Br:12]
Reactant: OCc1cc(F)cc(Br)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cc(Br)cc(CBr)c1
Reaction time: 3 h

Procedure:
To a solution of 3-Bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 mole) in CH2Cl2 (15 mL) was added 12.4 mL of 1.0M PBr3 (3.33 g, 0.0123 mole) in CH2Cl2, stirred for 3 hr, diluted with ether (100 mL), washed with H2O (50 ml, 3×), dried over MgSO4, concentrated, and purified by column chromatography using 1:9 ethyl acetate/hexane as an eluant solvent system. 3-Bromo-5-fluorobenzyl bromide was obtained as a white crystalline material was obtained, mp 41-43° C. 1H NMR (DMSO-d6) δ4.69 (s, 2H), 7.52(d, 1H, J=1.76 Hz) 7.54(d, 1H, J=1.91 Hz), 7.56(s, 1H); MS(EI): M+. m/z 266; Anal. Calc. For C7H5Br2F: C, 31.38, H, 1.88. Found: C, 31.75, H, 1.78.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([NH:13][C:14](=[O:30])[CH2:15][NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][CH:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]2)=[CH:40][CH:39]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[S:17]([NH:16][CH2:15][C:14]([NH:13][CH:4]([C:5]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6])[CH2:3][NH:2][C:50]([CH:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][N:38]=[CH:43][CH:42]=2)[CH2:49][CH2:48]1)=[O:51])=[O:30])(=[O:19])=[O:18]
Reactant: NCC(NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
N-[2-Amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamide hydrochloride salt (2.6 g) and triethylamine (3.18 ml) were added in turn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 89:10:1 mixture of ethyl acetate, methanol and ammonia as eluent. The material so obtained was triturated under diethyl ether to give 2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)-piperidin-4-ylcarbonylamino]ethyl}acetamide as a foam (1.9 g, 55%);
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Reactant: O=C(Cl)C1CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)C4CC4)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])SCCCS1.BrN1C(=[O:24])CCC1=O>CC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][C:5](=[O:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Solvent: O
Product: COCCC(=O)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
A solution of 10.6 g (38.1 mmol) of tert-butyl 2-(2-methoxyethyl)-1,3-dithiane-2-carboxylate in 365 ml of acetone and 18 ml of water was added dropwise to a solution, cooled to −18° C., of 54.2 g (305 mmol) of N-bromosuccinimide in 365 ml of acetone and 18 ml of water such that the internal temperature did not exceed −5° C. After the addition had ended, the mixture was stirred for another 10 min and the reaction was then terminated using 630 ml of sodium sulphite solution (1N). 420 ml of n-heptane were added to the reaction mixture and, after phase separation, the aqueous phase was extracted three times with 315 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed at 25° C. and 75 mbar. The resulting suspension was stirred with 100 ml of n-hexane and the precipitate was filtered off. The solvent was removed under reduced pressure, giving the target compound. Yield: 5.28 g (59% of theory)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:24]1[C@@H:28]([C:29]([NH2:31])=[O:30])[NH:27][CH2:26][C@H:25]1[F:32].Cl.CCN(C(C)C)C(C)C>>[F:32][C@@H:25]1[CH2:26][N:27]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:28]([C:29]([NH2:31])=[O:30])[CH2:24]1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C[C@@H](F)C[C@H]3C(N)=O)cc1OCC2
Yield: 22 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4-cis-fluoro-L-prolinamide hydrochloride with added DIPEA (2.2 eq.), were reacted and the crude product recrystallised from IMS to give 373 as a white solid (56 mg, 22%). LCMS: RT=2.59 min, [M+H]+=427. 1H NMR 400 MHz (DMSO-d6) δ: 9.05 (1H, s), 7.84 (1H, d, J=0.63 Hz), 7.80 (1H, s), 7.11 (1H, s), 6.92 (1H, s), 5.93-5.91 (2H, m), 5.42 (1H, s), 5.29 (1H, s), 4.46-4.44 (5H, m), 3.83-3.54 (2H, m), 2.28 (1H, dd, J=20.28, 14.80 Hz), 1.43 (6H, dd, J=6.59, 3.60 Hz)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([NH:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([N:12]([CH2:13][CH2:14][OH:15])[C:1](=[O:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: OCCNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Acetyl chloride (0.858 g, 10.8 mmol) was added drop by drop to a solution of N-benzyl ethanol amine (1.5 g, 9.9 mmol) and triethylamine (1.5 g, 14.9 mmol) in dry dichloromethane (20 ml) at 0° C. under nitrogen atmosphere and stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, 10% aq. NaHCO3, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel using 5% methanol in dichloromethane as eluent afforded 0.68 g of the desired product as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[Cl:45]CCl.Cl>CO>[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Yield: 84 %

Procedure:
(R)-[3-[1-((S)-2-Hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.16 g, 0.25 mmol) and 2 mL of dichloromethane were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of methanol was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 30 (120 mg, yield 84%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[CH2:15]1[C:19]2([CH2:24][NH:23][CH2:22][CH2:21][N:20]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:18][CH2:17][CH2:16]1>C(O)C>[OH:13][C@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:23]1[CH2:24][C:19]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCNCC12CCCC2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3(CCCC3)C2)ccc2c1COC2=O

Procedure:
A solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2) (38 mg, 0.20 mmol) in 2 mL ethanol was added to tert-butyl 6,9-diazaspiro[4.5]decane-6-carboxylate (42 mg, 0.20 mmol). The reaction mixture was microwaved at 140° C. for 55 minutes. The solvents were removed in vacuo to provide tert-butyl 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-6,9-diazaspiro[4.5]decane-6-carboxylate which was carried on without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH3:15][N:16](C)P(=O)(N(C)C)N(C)C>>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:15]#[N:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CNC(=O)c1ccc(I)c([N+](=O)[O-])c1
Product: CNC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
2 g (6.53 mmol) N-methyl-4-iodo-3-nitrobenzamide (Compound VII-1), 0.09 g (10.0 mmol) cuprous cyanide and 10 ml hexamethylphosphoric triamide were added into a reaction flask. The mixture was heated to 100° C. and reacted for 40 minutes, and after completing the reaction, the mixture was cooled to room temperature, and then extracted with ethyl acetate. The organic layer was washed with water for three times, dried over anhydrous sodium sulfate, decolorized with activated charcoal, filtered, and the filtrate was concentrated to dryness, recrystallized from ethyl acetate to obtain 0.74 g N-methyl-4-cyano-3-nitrobenzamide (Compound I-27), yield 55.2%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ncc[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1nccn1Cc1ccccn1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a solution of the 2-imidazolecarboxaldehyde (545 mg, 5.67 mmol) and 2-(bromomethyl)pyridine hydrobromide (1.58 g, 6.24 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (3.0 mL, 17.01 mmol). The reaction mixture was heated to 80° C. overnight. Then it was cooled and quenched with saturated NaHCO3 (20 mL). It was extracted with CH2Cl2 (c×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a dark brown oil. Purification by flash column chromatography on silica gel using 1%→2% CH3OH/CH2Cl2 afforded the product as a yellow solid (397 mg, 37%). 1H NMR (CDCl3) δ 5.71 (s, 2H), 7.18-7.24 (m, 2H), 7.32 (s, 1H), 7.36 (s, 1H), 7.65 (td, 1H, J=10.4, 1.5 Hz), 8.56 (d, 1H, J=4.5 Hz), 9.82 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N(CC)CC)C.[CH3:22][CH:23]([OH:26])[CH2:24][CH3:25]>>[CH:23]([O:26][CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14])([CH2:24][CH3:25])[CH3:22]
Reactant: CCC(C)O
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Solvent: CCN(CC)CC
Product: CCC(C)OCc1c(O)ccc2c1CCCC2=O

Procedure:
According to step (a) in the method of example A, 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0 mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in (±)butan-2-ol (3 ml, Aldrich Chemical) to produce 159 mg of desired product as an orange oil. Low resolution mass spectrum (APCI) m/z 249 [M+H]+.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH3:19][C:20]1[O:27][C:23](/[CH:24]=[N:25]\O)=[CH:22][CH:21]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:24]\[C:23]2[O:27][C:20]([CH3:19])=[CH:21][CH:22]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Reactant: Cc1ccc(/C=N\O)o1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccc(C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.5 %

Procedure:
In 75 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 20 g (76 mmol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 11.4 g (91 mol) of (Z)-5-methylfurfuraldoxime, and the solution was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the residue was treated with water. Crystals precipitated were collected by filtration and washed with water. The crystals were dried under reduced pressure and dissolved in acetone, and insoluble matters were filtered off. The filtrate was concentrated, and the residue was chromatographed on silica gel with chloroform-acetone (7:1), followed by recrystallization from ethyl acetate-hexane to yield 4.6 g of ethyl 5-fluoro-6-[(Z)5-methylfurfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 163°-164° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH3:14])[CH:3]=1.[OH-].[NH4+:16]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:16])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: [NH4+]
Reactant: COCn1cc(Br)c2c(Cl)ncnc21
Agent: [OH-]
Product: COCn1cc(Br)c2c(N)ncnc21
Temperature: 100 °C
Yield: 71 %

Procedure:
5-bromo-4-chloro-7-[(methyloxy)methyl]-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.723 mmol) was transferred to a 5 mL microwave vial and then ammonium hydroxide (1.5 mL, 38.5 mmol) was added. The mixture was heated in microwave reactor at 100° C. for 30 minutes. The solid was isolated by filtration and dried to give 5-bromo-7-[(methyloxy)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (132 mg, 71.0% yield) as a white solid. LC-MS (ES) m/z=257.0, 259.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.56 (s, 1H), 6.81 (br. s., 2H), 5.43 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:42])[C:29]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=2)([OH:34])[C:30]([F:33])([F:32])[F:31])=[C:24]([Cl:43])[CH:23]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:42])[C:29]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[C:24]([Cl:43])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 18 h

Procedure:
Copper(II)acetate (60 mg), (4-methoxycarbonylphenyl)boronic acid (CAS Reg. No. 99768-12-4, 59 mg), and triethylamine (44 mg) were added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 40 mg) in DCM (4 ml). The mixture was stirred with molecular sieves under air atmosphere for 18 h and then concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg) as a white foam. MS (m/e)=499.1 [M+H+].
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]=[N+:37]=[N-:38])[CH:30]=2)[CH:10]=1.[CH2:46]([OH:50])[CH2:47][C:48]#[CH:49]>CS(C)=O.N.O.[Cu]I>[OH:50][CH2:46][CH2:47][C:48]1[N:38]=[N:37][N:36]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:41]=[CH:42][CH:43]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:4]=2)=[O:40])=[O:39])[CH:49]=1
Reactant: C#CCCO
Reactant: [N-]=[N+]=NCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Cu]I
Agent: N
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3cc(CCO)nn3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(azidomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (55 mg, 0.09 mmol, 1.00 equiv, 95%) in DMSO (3 mL), but-3-yn-1-ol (19 mg, 0.27 mmol, 3.00 equiv), and copper(I) iodide (0.84 mg, 0.05 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 10 mL of 10% NH3.H2O. The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (60 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 10 mg (14%) of a yellow to green solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.48 (s, 1H), 9.55-9.58 (t, J=6 Hz, 1H), 8.93 (s, 1H), 8.36 (s, 2H), 7.96 (s, 1H), 7.85-7.96 (s, 1H), 7.71-7.77 (m, 3H) 7.64 (s, 1H), 7.55-7.60 (m, 5H), 7.44 (s, 1H), 5.67 (s, 2H), 4.63 (t, 2H), 3.58-3.61 (t, 2H), 3.40 (s, 4H), 2.75-2.77 (t, J=9 Hz, 2H), 1.61-1.78 (d, 6H). MS (ES, m/z): 684 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:26])([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[CH2:19][O:18]1>C(O)C>[CH3:10][Si:11]([CH3:26])([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:18])[CH2:19][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1
Reactant: OCCN1CCNCC1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
2-piperazin-1-yl-ethanol (0.95 g; 7.28 mMol) and 20 mL of ethanol were charged to a 100 ml RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for additional 4 hours. After the reaction was complete, ethanol was stripped off on the rotovap. The mixture was distilled under vacuum.