Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([N:7]1[C:11]2[NH:12][C:13](=[O:21])[CH:14]=[C:15]([C:16]([O:18]CC)=[O:17])[C:10]=2[C:9]([CH3:22])=[N:8]1)([CH3:6])[CH3:5]>CCO>[CH3:6][C:4]([N:7]1[C:11]2[N:12]=[C:13]([OH:21])[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]=2[C:9]([CH3:22])=[N:8]1)([CH3:3])[CH3:5]
Reactant: CCOC(=O)c1cc(=O)[nH]c2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(O)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide (52.6 mL, 52.6 mmol) was added to an EtOH solution (100 mL) of ethyl 1-(1,1-dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (7.3 g, 26.3 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo. The crude residue was suspended in water, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The solid product obtained was set aside. The aqueous phase was concentrated in vacuo and the crude product purified by reverse phase HPLC (mobile phase: 20-50% ACN/H2O, 0.1% TFA) to afford additional product. The combined products were collected as a solid, 5.76 g (88%). LCMS E-S (M+H)=250.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.5-13.9 (br s, 1H), 11.2-11.5 (br s, 1H), 6.78 (s, 1H), 2.46 (s, 3H), 1.70 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:12]1[N:13]=[C:14]3[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]3=[N:16][CH:17]=1)[C:6]2=[O:11].S(=O)(=O)([OH:33])N.[O-]Cl=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:12]1[N:13]=[C:14]3[C:20]([C:21]([OH:33])=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]3=[N:16][CH:17]=1)[C:6]2=[O:11]
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
To a solution of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (265 mg, 0.60 mmol) in 1,4-dioxane (35 mL) at 0° C. was added a solution of sulfamic acid (349 mg, 3.59 mmol) in water (4.35 mL. Then a solution of NaClO2 (88 mg, 0.78 mmol) and KH2PO4 (977 mg, 7.18 mmol) in water (8.7 mL) was added via dropping funnel over 15 min. The ice bath was removed and the yellow cloudy reaction mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated to give 269 mg (98%) of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27]C)=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][NH:15][C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=3)[C:14](=[O:24])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2c1ccccc1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2c1ccccc1

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to that described in Example 2, Step 4, except that 4-fluorobenzyl bromide was used in place of iodomethane, and 1N aqueous NaOH was used to quench the reaction and saponify the ester. ES MS (M+1)=472.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([C@@:16]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1.[Cl-].[NH4+].Cl>O1CCCC1.C(OCC)(=O)C>[C:9]([O:13][C:14]([C@@:16]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:35])[CH3:34])[CH:20]([F:50])[C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (4.10 mL) was added dropwise to a solution of (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester in tetrahydrofuran in a nitrogen atmosphere at −73° C. over 10 minutes. After stirring at the same temperature for 15 minutes, a solution of N-fluorobenzenesulfonimide (2.63 g, 8.33 mmol) in tetrahydrofuran (18 mL) was added dropwise over 15 minutes. After stirring at the same temperature for 30 minutes, a saturated ammonium chloride solution (20 mL) was added, and the mixture was heated to 0° C. The reaction solution was poured into a mixture of ethyl acetate (100 mL) and 1 mol/mL hydrochloric acid (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was sequentially washed with a saturated sodium bicarbonate solution (50 mL) and brine (50 mL×2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane was added to the resulting residue to prepare a slurry, and the solid was removed by filtration. The filtrate was concentrated, and the resulting solid was removed by filtration. The filtrate was further concentrated to give 3.44 g of the crude title compound as a pale yellow oil. The resulting crude was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[CH2:12]1O[CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:2]([C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][NH:9][CH2:12][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)[CH3:1]
Reactant: COc1ccc(CCN)cc1
Reactant: c1ccc(C2CO2)cc1
Product: COc1ccc2c(c1)C(c1ccccc1)CNCC2

Procedure:
According to the Procedure A above, 4-methoxyphenethylamine is reacted with styrene oxide and the resulting N-(2-hydroxy-2-phenyl)ethyl-4-methoxyphenethylamine is cyclized with acid to give 8-methoxy1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. A salt, for example the hydrochloride, of this compound is reacted with bromine to give the 7-bromo compound which is reacted with butyllithium and phenyl disulfide or trifluoromethanesulfenyl chloride to give 8-methoxy-1-phenyl-7-phenylthio(or 7-trifluoromethylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine. The 8-hydroxy compounds are prepared by O-demethylating the 8-methoxy compounds by standard procedures.
Reaction SMILES: C([N:7]1[N:11]2[C:12]3[C:26]4[CH:27]=[N:28][NH:29][C:25]=4[N:24]=[CH:23][C:13]=3[C:14](=[O:22])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[CH:9][CH:8]1[CH3:30])C1OC=CC=1.COCCOCCOC.[Se](=O)=O>>[CH3:30][C:8]1[CH:9]=[C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3[CH:23]=[N:24][C:25]4[NH:29][N:28]=[CH:27][C:26]=4[C:12]=3[N:11]2[N:7]=1
Reactant: CC1C=C2N(c3ccccc3)C(=O)c3cnc4[nH]ncc4c3N2N1Cc1ccco1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Product: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1
Reaction time: 2 h

Procedure:
0.01 mol. of 1-furfuryl-2-methyl-4-phenyl-4H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is heated in 50 ml. of diethyleneglycol dimethyl ether containing 0.01 mol. of selenium dioxide at reflux temperature with stirring for 2 hours. The mixture is filtered hot and evaporated to dryness. Crystalline 2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one remains.
Reaction SMILES: NC(=O)CO[CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C:13]([NH:15][OH:16])=[O:14])[O:8][N:7]=1.C1(CCCC(C2ON=C(C[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])N=2)CC(O)=O)CCCCC1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)ON>O1CCCC1.CO>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:11]([C:9]2[O:8][N:7]=[C:6]([CH2:5][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[N:10]=2)[CH2:12][C:13]([NH:15][OH:16])=[O:14])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Reactant: CCOC(=O)CCc1noc(C(CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)ON
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CCOC(=O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3R)-6-cyclohexyl-3-[3-(3-ethoxy-3-oxopropyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 94) (110 mg, 0.30 mmol) and N-methylmorpholine (60 μl, 0.54 mmol) in anhydrous tetrahydrofuran (6 ml) was cooled to 0° C., treated with isobutyl chloroformate (42 μl, 0.32 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (120 μl, 1.00 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a yellow oil (94 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([C:24]2[S:25][CH:26]=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:25][CH:26]=2)[CH2:7]1
Reactant: O=C(O)Cc1csc(-c2ccccc2)n1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1csc(-c2ccccc2)n1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 53.7 %

Procedure:
Example 36 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (2-phenyl-1,3-thiazol-4-yl)acetic acid (0.042 g) to give the title compound (0.049 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][CH2:26][OH:27])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.79 (1H, t, J=5.4 Hz), 10.81 (1h, br s), 10.07 (1H, br s), 8.18 (0.61H, s), 8.15 (0.39H, s), 7.35-7.23 (3H, m), 7.14-7.08 (2H, m), 4.73 (1H, br), 3.98 (2H, s), 3.51-3.41 (2H, m), 3.35-3.20 (2H, m); HRMS calcd for C18H16FN3O4+H+: 358.1203. Found 358.1194.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A suspension of 1.30 g (3.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 13 ml of N,N-dimethylformamide was treated with 1.72 g (0.017 mol) of dipropylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol as the eluent. The product was recrystallized from ether/n-hexane. There were obtained 1.32 g (87%) of 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl) -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 143°-146° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][C:14](O)=[O:15])[N:10]([CH2:17][CH3:18])[N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([Cl:27])=[O:15])[N:10]([CH2:17][CH3:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCn1nc(-c2ccc(Cl)cc2)nc1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Cl)cc2)nc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 mmol (318 mg) of [3-(4-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-5-yl]acetic acid and 0.1 mmol (7 mg) of DMF are dissolved in 5 ml of anhydrous dichloromethane 1.3 mmol of oxalyl chloride (163 mg) in 3 ml of anhydrous dichloromethane are added dropwise. The solution is stirred at room temperature for 8 h and then concentrated under reduced pressure. The [3-(4-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-5-yl]acetyl chloride obtained in this manner is processed further in crude form.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.CS(Cl)(=O)=O.[Cl-].[NH4+].C1CCN2C(=NCCC2)CC1>O.ClCCl>[CH3:15][O:14][C:12]1[C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=[C:4]([CH:3]=[CH2:2])[CH:13]=1
Reactant: COc1cc(CCO)cc2c1C(=O)OC2
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: C=Cc1cc2c(c(OC)c1)C(=O)OC2
Reaction time: 0.33 h

Procedure:
A dichloromethane solution of 5-(2-hydroxyethyl)-7-methoxy-2-benzofuran-1(3H)-one was placed cooled to 0° C., and slowly treated with methanesulfonyl chloride (0.11 mL, 1.4 mmol) and TEA (0.2 mL, 1.44 mmol). The resulting mixture was then stirred for 20 min. TLC (hexanes/EtOAc=1/1) indicated completion of the reaction. The mixture was poured into saturated ammonium chloride and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4) and concentrated in vacuo. To the residue (LC/MS: [(M+1)]+=287; tR=0.81 min) (0.16 g, 0.56 mmol) was added DBU (0.19 mL, 1.26 mmol) and dichloromethane (2 mL) and stirred for 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1N HCl, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4) and concentrated to dryness. The resulting oil was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:46]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:47])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCCCC1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using cyclohexanecarbonyl chloride. The final product was obtained in 48% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:21])[CH:11]=[CH:10]2
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(C(O)c3ccccc3)ccc2c1

Procedure:
Using general procedure B, 2-bromo-6-methoxy-naphthalene was reacted with benzaldehyde to give (6-methoxy-naphthalen-2-yl)-phenyl-methanol as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:21][CH:22]=3)[C:17]([C:28]3[N:29]=[C:30]4[C:36]([C:37]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][N:34]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:31]4=[N:32][CH:33]=3)=[N:16]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:40]([NH:39][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:19]=4)[N:15]([CH2:14][CH:10]4[O:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:16]=3)[N:29]=2)[N:34]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:35]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CNCCO4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a stirred solution of 2-(1-((4-benzylmorpholin-2-yl)methyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (see Example 340, 130 mg, 181 μmol) in ethyl acetate (2 mL) and methanol (1 mL) was added palladium on carbon (19.2 mg) and the mixture hydrogenated using a balloon filled with hydrogen gas. After stirring at room temperature for 15 h, the mixture was transferred to a Parr hydrogenator and shaken under 40 psi for 1 h. The mixture was filtered, concentrated in vacuo and then purified by chromatography (silica, 24 g Analogix column, 0-100% ethyl acetate in hexanes followed by 5% methanol in ethyl acetate) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(morpholin-2-ylmethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.10 g 88%). MS (M+H)+=630.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([NH:28][C:29]2[N:34]=[CH:33][C:32]3=[CH:35][CH:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:39]=4)[N:31]3[N:30]=2)[CH:25]=[CH:24][C:23]=1[Cl:48])=O)(C)(C)C>>[Cl:48][C:23]1[CH:24]=[CH:25][C:26]([NH:28][C:29]2[N:34]=[CH:33][C:32]3=[CH:35][CH:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([CH3:47])(=[O:45])=[O:46])[CH:39]=4)[N:31]3[N:30]=2)=[CH:27][C:22]=1[O:21][CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(Cl)c(OC[C@@H]5CCCN5)c4)nn23)c1

Procedure:
This example was made by TFA deprotection of (S)-2-{2-Chloro-5-[7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenoxymethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.5 (brs, 1H), 9.0 (s, 1H), 8.7 (brs, 1H), 8.6 (s, 1H), 8.4 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.8 (t, 1H), 7.6 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.7 Hz, 1H), 7.0 (d, J=4.7 Hz, 1H), 4.1 (m, 1H), 3.95 (m, 2H), 3.3 (s, 3H), 3.2 (m, 2H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H); LC/MS (ESI+): 498 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.[C:24](O)(=[O:26])C>O>[NH2:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][C:9]([CH:24]=[O:26])=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)c1cc(C=O)cc(C(C)C)c1N
Temperature: 120 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 2,6-diisopropylaniline (10.0 g, 56.4 mmol) in acetic acid (160 ml) were added water (40 ml) and hexamethylenetetramine (15.8 g, 0.113 mol) and stirred at 120° C. for 3 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 200 g, developing solvent; hexane:ethyl acetate=10:1) to provide 10.6 g (yield 92%) of 4-amino-3,5-diisopropylbenzaldehyde as yellow solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg].[F:13][C:14]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[C:18]([N+:27]([O-:29])=[O:28])=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23].S(=O)(=O)(O)O>CCOCC.C(Cl)(Cl)(Cl)Cl.C(O)C>[F:13][C:14]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[C:18]([N+:27]([O-:29])=[O:28])=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=1)[C:22]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc([N+](=O)[O-])c(Oc2ccc(F)cc2F)cc1C(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoic acid (1.4 g) and phosphorus pentachloride (1 g) in benzene (10 ml) was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give an oil of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g). A solution of diethyl malonate (0.88 g) and ethanol (0.5 ml) in ether (5 ml) was added dropwise to a stirred solution of magnesium (132 mg), ethanol (0.2 ml), and carbon tetrachloride (0.3 ml) in ether (5 ml) at room temperature. The mixture was stirred for 1 hour at room temperature and refluxed for 30 minutes. To the resulting mixture was added dropwise a solution of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g) in ether (3 ml) at 5° C. The mixture was stirred for 2 hours at room temperature and refluxed for 1 hour. The reaction mixture was poured into 10% sulfuric acid (40 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give an oil of diethyl 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoylmalonate (2.1 g).