Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[O:12][C:11]3=[C:6]2[O:5][C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3]1.S1C=CC=C1.[H][H]>CO.[Pd]>[CH3:16][C:13]1[O:12][C:11]2=[C:6]3[O:5][CH:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3][CH2:2][C:7]3=[CH:8][CH:9]=[C:10]2[C:14]=1[CH3:15]
Reactant: CCOC(=O)c1cc(=O)c2ccc3c(C)c(C)oc3c2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)C1CCc2ccc3c(C)c(C)oc3c2O1
Yield: 72.9 %

Procedure:
A solution of ethyl 6-oxo-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-carboxylate (0.1 mol) in methanol (250 ml) was hydrogenated for 10 hours at 170° C. (pressurized) with palladium on activated carbon, palladium content 5% (2 g) as a catalyst in the presence of a 4% thiophene solution (10 ml). After uptake of hydrogen (3 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated, yielding 20 g (72.9%) of (±)-ethyl 7,8-dihydro-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-carboxylate (interm. 16-a).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][OH:15].C[O-].[Na+].Cl>O>[CH3:14][O:15][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.83 h

Procedure:
A reaction vessel equipped with a stirrer, a thermometer, and a nitrogen inlet tube was charged with 856 g of 2-nitrobenzenesulfonyl chloride and 7 L of methanol, and then a mixed solution of 745 g of 28% sodium methylate and 600 ml of methanol was dropped for 45 minutes at a temperature of 10° C. or less. The mixture was then stirred for 50 minutes while maintaining the temperature at 10° C. The reaction mixture was acidified by adding 1.6 kg of 0.1 mol/l hydrochloric acid, and then adding 3 L of water, whereby crystals deposited. The crystals were filtered, washed with 2 L of water, and then dried under reduced pressure for 10 hours at 30° C. to obtain 702 g of 2-nitrobenzene sulfonic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[F:10][C:11]1[CH:48]=[CH:47][C:14]([C:15]([C:17]2[N:26]=[C:25](C3C(C(C)C)=C(S([O-])(=O)=O)C(C(C)C)=CC=3C(C)C)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:13][CH:12]=1.O>CC(N(C)C)=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[N:26]=[C:25]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:47][CH:48]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Cc1ccc2c(-c3c(C(C)C)cc(C(C)C)c(S(=O)(=O)[O-])c3C(C)C)nc(C(=O)c3ccc(F)cc3)nc2c1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 14.4 %

Procedure:
A solution of 5-methyl-1H-pyrazol-3-amine (225 mg, 2.31 mmol), potassium iodide (188 mg, 0.088 mmol), and 2-(4-fluorobenzoyl)-7-methylquinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate (380 mg, 0.69 mmol) in DMA (2 mL) was stirred at 50° C. for 6 h, then water was added and the solution was filtered. The solid was then dried and triturated with acetonitrile to give (4-fluorophenyl)(7-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (36 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.50 (s, 3H), 6.53 (s, 1H), 7.38 (t, 2H), 7.51 (d, 2H), 7.66 (s, 1H), 8.08 (m, 2H), 8.62 (d, 1H), 10.57 (s, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]([NH:19][NH2:20])=[CH:17][C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH3:23])[C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=S.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]2[NH:19][N:20]=[C:24]([NH:25][CH3:26])[C:17]=2[C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH3:23])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(CCOCc2ccccc2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(CCOCc2ccccc2)c1=O
Reaction time: 20 h

Procedure:
A solution of 1-(2-benzyloxyethyl)-6-hydrazino-3-propyluracil (2.0 g, 6.3 mM) and methyl isothiocyanate (1.2 ml, 18 mM) in DMF (20 ml) was stirred at 60° C. for 1 hour and then at 100° C. for 20 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless prisms (1.39 g, 62%), m.p. 224°-226° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([C@@H:31]([NH:33][CH2:34][C:35]([C:37]2([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38]2)=[O:36])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([N:33]([CH2:34][C:35]([C:37]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH2:39]1)=[O:36])[C@H:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:32])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)CN[C@@H](C)c2ccccc2)CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Diethylphosphonoacetic acid (15.1 g, 76.8 mmol) was dissolved in anhydrous tetrahydrofuran (120 ml), and after adding 1,1′-carbonyldiimidazole (13.7 g, 84.5 mmol) while cooling with ice, it was stirred at room temperature for 1 hour. After adding an anhydrous tetrahydrofuran (30 ml) solution of ethyl 1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (17.6 g, 64.0 mmol) to the reaction solution while cooling with ice, it was stirred at room temperature for 1 hour. After adding 1 mol/l hydrochloric acid (100 ml) and ethyl acetate (100 ml) to the reaction solution and performing an extraction operation, the organic layer was separated. The aqueous layer was then subjected to extraction with ethyl acetate (100 ml) and the combined organic layer was washed with saturated sodium bicarbonate water (100 ml) and saturated saline solution (100 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering and then concentrating the filtrate under a reduced pressure, 28.7 g (99%) of the title compound was obtained as a yellow syrup.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:26][CH:25]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Reactant: COc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo [b,e][1,4]oxazepine (Preparation Example 1) (280 mg, 1.0 mmol), 3-(4-methoxyphenyl)-1-propyl bromide (320 mg, 1.4 mmol), sodium carbonate (150 mg, 1.4 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (20 ml), and the mixture was heated under reflux at 90° C. for 13 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned in ethyl acetate and water. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was treated by the column chromatography and then eluted with dichloromethane as the eluent. A suitable fraction was collected, and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow oil (310 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([F:21])=[C:9]([CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:10]=1.[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:14]([CH:11]([C:12]#[N:13])[C:9]1[CH:10]=[C:5]([CH:6]=[CH:7][C:8]=1[F:21])[O:4][CH2:3][CH2:2][NH:1][S:28]([C:26]1[N:25]=[CH:24][N:23]([CH3:22])[CH:27]=1)(=[O:30])=[O:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: N#CC(Cc1ccccc1)c1cc(OCCN)ccc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc(F)c(C(C#N)Cc3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[5-(2-amino-ethoxy)-2-fluoro-phenyl]-3-phenyl-propionitrile (536 mg, 1.885 mmol) in dry dichloromethane was added 4-dimethylaminopyridine (345 mg, 2.83 mmol) followed by 1-methyl-1H-imidazole-4-sulfonyl chloride (409 mg, 2.262 mmol). The mixture was stirred at RT under argon over night. Dichloromethane was added and the mixture was subsequently washed twice with 1N hydrochloric acid, water, sodium bicarbonate solution, brine and then dried over sodium sulfate, filtered and concentrated to obtain the desired product as a pale yellow solid.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4][CH2:5][CH:6]([S:10][C:11](CC1C=CC=CC=1)=S)[C:7]([OH:9])=[O:8].Cl>C(O)C>[O:1]=[C:11]1[NH:4][CH2:5][CH:6]([C:7]([OH:9])=[O:8])[S:10]1
Reactant: [OH-]
Reactant: NCC(SC(=S)Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1NCC(C(=O)O)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12.0 ml of a 1 N aqueous solution of sodium hydroxide were added to a suspension of 1.2 g of 3-amino-2-(benzylthiocarbonylthio)propionic acid hydrochloride in 35 ml of ethanol, and the resulting mixture was stirred at room temperature for 30 minutes, after which 12.0 ml of 1 N aqueous hydrochloric acid were added, whilst ice-cooling. The solvent was then removed by distillation under reduced pressure, the resulting residue was dissolved in diethyl ether and the solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 0.50 g of a colorless powder. This powder was recrystallized from ethyl acetate, to give 0.25 g of the title compound as colorless columnar crystals, melting at 148°-150° C.
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.C([O-])([O-])=O.[K+].[K+].CC(O)(C)C.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: C1CCNC1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CN1CCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A slurry of Compound 4 (60 mg) and K2CO3 (43 mg) in deionized water (1 mL) was stirred at room temperature for 30 min. To the resulting reaction mixture, t-BuOH (1 mL) and pyrrolidine (52 μL) were added and heated at 70° C. for 5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in acetic acid (10 mL) and stirred at room temperature for 2 hours. The acetic acid solution was concentrated again under vacuum. Finally, the residue was partitioned between chloroform (2×15 mL) and 7% aqueous NaHCO3 solution (5 mL). The collective organic layers were dried, concentrated and purified on a silica gel using 10% ethanol in dichloromethane to afford the required product in 83% yield (45 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:33][O:34][CH:35]=[CH:36][C:37](Cl)=[O:38]>C1C=CC=CC=1>[CH3:33][O:34][CH:35]=[CH:36][C:37]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:38]
Reactant: COC=CC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)cc3)CC2)cc1OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC=CC(=O)Nc1ccc(N2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)cc1
Yield: 72.9 %

Procedure:
A solution of 11 g of p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline in 100 ml of benzene was added 4.56 ml of triethylamine and refluxed while adding dropwise a solution of 3.94 g of β-methoxyacryloyl chloride in 20 ml of benzene. After completion of addition, the mixture was refluxed for 1 hour. After completion of reaction, the reaction mixture was washed with water and dried. The solvent was distilled off and the residue was purified through silica gel column chromatography to give 10 g of N-(β-methoxyacryloyl)-p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.CO>[Fe].O>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2nc[nH]n2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: Nc1ccc(Sc2nc[nH]n2)cc1N

Procedure:
A mixture of 3.2 g. 2-amino-1-nitro-4-(1,2,4-triazol-3-ylthio)benzene, 3.2 g. of iron powder, 1.6 g. ferrous sulfate in 240 ml. methanol and 60 ml. water is refluxed for 6 hours (with one additional portion of iron being added after 3 hours. The mixture is cooled, filtered and the filtrate stripped under vacuum to yield 1,2-diamino-4-(1,2,4-triazol-3-ylthio)benzene.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[Cl-].[NH4+]>O.CN(C)C=O>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1)[CH3:16]
Reactant: Oc1cc(O)cc(Cl)c1
Reactant: CCOC(CCl)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1cc(O)cc(Cl)c1)OCC
Temperature: 90 °C

Procedure:
The monosodium salt of 3-hydroxy-5-chlorophenol (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reacton vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-diethoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 3-(2,2-diethoxyethoxy)-5-chlorophenol.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([CH:53]([C:57]([O-])=[O:58])[N:54]([CH3:56])[CH3:55])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:57](=[O:58])[CH2:53][N:54]([CH3:56])[CH3:55])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CN(C)C(C(=O)[O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)CN(C)C)cc2)n1
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.104 mmol) in N,N-dimethylformamide (1 mL) was treated with diisopropylethylamine (0.4 mmol) and then pentafluorophenyl-N,N-dimethylglycinate (0.104 mmol). The reaction was stirred 18 h and purified directly on the Gilson reverse phase HPLC which provided the title product as a yellow solid (57%). ESMS [M+H]+: 564.2
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])C.C(OCC)(=O)C.[CH3:19][NH2:20]>CO>[CH3:19][NH:20][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1ccncc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
4-Ethoxy-3-nitropyridine (10.0 g) was dissolved in a 40% methanol solution of methyl amine (100 mL), and this was heated at 80° C. for 60 hours. The solution was cooled, ethyl acetate (500 mL) was added, and the organic layer was washed twice with 300 mL of water and once with 300 mL of saturated aqueous sodium chloride solution. This was then dried over anhydrous magnesium sulfate. The solution was filtered, and concentrated under reduced pressure to give the title compound (7.00 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:34][C:35]1[CH:41]=[C:40]([I:42])[CH:39]=[CH:38][C:36]=1[NH2:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.BrN1C(=O)CCC1=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:21])[NH:37][C:36]3[CH:38]=[CH:39][C:40]([I:42])=[CH:41][C:35]=3[F:34])[CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)Nc1ccc(I)cc1F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-naphthalen-2-yl-propionic acid (1.0 g, 2.30 mmol) and 2-fluoro-4-iodoaniline (434 mg, 1.84 mmol), triphenylphosphine (0.94 g, 3.45 mmol) and pyridine (0.39 mL, 4.60 mmol) in dichloromethane (10 mL) at 0° C. was added N-bromosuccinimide (0.61 mg, 3.45 mmol) in two portions under an atmosphere of dry nitrogen. The mixture was stirred for 2 hours at 0° C. The reaction mixture was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-naphthalen-2-yl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a yellow solid foam (1.05 g, 70%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:22])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[Si:38]([O:22][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of (S)-ethyl 1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate (17.0 g, 56.2 mmol) and DIPEA (17.68 ml, 101 mmol) in CH2Cl2 (187 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (16 ml, 69.6 mmol) slowly. The reaction was monitored with HPLC. The reaction completed in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted with DCM. The organic phase was combined and dried with Na2SO4. After concentration, the crude material was further purified on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to afford a purified product (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidine-3-carboxylate (22.25 g, 53.4 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.79 (1H, m), 4.15 (2H, m), 2.88 (1H, m), 2.75 (1H, m), 2.60 (1H, dd), 2.48 (1H, m), 2.40 (1H, dd), 2.33 (1H, tt), 2.12 (1H, tt), 1.90 (1H, m), 1.68 (1H, dt), 1.52 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)cccc3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=410.0.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[OH:33])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:52]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:53][C:54]([NH:56][C@H:57]([C:59]([NH:61][C@H:62]([C:72]([NH:74][C@H:75]([C:80]([NH:82]N)=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:63][O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:60])[CH3:58])=[O:55]>>[NH:52]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:53][C:54]([NH:56][C@H:57]([C:59]([NH:61][C@H:62]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:30][CH2:31][C:32](=[O:33])[OH:34])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:63][O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:60])[CH3:58])=[O:55]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Product: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Yield: 76.8 %

Procedure:
By using 2.56 g of Boc-Ser(Bzl)-Thr(Bzl)-Glu-OBzl and 2.00 g of Boc-Gly-Ala-Ser(Bzl)-Leu-NHNH2, and the same procedure as in Reference Example 7 was repeated to obtain 3.13 g (yield: 76.8%) of the above-mentioned objective product.