Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 31 mg (0.26 mmol, 1.2 eq.) of phenyl isocyanate were reacted according to General Method 4. Yield: 72 mg (79% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[NH:6][C:7]1[NH:8][C:9](=[O:18])[C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[NH:6][C:7]1[NH:8][C:9](=[O:18])[C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cnc(Nc2cccc(OC)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(Nc2ncc(C(=O)O)c(=O)[nH]2)c1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Ethyl 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (3 g) and sodium hydroxide (1 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (60 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (1.8 g). M.p. 247°-249° C.
Reaction SMILES: [NH:1]([CH3:22])[C@H:2]([C:6]([N:8](C)[C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:23]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[NH:23]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:24]([C:32]([N:1]([CH3:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:4])[CH3:5])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of N-Me-Val-N-Me-Tyr-NH2(185 mg, 0.603 mmol) in THF (6 ml), Fmoc-Phe-OH (304 mg, 0.784 mmol), CMPI (200 mg, 0.784 mmol) and TEA (0.168 ml, 1.21 mmol) were added under cooling with ice, followed by stirring at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (197 mg, 48%).
Reaction SMILES: [OH-].[NH4+].Cl[C:4]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[C:6](Cl)[C:5]=1[Cl:13]>[Zn].C1(C)C=CC=CC=1>[Cl:10][C:8]1[C:7]([Cl:11])=[CH:6][C:5]([Cl:13])=[CH:4][N:9]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: Cc1ccccc1
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 35 h

Procedure:
To a 500 milliliter, 3-neck flask which was fitted with a reflux condenser, heater, thermometer and stirrer was added 200 milliliters (1.2 moles) of 6N ammonium hydroxide, 39.0 grams (0.60 gram atom) of zinc dust, 100 milliliters of toluene and 25.1 grams (0.1 mole) of pentachloropyridine. The pH of the mixture was 12.6. The mixture was heated to 70° C., with stirring, and held under these conditions for 35 hours. At the end of this period, the reaction mixture was cooled to 20° C. and filtered to remove insolubles. The filter cake was washed with toluene and the toluene combined with the filtrate and concentrated by distillation. Analysis indicated a 2,3,5-trichloropyridine yield of 9.39 grams (52 percent of theoretical).
Reaction SMILES: [Br:1][C@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11].CO>C1COCC1>[Br:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@@H:8]1[OH:7]
Reactant: N
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@H]2Br
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)[C@H]1CC[C@@H](Br)[C@@H](O)C1

Procedure:
(1S,4R,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (352a) (2.88 g, 14.0 mmol) was taken up in THF (27 mL) and treated with 0.880 ammonia (7.1 mL) at 20° C. for 24 h with stirring. The solvent was then removed in vacuo to give a white solid in quantitative yield; [α]D=−55.4° (c=1, MeOH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1COCC1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[Mg]Br>CCCCCC>[CH2:2]([C:19]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1c(C)cc(C)cc1C

Procedure:
1-Bromodecane (110.8 mg, 0.5 mmol) and a THF solution (0.66 mL, 1.14 M, 0.75 mmol) of 2,4,6-trimethylphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 2,4,6-trimethylphenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After thin-layer chromatography (hexane), the title compound was obtained as a colorless liquid (0.099 g, yield 76%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]([C@@H:25]([CH:33]3[CH2:35][CH2:34]3)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:19]2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH:15]=[CH:16][CH:17]=1.[CH2:43](Br)[CH:44]=[CH2:45]>C1COCC1>[CH2:45]([C@H:22]1[CH2:23][C@H:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)[C@@H:19]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[N:20]([C@@H:25]([CH:33]2[CH2:35][CH2:34]2)[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[C:21]1=[O:24])[CH:44]=[CH2:43]
Reactant: CC(C)(C)OC(=O)[C@H](C1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C(=O)OC(C)(C)C)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in THF, 0.165 mL, 0.165 mmol) was added dropwise at −78° C. to a solution of (S)-tert-butyl 2-(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate (Example 249, Step C, 71 mg, 0.15 mmol) and allyl bromide (15.54 uL, 0.165 mmol) in 0.5 mL of THF. The reaction was allowed to warm to ambient temperature. After stirring for 2 h, the reaction was quenched with sat. aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution and dried over sodium sulfate, then filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with ethyl acetate/hexane provided the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:1]([O:4][C:5]1[S:6][C:7]([CH:17]=[O:18])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)Oc1cccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
To a solution of 2-isopropoxythiophene (250 mg, 1.76 mmol) in 9 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.77 mL, 2.5 M in hexanes) dropwise. After stirring at −78° C. for 20 minutes, dimethylformamide (0.68 mL, 8.80 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 30 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (2×35 mL), washed with 1 N hydrochloric acid (2×20 mL), water (20 mL) and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (7% ethyl acetate in hexanes) to give 5-isopropoxy-2-thiophenecarbaldehyde (108 mg, 36%). Used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(F)c(F)c3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BX) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 84%, 407.9815 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH:22]([CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:23]1[CH2:27][C@@H:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25](OC(=O)C)[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH:22]([C@@H:23]1[CH2:27][C@@H:26]([O:28][C:29](=[O:31])[CH3:30])[C@H:25]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:24]1)[CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC1O[C@H](C(OC(=O)c2ccccc2)C2CCCC2)C[C@H]1OC(C)=O
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@@H](C(OC(=O)c2ccccc2)C2CCCC2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (370 mg, 2.0 mmol) in ACN (20 mL) was added BSA (2.1 g, 10 mmol). The resulting reaction mixture was then stirred at 70° C. for 0.5 hour under argon to form a clear solution. After the solution was cooled to room temperature, [cyclopentyl-[(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]methyl] benzoate (compound 11c, 400 mg, 1.0 mmol) and TMSOTf (2.25 g, 10 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was collected and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:1 EtOAc in petroleum ether) to afford 160 mg of [[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]-cyclopentyl-methyl] benzoate (compound 11d).
Reaction SMILES: [ClH:1].[CH2:2]([NH2:5])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH2:15]([O:22][C:23](=[O:26])[CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[ClH:1].[CH2:15]([O:22][C:23](=[O:26])[CH2:24][NH:5][CH2:2][CH:3]=[CH2:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCN
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of allylamine hydrochloride (5.0 g, 53.4 mmol) in tetrahydrofuran (100 mL) was added diisopropylethylamine (10 mL) and bromoacetic acid benzyl ester (3.06 g, 13.3 mmol) at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added ethyl acetate and 1 N-hydrochloric acid solution, the organic layer was separated, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were combined, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and to the obtained oil was added 4N-Hydrogen chloride in 1,4-Dioxane (3.5 mL). The mixture was concentrated under reduced pressure and lyophilized to give the title compound (2.12 g, 8.79 mmol, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[ClH:35]>CC(O)C.CO>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH:29]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]5)(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)C1CCCNC1
Yield: 20 %

Procedure:
N-(2-(1-(1-(4-chlorophenyl)cyclobutyl)-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl)pyridine-3-sulfonamide (110 mg, 0.221 mmol, example 10) and a 6 molar solution of HCl in 2-propanol were dissolved in methanol (10 ml) and treated in an hydrogenation flow reactor (H-Cube®, Platinium (IV) oxide cartridge THS02119, ThalesNano) at 30 bar and 30° C. with a flow of 0.5 ml/min under circulating conditions for 14 h. The final product was purified by HPLC using . . . to yield the final product as a white powder (25.0 mg, 0.043 mmol, 20%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1
Reactant: COC(=O)c1coc(CCl)n1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Yield: 91.4 %

Procedure:
A suspended mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.60 g, 5.70 mmol), methyl 2-(chloromethyl)oxazole-4-carboxylate (1.00 g, 5.70 mmol) and cesium carbonate (3.71 g, 11.4 mmol) in tetrahydrofuran (10 mL) was refluxed for 16 h. The reaction mixture was cold down to ambient temperature and concentrated in vacuo. The residue was treated with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 20% to 30% gradient of ethyl acetate in hexanes to afford methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (2.19 g, 92%) as a colorless solid: mp 183-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 5.90 (d, J=2.1 Hz, 2H), 5.23-5.17 (m, 2H), 4.74 (ABq, 2H), 3.74 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 161.3, 160.2, 155.6, 148.8, 146.9, 142.3, 142.0, 132.8, 132.4, 129.4, 124.1, 123.9, 120.4, 109.7, 103.9, 101.9, 93.7, 80.0, 57.9, 52.3, 37.4; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Cl:19]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([Cl:19])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
1.0 g (4.40 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate was initially charged in 10.0 ml of acetonitrile, and 540 mg (4.40 mmol) of N-chlorosuccinimide were added a little at a time at 0° C. After 30 min, the mixture was warmed to RT and stirred at this temperature overnight. After concentration under reduced pressure, the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. By chromatography on silica gel (mobile phase gradient cyclohexane/ethyl acetate 10:1→6:1), 217 mg of a mixed fraction (about 1:1) consisting of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclo-propanecarboxylate and tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate, and also 995.5 mg of tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate, slightly contaminated by the starting material tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, were isolated from the crude product obtained in this manner. The mixed fraction (217 mg) was separated further by preparative RP-HPLC [column: Sunfire C18 5 μm, 250 mm×20 mm; injection volume: 0.50 ml; temperature: 25° C.; mobile phase: 55% acetonitrile/40% water/5% (water+1% TFA); flow rate: 35 ml/min; detection: 210 nm]. In this manner, it was possible to isolate 85 mg (7.5% of theory) of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 22A). Starting with 995.5 mg of the slightly contaminated material, 677.6 mg (59.5% of theory) of pure tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 23A) were isolated by preparative RP-HPLC (mobile phase: acetonitrile/water gradient).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([NH:30][CH2:31][CH3:32])=[C:24]([N+:27]([O-])=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Fe]>[NH2:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[NH:30][CH2:31][CH3:32])[N:20]=[CH:19][N:18]=[C:17]2[N:14]1[CH2:15][CH2:16][N:11]([C:9](=[S:10])[NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Yield: 92 %

Procedure:
To a suspension of 4.26 g (9.44 mmol) of N-benzyl-4-(7-ethylamino-6-nitro-4-quinazolinyl)-1-piperazinethiocarboxamide obtained in Example 361 in 100 ml of ethanol and 10 ml of water were added 4.26 g (76.3 mmol) of iron powder and 430 mg (1.59 mmol) of ferric chloride hexahydrate under ice-cooling, followed by heating under reflux in an atmosphere of argon for 4 hours. After the iron powder was separated by filtration using Celite, the solvent was evaporated, and the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[Li]CCCC.CC([O:24][B:25](OC(C)C)[O:26]C(C)C)C>O1CCCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([B:25]([OH:26])[OH:24])=[CH:7][CH:6]=1
Reactant: Fc1ccccc1Oc1ccc(I)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2F)cc1
Temperature: -78 °C
Yield: 90.2 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1-(2-fluorophenoxy)-4-iodobenzene (3.3 g, 10.51 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). n-BuLi (4.4 mL) was added dropwise with stirring at −78° C. The resulting solution was stirred for 10 mins at −78° C. and then tris(propan-2-yl)borate (2.1 g, 11.17 mmol, 1.06 equiv) was added dropwise with stirring at −78° C. over 10 min. The resulting solution was stirred while the temperature warmed from −78° C. to room temperature. The reaction was then quenched by the addition of saturated aqueous NH4Cl and concentrated under vacuum. The resulting solution was diluted with 10% aquious potassium hydroxide and then washed with ether. The pH of the aqueous was adjusted to 2-4 with hydrogen chloride (37%). The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.2 g (90%) of [4-(2-fluorophenoxy)phenyl]boronic acid as a white solid
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[CH3:24][C:25]1[O:26][C:27]([CH3:33])=[C:28]([C:30](Cl)=[O:31])[N:29]=1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:28]5[N:29]=[C:25]([CH3:24])[O:26][C:27]=5[CH3:33])=[O:31])[CH:23]=[CH:22][CH:21]=4)=[CH:11][N:10]3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C)o1
Yield: 70.2 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring under ice-cooling 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (108 mg, 0.678 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (68.6 mg, 70%) as a white solid.