Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([CH3:33])=[CH:20][CH:21]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(C)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-p-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=391.12.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 51.6 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (63 mg, 0.15 mmol) and 2-bromo ethanol (90 mg, 0.72 mmol) to give 7-cyclopentyl-2-[1′-(2-hydroxy-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (37 mg, 53%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:30]1([CH2:36][B-](F)(F)F)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)CN1CCCCC1
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCCCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and potassium piperidin-1-ylmethyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1([C:8](Cl)=[O:9])[CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1.Cl>C(=S)=S>[CH:5]1([C:8]([C:20]2[O:19][C:18]([C:15]3[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=3)=[CH:22][CH:21]=2)=[O:9])[CH2:7][CH2:6]1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1ccc(-c2ccc(Cl)cc2)o1)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a stirring mixture of 128 g (0.96 mole) of AlCl3 and 720 ml of CS2 was added portionwise 100 g (0.96 mole) of cyclopropanecarboxylic acid chloride while keeping the temperature below 30° by means of an ice bath. A solution of 172 g (0.96 mole) of 2-(4-chlorophenyl)furan in 480 ml of CS2 was added dropwise while maintaining the temperature between 10°-15° with large volume of HCl gas being given off. The reaction mixture was stirred in an ice bath for 15 minutes, allowed to warm to room temperature over a one hour period, and then added to 2000 ml of ice/water. The aqueous layer was separated from the CS2 layer and extracted with 2 × 500 ml portions of CH2Cl2. The CS2 and CH2Cl2 layers were combined, were washed with 1000 ml of 6% Na2CO3 solution and with 1000 ml of water, and then dried over magnesium sulfate. The solvent was removed on a rotary evaporator leaving red-brown residue which was extracted several times with boiling hexane. The combined hexane extracts were cooled and the resulting solid filtered and air dried to yield 41 g (17%) of product. An analytical sample was prepared by recrystallizing a sample from hexane/Darco, m.p. 88°-89°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][N:14]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Reaction time: 15 h
Yield: 87.8 %

Procedure:
In 100 ml of methylene chloride were added 6.0 g of piperazine and 1.2 g of anhydrous potassium carbonate, and to the mixture was added dropwise 30 ml of a methylene chloride solution containing 2.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for 15 hours, and then the reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the methylene chloride was distilled therefrom. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.14 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35) in a yield of 89%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Product: O=C1CCCc2cc(O)ccc21
Yield: 85 %

Procedure:
A solution of 6-methoxy-1-tetralone (5.0 g) in 48% hydrobromic acid (62 ml) was refluxed for 8 hours. The mixture was cooled, filtered and washed with water (50 ml) to give 6-hydroxy-1-tetralone (3.91 g): NMR δ (d6DMSO) 1.9-2.05(m,2H), 2.4-2.55(m,2H), 2.8-2.9(m,2H), 6.65(d,1H), 6.7(dd,1H), 7.75(d,1H),; m/e 163(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](O)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.OS([O-])(=O)=O.[K+].[BH4-].[Na+]>C(Cl)Cl.C1COCC1.CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][OH:17])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Temperature: -65 °C
Reaction time: 0.83 h

Procedure:
A suspension of trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexane-carboxylic acid (155 g, 603 mmol) in CH2Cl2 (1.35 L) was cooled at −65° C. and triethylamine (126 mL, 904 mmol) and a solution of ethyl chloroformate (58 mL, 751 mmol) in CH2Cl2 (200 mL) were added below −60° C. The reaction mixture was stirred at 0° C. for 50 min. The mixture was acidified with saturated aqueous KHSO4 (pH=3), and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with saturated aqueous Na2CO3 and brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. A solution of the above oil in THF (1.5 L) was cooled at −65° C. and NaBH4 (26.6 g, 703 mmol) and MeOH (45 mL) were added. The mixture was stirred at −40° C. for 25 min, and stirred at 4° C. for 3 hr. The mixture was acidified with saturated aqueous KHSO4 (pH=3), and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was washed with saturated aqueous Na2CO3 and brine, dried over MgSO4, filtered, and concentrated, and purified by flash chromatography (silica gel, 17% MeOH in CHCl3) to give trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (123 g, 84%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH:33]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C

Procedure:
A microwaveable vial was charged with 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 6) (74 mg, 0.192 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.) (63 mg, 0.250 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.029 mmol), potassium carbonate (56 mg, 0.405 mmol), water (0.5 ml), and 1,4-dioxane (1.5 ml). The vial was sealed and heated at 120° C. for 30 min (microwave). The reaction solution was diluted with water (10 ml), extracted with ethyl acetate (3×15 ml). The organics were combined, dried (hydrophobic frit). The solvent was evaporated in vacuo. The residue was dissolved in methanol/DMSO (1:1, 1 ml) and purified by MDAP (TFA). The solvent was evaporated under a stream of nitrogen, the residue was redissolved in methanol and filtered through an aminopropyl SPE (2 g). The solvent was evaporated in vacuo, to give 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (40 mg) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](C(N)=O)=[C:6]2SC1C=CC=CC=1)=[O:2].[CH3:22]I>CO.C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[CH:7]=[CH:6]2)=[O:2]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CI
Solvent: CO
Solvent: ClCCl
Product: Cn1ccc2cc(C=O)ccc21

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph; 400 mg, 1.35 mmol) with MeI (101 μl) as described in General Procedure XIV to provide the 5-formyl-1-methylindole the title compound 14 (280 mg, 67%), Rf (5% MeOH/CH2Cl2)=0.75.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)CCc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CCc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and 3-phenyl-propionic acid chloride (157 μl, 1.06 mmol). The title compound was obtained as yellow powder (201 mg, 47%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:34]([C:35]#[C:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:33][N:13]([C@@H:14]2[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])[CH2:15]2)[C:12](=[O:45])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([NH:9][C:10]1[C:34]([C:35]#[C:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:42])([F:41])[F:43])=[CH:33][N:13]([C@@H:14]2[O:32][C@H:22]([CH2:23][OH:24])[C@@H:16]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])[CH2:15]2)[C:12](=[O:45])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1OCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material (15) (140 mg, 0.22 mmol) was dissolved in THF (7.5 ml). TBAF (1M soln. in THF, 0.25 ml) was added slowly and stirred for 2 h at room temperature. Volatile material removed under reduced pressure to yield a brown gel that was purified by flash chromatography (EtOAc:DCM 7:3) to yield the desired product (16) as a light coloured crystalline solid (0.9 g, 76%). 1H NMR (d6 DMSO): δ 2.16 (m, 1H, H-2′), 2.22 (m, 1H, H-2′), 3.70 (d, 1H, J=11.5 Hz, H-5′), 3.75 (d, 1H, J=11.3 Hz, H-5′), 4.01 (m, 1H, H-4′), 4.10 (m, 1H, CH2NH), 4.23 (m, 1H, H-3′), 4.76 (s, 2H, CH2S), 5.32 (s, 1H, 5′OH), 5.99 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.81 (d, 1H, J=7.35 Hz, Ph), 7.95 (s, 1H, H-6), 9.78 (br s, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C22H20F3N7O6 535.44. Found 534.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]([CH3:11])[CH3:12])[CH2:25][CH2:24]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-tert-butoxycarbonyl-L-valine (2.27 g, 10 mmol) and 1-(2-chlorophenyl)piperazine (2.00 g, 10 mmol) in N,N-dimethylformamide (50 ml) under ice-cooling was dropwise added a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g, 11 mmol) and 1-hydroxybenzotriazole (1.5 g, 11 mmol) in dichloromethane (50 ml), and the reaction mixture was stirred at room temperature for 15 hours. The dichloromethane was then distilled off under reduced pressure and ethyl acetate (200 ml) was added to the residue. The ethyl acetate layer was washed successively with 10 w/v % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine in the order mentioned and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was subjected to silica gel chromatography. Elution with ethyl acetate-n-hexane (1:2, v/v) gave 1,1-dimethylethyl 2-(4-(2-chlorophenyl)piperazinyl)-2-oxo-(s)-1-(2-propyl)ethylcarbamate. This colorless oil was dissolved in ethyl acetate (50 ml), and 4N HCl/ethyl acetate (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction product was filtered and washed with ethyl acetate-n-hexane (1:1, v/v) to give 1-((s)-2-amino-3-methyl-1-oxobutyl)-4-(2-chlorophenyl)piperazine hydrochloride (3.32 g, 95.8%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Brc1ccccc1-c1ccccc1
Product: Cc1ccc(-c2ccccc2-c2ccccc2)cc1

Procedure:
Prepared from 2-bromobiphenyl and 4-methylphenyltrimethylstannane by the procedure described in Example 69, Step B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccncc1
Product: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and pyridine-4-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=0.906 min, m/z=448.1; 1H NMR (CDCl3) 1.59 (d, 3H), 2.15 (m, 1H), 2.24-2.32 (m, 4H), 2.45 (m, 1H), 3.07 (m, 2H), 5.66 (m, 1H), 5.71 (m, 1H), 5.84 (m, 1H), 7.03 (m, 2H), 7.05 (m, 2H), 7.22 (m, 1H), 7.25 (m, 1H), 7.50 (d, 2H), 7.93 (d, 2H), 8.84 (d, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[C:19]([N+:31]([O-])=O)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[NH2:31][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[OH:23])[O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cc(OCCN2CCC(Cc3ccccc3)CC2)ccc1OCc1ccccc1
Solvent: CO
Product: Nc1cc(OCCN2CCC(Cc3ccccc3)CC2)ccc1O
Yield: 98.8 %

Procedure:
A mixture of 4-benzyl-1-(2-(4-benzyloxy-3-nitrophenoxy)ethyl)piperidine (1.40 g, 3.1 mmol) and 10% pd/C (about 500 mg) in MeOH (30 mL) was hydrogenated to give 1.0 g (98%) of 1-(2-(3-amino-4-hydroxyphenoxy)ethyl)-4-benzylpiperidine as a viscous oil. 1H NMR (CDCl3): 1.40-1.68 (m, 5H), 2.06-2.13 (m, 2H), 2.530 (t, 2H, J=5.5), 6.000 (d, 2H, J=8), 6.242 (bs, 1H), 6.534 (d, 1H, J=8), 7.12-7.19 (m, 5H).
Reaction SMILES: [NH:1]([C:13](CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[CH3:28][C:29]([NH:31][CH:32]([C:39]([OH:41])=[O:40])[CH2:33][S:34][C:35]([NH:37][CH3:38])=[O:36])=[O:30].C1CN(C(CN)=O)[C@H](C(O)=O)C1.CC(NC(C(O)=O)CSC(NC)=O)=O.N(C(OCC1C=CC=CC=1)=O)CC(N1CCC[C@H]1C(NC1C=C2C(C(C)=CC(=O)O2)=CC=1)=O)=O.C1CN(C(CN)=O)[C@H](C(NC2C=CC3C(C(F)(F)F)=CC(OC=3C=2)=O)=O)C1>>[NH:1]([CH:13]=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[CH3:28][C:29]([NH:31][CH:32]([C:39]([OH:41])=[O:40])[CH2:33][S:34][C:35]([NH:37][CH3:38])=[O:36])=[O:30]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: CNC(=O)SCC(NC(C)=O)C(=O)O
Agent: Cc1cc(=O)oc2cc(NC(=O)[C@@H]3CCCN3C(=O)CNC(=O)OCc3ccccc3)ccc12
Agent: NCC(=O)N1CCC[C@H]1C(=O)Nc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Product: O=CNCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
To examine whether FAP could cleave other N-substituted-Gly-Pro-based substrates, N-methyl-, formyl-, succinyl-, benzyloxycarbonyl-(Z-) and biotinyl-Gly-Pro-AMCC substrates 6 were synthesized and reacted with FAP (37 nM) and DPP-4 (6.8 nM). With the exception of succinyl-Gly-Pro-AMCC, FAP cleaved all N-substituted-Gly-Pro-AMCC substrates 6 at rates 35-150% of the normalized rate for Gly-Pro-AMCC hydrolysis (Table 2), indicating that the protease tolerates other N-terminal blocking groups. Kinetic analysis with commercially available Z-Gly-Pro-AMC (Table 5) showed a catalytic efficiency about 3-fold lower than that for Gly-Pro-AFC (Table 4), consistent with these results. In contrast with FAP, DPP-4 cleaved only N-methyl-Gly-Pro-AMCC at a rate comparable to Gly-Pro-AMCC. A low rate of hydrolysis was obtained with formyl-Gly-Pro-AMCC substrates but no cleavage of succinyl-, Z-, or biotinyl-Gly-Pro-AMCC substrates was observed at concentrations up to 1 mM, indicating that DPP-4 does not tolerate N-acyl-Gly-Pro-based substrates. DPP-4 also showed little activity against commercially available Z-Gly-Pro-AMC (Table 5).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:20]>O>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[Ag:20]
Reactant: [Ag+]
Agent: CCCCc1ccc2[nH]nnc2c1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Ag]
Reaction time: 0.07 h

Procedure:
1.0 g of 5-butylbenzotriazole, 0.24 g of sodium hydroxide, and 25 g of phthalated gelatin were dissolved in 700 mL of water. The solution was kept at 60° C. and stirred. Then, to the resulting solution were added a solution prepared by dissolving 5 g of 5-butylbenzotriazole and 1.2 g of sodium hydroxide in 150 mL of water and a solution prepared by dissolving 5 g of silver nitrate in 150 mL of water, simultaneously, over a period of 4 minutes. The resulting solution was stirred for 5 minutes. After that, to the solution were added a solution prepared by dissolving 5 g of 5-butylbenzotriazole and 1.2 g of sodium hydroxide in 150 mL of water and a solution prepared by dissolving 5 g of silver nitrate in 150 mL of water, simultaneously, over a period of 6 minutes. The pH of the resulting emulsion was adjusted so as to cause precipitation and excess salt was removed. After that, the pH was adjusted to 6.0, and a silver 5-butylbenzotriazole emulsion in an yield of 470 g was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([O:8]/[CH:9]=[C:10]2\[CH:11]3[CH2:25][CH:24]=[CH:23][CH:12]3[N:13](C(OC(C)(C)C)=O)[C:14]\2=[O:15])[CH:3]=1.[Cl-].[Mg+2].[Cl-].C(Cl)Cl>C(#N)C>[CH3:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([O:8]/[CH:9]=[C:10]2\[CH:11]3[CH2:25][CH:24]=[CH:23][CH:12]3[NH:13][C:14]\2=[O:15])[CH:3]=1
Reactant: CC1=CC(O/C=C2/C(=O)N(C(=O)OC(C)(C)C)C3C=CCC23)OC1=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC#N
Product: CC1=CC(O/C=C2/C(=O)NC3C=CCC23)OC1=O
Yield: 40 %

Procedure:
A solution of tert-butyl (3E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-2-oxo-4,6a-dihydro-3aH-cyclopenta[b]pyrrole-1-carboxylate Ib-1 (28 mg, 0.080 mmol) in acetonitrile (1 mL) was stirred with magnesium chloride (23 mg, 0.24 mmol) at 40° C. for 7 h. The solution was then diluted into CH2Cl2, filtrated, concentrated and purified by flash chromatography (EtOAc, then 5% MeOH in CH2Cl2) giving the desired compound as a colorless oil (8 mg, 40%); 1H NMR (400 MHz, CDCl3) 7.27 (1H, s), 6.93 (1H, s), 6.54 (1H, brs), 6.14 (1H, s), 5.87 (1H, d), 5.71 (1H, brs), 4.65 (1H, d), 3.66 (1H, m), 2.83 (1H, m), 2.46 (1H, d), 2.02 (3H, s): LCMS (Method A): 0.63 min; ES+270 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:12])=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13]1(C)C=CC=C[CH:14]=1>C(O)C>[CH2:13]([O:6][C:5](=[O:7])[C:4]1[C:8]([Cl:12])=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1)[CH3:14]
Reactant: O=C(O)c1cc(O)c(O)cc1Cl
Reactant: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(O)c(O)cc1Cl
Yield: 95 %

Procedure:
A solution of 3,4-dihydroxy-6-chlorobenzoic acid (48 g: 250 mMol.) in a mixture of toluene (180 ml) and ethanol (180 ml) is heated under reflux under Dean Stark apparatus filled with Molecular Sieves for 12 hours. The reaction mixture is cooled and washed with aqueous sodium hydrogen carbonate and water, dried and concentrated under reduced pressure to give 6-chloro-3,4-dihydroxybenzoic acid ethyl ester (52.7 g). Yield: 95%.