Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][CH2:4]OC.Br[C:8]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14](Br)=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.ClCCl.CCCCCC>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:14]1[C:15]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:16][C:17]2[C:18]3[C:10](=[CH:9][C:8]([C:4]4[CH:3]=[CH:17][C:18]5[C:10](=[CH:9][CH:8]=[CH:20][CH:19]=5)[CH:11]=4)=[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:19]=3)[CH2:11][C:12]=2[CH:13]=1
Reactant: CC(C)(C)c1cc2c(cc1Br)Cc1cc(Br)c(C(C)(C)C)cc1-2
Reactant: OB(O)Oc1ccc2ccccc2c1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc2c(cc1-c1ccc3ccccc3c1)Cc1cc(-c3ccc4ccccc4c3)c(C(C)(C)C)cc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
Under a nitrogen atmosphere, 45 mL of dehydrated 1,2-dimethoxyethane was added to 3.02 g (6.92 mmol) of 2,7-dibromo-3,6-ditert-butyl-fluorene synthesized in Synthesis Example 1-1(i) and 0.40 g (0.35 mmol) of Pd(PPh3), and the mixture was stirred at room temperature for 20 minutes. To this solution, a solution prepared by dissolving 2.62 g (15.2 mmol) of 2-naphthylboric acid in 15 mL of ethanol was added, and the mixture was stirred at room temperature for 20 minutes. Then, 13.8 mL (27.7 mmol) of a 2.0 mol/L aqueous solution of sodium carbonate was added. The mixture was heated to reflux for 21 hours, and then left to be naturally cooled. Subsequently, the reaction was terminated with 1N hydrochloric acid in an ice bath. Thereafter, dichloromethane was added to perform liquid-liquid phase separation. The aqueous layer was subjected to extraction with diethyl ether twice, and the resultant was combined with the organic layer obtained previously. The resulting liquid was washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting solids were subjected to separation by silica gel chromatography. To the yellow powder obtained, a mixed solution of n-hexane and a small amount of dichloromethane was added. The mixture was heated to 65° C. to dissolve the powder completely, and was then left to stand overnight at room temperature. Crystals precipitated were washed three times with 10 mL of n-hexane to obtain a target product as a white powder (yield 2.71 g (74%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[N:1]=1
Reactant: Nc1cccc(F)c1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Yield: 70.4 %

Procedure:
Prepared according to Procedure B with 1e (500 mg, 1.89 mmol) and chloroacetyl chloride (0.45 mL, 5.67 mmol) in acetic acid (10 mL). Purified by extraction from aq. K2CO3 and recrystallization from isopropanol to afford 430 mg of an off-white crystalline solid (70%). 1H NMR (CDCl3) δ: 7.76 (dt, J=5.3, 8.2 Hz, 1H); 7.56-7.65 (m, 2H); 7.47-7.56 (m, 3H); 7.16-7.25 (m, 1H); 4.35 (d, J=12 Hz, 1H), 4.07 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[N:55]1([C@H:60]2[CH2:65][CH2:64][CH2:63][CH2:62][C@H:61]2[NH2:66])[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:18])[F:19])[C:4]=1[C:5]([NH:66][C@@H:61]1[CH2:62][CH2:63][CH2:64][CH2:65][C@@H:60]1[N:55]1[CH2:56][CH2:57][CH2:58][CH2:59]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
2,4-Bis(trifluoromethyl)-6-methoxy-benzoic acid (200 mg, 0.69 mmol) was dissolved in 5 mL dimethylformamide. N,N-Diisopropyl ethyl amine (359 mg, 2.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (264 mg, 0.69 mmol) were added. After 5 minutes of stirring at room temperature cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) (171 mg, 0.71 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-2-methoxy-N-(2-pyrrolidin-1-yl-cyclohexyl)-4,6-bis-trifluoromethyl-benzamide as a white solid (158 mg, 52%), MS: m/e=439.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH2:26]([C:28](B1OC2C=CC=CC=2O1)=[CH:29][CH2:30][CH3:31])[CH3:27]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:28]([CH2:26][CH3:27])=[CH:29][CH2:30][CH3:31])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCC=C(CC)B1Oc2ccccc2O1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 146.8 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.89 mmol) and 2-(1-Ethyl-but-1-enyl)-benzo[1,3,2]dioxaborole (709 μL, 3.56 mmol) in dioxane (15 mL) is added Pd(PPh3)4 (103 mg, 8.9% mmol) and 2M aqueous solution of CsCO3 (1.34 mL, 2.67 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 2 h. After concentration in vacuo, the residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (128) as a brown semi-solid (530 mg, 73%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[CH:8]=[C:9]([N:11]3[C:15]([CH3:16])=[N:14][N:13]=[N:12]3)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C)c2)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a stirred solution of 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester (1 mmol, 308 mg) in 10 ml of THF was added a solution of LiOH.H2O (5 mmol, 210 mg) in 2 mL of water. The reaction mixture was heated to reflux for 3.5 hours and then cooled to room temperature. Solvent was removed under reduced pressure and the liquid residue was pH adjusted to 2.0 by addition of 2N aqueous HCl solution. The mixture was extracted with ethyl acetate and the combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid as white solid (279 mg, 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)=[C:9]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:8]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>ClCCl>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)=[O:21])=[CH:15][CH:14]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)N3CCN(C)CC3)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 76.8 %

Procedure:
In a round bottom flask, under an atmosphere of argon, 4′-(3-ethoxy-3-oxopropyl)-2′-(3-methoxypropoxy)biphenyl-4-carboxylic acid (0.48 g, 1.2 mmol) was dissolved in dichloromethane (20 mL). EDCl (0.29 g, 1.5 mmol), HOBT (0.20 g, 1.5 mmol) and diisopropylethylamine (1.08 mL, 6.2 mmol) were added at room temperature. After consumption of all the acid, N-methylpiperazine (0.11 mL, 1.0 mmol) was added and the mixture, was stirred for 18 hrs. The organic layer was washed twice with water. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol, 90/10) to yield 0.36 g (62%) of the desired product as a yellow oil.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:26]=[C:27](C(F)(F)F)[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C1(C)C=CC=CC=1>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[NH:14][CH:13]([OH:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)[C:5]1[CH:4]=[CH:3][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C1NC(O)C(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(rac)-8-Benzyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (10.0 g, 30 mmol synthesis described in example 156) was dissolved in toluene (200 mL). Diisobutyl aluminium hydride (220 mL, 1M in THF, 220 mmol) was slowly added while cooling with an ice bath so that the reaction temperature did not exceed 10° C. The reaction mixture was stirred at room temperature for 2 days. A mixture of methanol (6 mL) and water (6 mL) was added at room temperature. The resulting gel was filtered through dicalit and washed with methylene chloride. The filtrate was evaporated to give 8-benzyl-3-hydroxy-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one as a mixture of diastereomers (8.0 g, 80%).
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C@@H:5]2[C@@H:14]([C@:15]3([CH3:22])[CH:20]\1[CH2:19][C:18](=O)[CH2:17][CH2:16]3)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C:9]1=[O:23].[ClH:24].Cl.[NH2:26][C@H:27]([CH3:31])[CH2:28][O:29][NH2:30]>>[NH2:26][C@H:27]([CH3:31])[CH2:28][O:29][N:30]=[C:18]1[CH2:19][CH2:20][C@@:15]2([CH3:22])[CH:16]([CH2:3][CH2:4][C@@H:5]3[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[CH2:7][CH2:8][CH2:9]2)[CH2:17]1.[ClH:24].[OH:1]/[N:2]=[C:3]1\[CH2:4][C@@H:5]2[C@@H:14]([C@:15]3([CH3:22])[CH:20]\1[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C:9]1=[O:23]
Reactant: C[C@@H](N)CON
Reactant: C[C@]12CCC(=O)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@@H](N)CON=C1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]32)C1
Product: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 93 %

Procedure:
Prepared as described in Example 1 starting from 6-(E)-hydroxyiminoandrostane-3,17-dione (II-at, Prepn. 20, 500 mg) and (R)-2-aminopropoxyamine dihydrochloride (Prepn. 93, 257 mg). The crude product was crystallized from MeOH/EtOAc to give the title compound as a white solid (503 mg, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.50 (1H, s), 7.98 (3H, m), 3.97 (2H, m), 3.40 (1H, m), 3.11 (0.5H, m), 3.05 (0.5H, m), 2.54-1.15 (22H, m), 0.79 (3H, s), 0.78 (3H, s).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1[N+:18]([O-:20])=[O:19]>C(Cl)Cl>[CH3:9][N:10]1[C:14]([N+:7]([O-:8])=[O:6])=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]=O
Reactant: Cn1cc([N+](=O)[O-])nc1[N+](=O)[O-]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cn1c([N+](=O)[O-])nc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Nitronium tetrafluoroborate (NO2BF4, 5.0 g, 37.6 mmol) was added to the solid of 1-methyl-2,4-dinitroimidazole (4.0 g, 23.3 mmol) at room temperature. Then the reaction temperature was brought to 105° C. within 15 minutes. At that temperature, all solids melted. The reaction mixture was then stirred at that temperature for 1.5 hrs, then cooled to room temperature and diluted with methylene chloride before being poured onto ice/water. The product was extracted with methylene chloride (3×60 ml). The combined organic phase was washed successively with water (50 ml), 10% aq. NaHCO3 (30 ml), and water (50 ml) and dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized with ethanol to give 3.72 g (74%) of 1-methyl-2,4,5-trinitroimidazole as pale yellow crystals, mp=84.0-85.0° C. (literature, mp=82° C.). The structure of the compound was confirmed by NMR spectroscopy.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([OH:16])=O)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[CH2:23]([C:27]1[N:32]=[C:31]([N:33]([CH3:35])[CH3:34])[N:30]=[C:29]([NH:36][NH2:37])[N:28]=1)[CH2:24][CH:25]=[CH2:26].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:23]([C:27]1[N:32]=[C:31]([N:33]([CH3:35])[CH3:34])[N:30]=[C:29]([NH:36][NH:37][C:14]([C@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:12][N:3]([O:4][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:1]=[O:2])=[O:16])[N:28]=1)[CH2:24][CH:25]=[CH2:26]
Reactant: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Reactant: C=CCCc1nc(NN)nc(N(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)NNc1nc(CCC=C)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-({N-formyl-N-benzoxy-amino}methyl)-7-octenoic acid (233 mg, 1.121 mmol), 4-(3-buten-1-yl)-6-(dimethylamino)-2-hydrazino-1,3,5-triazine (342 mg, 1.121 mmol), NMM (0.62 mL, 5.61 mmol) and HOAt (183 mg, 1.345 mmol) in DMF (11 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (258 mg, 1.345 mmol). After stirring at room temperature overnight, the reaction mixture was then purified by HPLC to afford the title compound as a white solid. MH+496.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[S:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[S:23][C:22]([C:24]([F:25])([F:27])[F:26])=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2sc(C(F)(F)F)cc21
Product: CC1c2cc(C(F)(F)F)sc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-2-trifluoromethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[Cl-].[Cl-].[Zn+2:12]>O>[Zn:12].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4]
Reactant: [Zn+2]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: [Cl-]
Solvent: O
Product: CC(C)(S)[C@H](N)C(=O)O
Product: [Zn]
Temperature: 45 °C

Procedure:
D-penicillamine (Aldrich Chemical Co., Inc.) 30 mM in doubly distilled water is mixed with equal volume of 30 mM ZnCl2 (Aldrich Chemical Co., Inc.). The mixture is heated to 45° C. for 30 minutes, cooled and the complex Zn/penicillamine (1.0:1.0)is formed.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[CH2:22][CH2:23][C:24](O)=[O:25].C(Cl)(C(Cl)=O)=O.[Cl-].[Al+3].[Cl-].[Cl-].C(COC)OC>ClCCCl.O>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:7]=[C:6]3[CH2:22][CH2:23][C:24](=[O:25])[C:4]=1[C:5]=23
Reactant: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccc(C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(O)ccc42)C(=O)CC3)cc1
Reaction time: 0.33 h

Procedure:
To a DCE (600 ml) solution of 3-(5-methoxy-1-p-toluenesulfonyl-indol-3-yl)propionic acid (28.9 g, 77 mmol) was added, while stirring under ice-cooling, (COCl)2 (8.3 ml, 95 mmol), and the mixture was stirred for about 2.5 hours at room temperature. The reaction mixture was concentrated, and the residue was dissolved in DCE (100 ml). The solution was added to a suspension of aluminum chloride powder (33.9 g, 254 mmol) in DCE (430 ml) at 5° C. taking 20 minutes. The mixture was left standing as it was at 5° C. for one hour, then stirred for 2.5 hours at room temperature. To the reaction mixture were added, under ice-cooling, dimethoxyethane (300 ml) and water (300 ml). Resulting precipitates were filtered off, then the organic layer was separated. The aqueous layer was subjected to extraction with chloroform (200 ml). The extract solution was combined with the organic layer, which was washed with an aqueous saline solution. The resultant organic layer was dried (anhydrous sodium sulfate), then the solvent was distilled off under reduced pressure to leave 25 g of crude crystals. The crude crystalline product was subjected to silica gel column chromatography, eluting with chloroform, to obtain crystals, followed by recrystallization from chloroform-n-hexane to afford the title compound (m.p.210°-211° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[C:27]([C:30]1[CH:60]=[CH:59][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=3)[CH2:37][CH2:36]2)=[CH:32][CH:31]=1)(O)=[O:28]>CN(C=O)C>[N:1]1([C:27]([C:30]2[CH:60]=[CH:59][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:56])[F:55])[CH:48]=4)[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Piperidine (0.048 mmol), diisopropylcarbodiimide (0.45 mmol) in DMF (0.15 mL), 1-hydroxybenzotriazole hydrate (0.45 mmol) in DMF (0.15 mL) were added to a solution of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (0.040 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 17 h, loaded onto Varian™ SCX column, and washed with CHCl3/CH3OH 1:1 (5 mL) and CH3OH (5 mL) Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 1-{(4-(piperidinocarbonyl)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1572) (14.3 mg, 66%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 545 (M++H, C29H35F3N4O3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]2[NH:1][N:14]=[CH:13][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(Br)ccc(N)c1C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(Br)ccc2[nH]ncc12
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (5.44 g, 22.3 mmol) in acetic acid (110 mL) was added a solution of sodium nitrite (1.69 g, 24.5 mmol) in water (11 mL) at room temperature and, after stirring for 20 hr, the organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→30/70) to give the title compound (4.86 g, yield 86%).
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N(CC)CC)C.ClC(OCC(C)C)=[O:37].C1(N2CCNCC2)C=CC=CC=1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:37])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC(C)COC(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 223.4 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.214 g, 0.58 mmol, 1.0 eq), and triethylamine (96 uL, 70 mg, 0.64 mol, 1.20 eq), in acetonitrile (6 mL) was treated with isobutyl chloroformate (83 uL, 86 mg, 0.63 mmol, 1.1 eq) followed by 4-phenylpiperazine (170 uL, 186 mg, 1.15 mmol, 2.0 eq). Workup as above provided 170 mg (57%) of L-isoleucine, N-[1-[2-(4-phenylpiperazine)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([Cl:12])=[C:8]2[C:4]=1[C:5]([C:13](=[O:17])[C:14]([O-:16])=O)=[CH:6][NH:7]2.[K+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:14](=[O:16])[C:13]([C:5]2[C:4]3[C:8](=[C:9]([Cl:12])[N:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][CH:6]=2)=[O:17])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C(c1ccccn1)N1CCNCC1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccn4)CC3)c12

Procedure:
Precursor 5l, 1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate, Precursor 4d, and picolinoyl-piperazine. 1H NMR (500 MHz, DMSO-d6) δ8.63-7.45 (m, 7H), 3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/z: (M+H)+ Calc'd for C20H19ClN5O4: 428.11; Found 428. 11. HPLC retention time: 1.09 minutes (column A).