Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:18][NH2:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
In a sealed flask, a solution of 6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (750 mg, 2.6 mmol) in THF (20 mL) was cautiously added to well stirred BH3.THF complex (1.0 M solution in THF, 13 mL, 13.0 mmol) at 0° C. The reaction mixture was heated at 40° C. for 1 h and cooled to RT. MeOH (large excess) and Amberlyst 15 (35 g) were successively added and the resulting mixture was shaken at RT for 30 min. The resin was filtered, washed with MeOH (500 mL), and the desired compound was released with ammonia (1.0 M solution in MeOH, 1.2 L). The NH3-MeOH fraction was evaporated to yield the crude C-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-methylamine (778 mg) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:12](Cl)(=[O:15])[CH2:13][CH3:14].Cl>C(=S)=S>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Ic1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(I)cc1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 37.7 %

Procedure:
Iodobenzene (100 g, 0.49 mol) was taken in a dry 1 L 3 neck flask equipped with a N2 inlet and to it 200 ml of CS2 was added. The contents were cooled to 0-5° C. and then AlCl3 (80 g, 0.6 moles) and subsequently propionyl chloride (60 g, 0.64 mol) were added while keeping the temperature (internal) at 5-10° C. The contents were stirred for 24 hrs. The reaction mixture was poured into a 5 liter plastic beaker containing 1 L of 10% HCl+1 Kg of crushed ice. The resultant slurry was extracted with 1 L of ethyl acetate. The organic layer was separated and washed with 2×500 ml of water and 500 ml of brine. The organic layer was dried over sodium sulphate and concentrated at 40° C. to give 4′-iodopropiophenone (48 g, 38%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH:7]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]2.O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:13][C:10]1[C:9]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]4)=[CH:7][C:8]=2[O:12][CH:11]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1coc2cc(OCCCBr)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(C)coc4c3)ccc21
Temperature: 80 °C
Reaction time: 68 h
Yield: 108.3 %

Procedure:
To a mixture of 6-(3-bromopropoxy)-3-methyl-1-benzofuran (87 mg, 0.32 mmol) (Example 63) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (59 mg, 0.269 mmol) (Example 6) in DMF containing 1 vol % water (2.4 mL) was added Cs2CO3 (105 mg, 0.323 mmol). The mixture was stirred for 68 h at 80° C., and the reaction mixture cooled to rt, then concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a small plug of silica to give 119 mg (90%) of a light-yellow solid that was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3](=[O:27])[O:4][CH:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>C1COCC1>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][C@H:5]2[O:4][C:3](=[O:27])[CH2:2][C@@:7]([OH:8])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: N#Cc1ccc(CCCCC(CC(=O)c2ccccc2)OC(=O)CBr)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCC[C@@H]2C[C@](O)(c3ccccc3)CC(=O)O2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of the product of step B (2.71 g, 6.35 mmol) in dry THF (50 mL) at -78° C. under an atmosphere of nitrogen was added a 0.1 M solution of SmI2 (135 mL, 13.5 mmol) over 10 minutes. The blue solution was stirred at -78° C. for 1 hour, poured into dilute ag. HCl, extracted with EtOAc, washed with sat'd NaHCO3, dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. Silica gel chromatography (35-50% EtOAc/hexane) afforded 1.90 g (86% ) of title product.
Reaction SMILES: C(OC([NH:11][C:12]1[N:17]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][N:13]=1)=O)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[NH2:11][C:12]1[N:17]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[CH:15]=[CH:14][N:13]=1
Reactant: O=C(Nc1nccc(C(O)C(F)(F)F)n1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1nccc(C(O)C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a solution of 1-[2-(N-benzyloxycarbonylamino)pyrimidin-4-yl]-2,2,2-trifluoroethanol (9a) in ethanol-tetrahydrofuran (1:1) (500 mL) under nitrogen-atmosphere was added palladium on carbon (785 mg). The mixture was put under a hydrogen atmosphere (balloon) and stirred at room temperature. After 45 minutes the reaction mixture was filtered through celite and concentrated under vacuum and purified by flash chromatography (dichloromethane/methanol 99:1 to 95:5) to give the title compound (1.52 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[CH3:20]B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O.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>[Cl:12][C:8]1[C:7]([F:13])=[C:6]2[C:11]([C:2]([CH3:20])=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CB(O)O
Reactant: Fc1c(Cl)ccc2c(Br)cc(-c3ccccc3)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)nc2c(F)c(Cl)ccc12
Temperature: 108 °C

Procedure:
4-Bromo-7-chloro-8-fluoro-2-phenylquinoline (1.1 g, 03.3 mmol), methane boronic acid (196 mg, 3.27 mmol), potassium carbonate (1.4 g, 9.8 mmol) and 1,4-dioxane (4 mL) were combined and stirred in a 10 mL R.B. flask. The flask was subjected to 3 vacuum-argon cycles. Tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol) was added, and the reaction was again subjected to 3 vacuum argon-cycles. The reaction was heated at 108° C. (external temperature) for 27 h, at which point the reaction was allowed to cool, and was diluted with ethyl acetate (30 mL), and water (30 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (30 mL). The organics were combined, dried over sodium carbonate, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexanes:methylene chloride 2:1. This afforded the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 2.75 (s, 3H), 7.47-7.55 (m, 4H), 7.69-7.72 (dd, 1H, J=8.9 & 1.6 Hz), 7.77 (s, 1H), 8.18-8.21 (m, 2H); MS (APCI+): 272.07 (100) [MH+], 274.03 (30) [(M+2)H+]; HPLC tR=3.80 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOCC1
Agent: [Pd]
Solvent: CO
Product: OC1(c2ccc3c(c2)CNC3)CCOCC1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution 0.39 mmol 4-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-tetrahydro-pyran-4-ol in 20 ml methanol was added 40 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen for 3 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to yield the title compound as a yellow solid (100% yield). MS (m/e): 220.3 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:50])[F:51])[CH:43]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Reactant: C#CCN1CCC(O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (191 mg, 1.374 mmol) and diisopropylamine (0.45 mL, 3.23 mmol) were added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (400 mg, 0.687 mmol; prepared as described in example 34) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10.4 mg, 0.055 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24.1 mg, 0.034 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 96:4) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:8][CH:7]=3)=[CH:14][CH:13]=2)[CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of 4-[1-(4′-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (270 mg, 0.68 mmol) in methylene chloride (7 mL) are added triethyl amine (0.28 mL, 2.03 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (141 mg, 1.01 mmol) and EDCI (389 mg, 2.03 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid methyl ester (215 mg).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[C:11]([CH3:24])=[C:12]([CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>CO.[Ni]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:24])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cc1c(CC=CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1c(CCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
Hydrogen was passed through a mixture of 16.27 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hex-4-enoic acid in 80 ml of methanol and 16.3 g of Raney nickel and then the catalyst was filtered off. The methoanol was distilled from the filtrate and the residue was taken up in methylene chloride. The solution was dried, treated with activated carbon, filtered and evaporated to dryness to obtain, after crystallization from a 1-1 isorpopyl ether-petroleum ether mixture, 11.15 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hexanoic acid melting at 82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[CH:20][N:21]=[CH:22][C:14]2=3)=O)[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[CH:20][N:21]=[CH:22][C:14]2=3)=[S:32])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ccncc32)cc1Br
Solvent: Cc1ccccc1
Product: COc1c(Br)cc(C(=S)N2CCOc3ccncc32)cc1Br
Reaction time: 2 h
Yield: 97.9 %

Procedure:
In a 25 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (100 mg, 0.23 mmol) was suspended in toluene, and Lawesson's reagent (113 mg, 1.2 equivalents) was added thereto and then stirred at 120□ for 2 hours. Toluene was evaporated under reduced pressure and the residue was purified on amine silica by using a solvent of dichloromethane:methanol=50:1 to obtain (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanethione (100 mg, 98%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[OH:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: OCc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(CO)cccc21
Yield: 77.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 173 mg of 4-(hydroxymethyl)indoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 288 mg of 2-{2-[4-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: C([C:8](CC1C=CC=CC=1)([C:20]([N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:30][C@H:31]([C:37]([O-:39])=[O:38])[CH2:32][CH2:33][C:34]([O-:36])=[O:35])=[O:29])=[O:21])[NH:9]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[ClH:47]>[Pd].O.O1CCCC1.CO>[ClH:47].[NH2:9][CH2:8][C:20]([N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C@H:23]1[C:28]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[O:21]
Reactant: O=C([O-])CC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)C(Cc1ccccc1)(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCC(=O)N1C(=O)CC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of protected tripeptide 7 (0.45 g, 0.80 mmol), conc. hydrochloric acid (38%, 0.13 cm3) and 10% palladium on activated carbon (0.08 g, 0.08 mmol) in 20% water/tetrahydrofuran (60 cm3) was stirred under an atmosphere of hydrogen at room temperature for 4 h. The solution was filtered through a Celite™ pad, washed with 20% water/tetrahydrofuran (2×30 cm3) and the filtrate evaporated to dryness to form GPyroE.HCl (0.19 g, 74%) as solid. GPyroE.HCl was shown to be exclusively the trans conformer by 1H and 13C NMR analysis5: mp 42-44° C.; [α]D −57.3 (c 0.09 in MeOH); OH (400 MHz; D2O) 2.07-2.14 (1H, m, Gluβ-HAHB), 2.20-2.25 (1H, m, Gluβ-HAHB), 2.30-2.34 (1H, m, Pyroβ-HAHB), 2.60-2.65 (3H, m, Pyro-HAHB and Gluγ-H2), 2.74-2.89 (2H, m, Pyroγ-H2), 4.48-4.59 (3H, Glyα-H2 and Gluα-H) and 4.93-4.95 (1H, m, Pyroα-H); δC (75 MHz, D2O) 22.5 (CH2, Pyroβ-C), 26.4 (CH2, Gluβ-C), 30.5 (CH2, Gluγ-C), 31.8 (CH2, Pyroγ-C), 44.3 (CH2, Glyα-C), 52.7 (CH, Gluα-C), 59.3 (CH, Pyroα-C), 168.5 (quat., Gly-CO), 173.6 (quat., Pyro-CO), 175.2 (quat., Pyro-CO), 177.6 (quat., Glu-CO) and 178.9 (quat., Glu-CO); m/z (FAB+) 316.1138 (MH+.C12H18N3O7 requires 316.1145).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]4)=[CH:28][CH:27]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)cc21
Reaction time: 8 h
Yield: 44 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(4-methyl-1-piperazinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified by silica gel chromatography eluting with 90:9:1 EtOAc:MeOH:NH4OH. The product fractions were pooled and concentrated to a solid that was triturated in boiling hexanes. The solid was collected and crystallized to give 1-ethyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-1H-[1,6]naphthyridin-2-one (84 mg, 44%): mp (CH2Cl2 /hexanes) 188-189° C.
Reaction SMILES: [CH3:1][O:2]C1C=CC=CC=1CC#N.ClCCCl.[C:16]1([C:22]2([CH2:26][C:27](=[O:31])[C:28]([OH:30])=[O:29])[CH2:25][CH2:24]C2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:22]1([CH2:26][C:27](=[O:31])[C:28]([OH:30])=[O:29])[CH2:25][CH2:24]1
Reactant: COc1ccccc1CC#N
Reactant: O=C(O)C(=O)CC1(c2ccccc2)CCC1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccccc1C1(CC(=O)C(=O)O)CC1

Procedure:
Corresponding to J. Org. Chem. 40 (1975) 3497, 16.7 g of 2-methoxyphenylacetonitrile, 158 ml of lithium triisopropyl-amide (2 mol solution) and 46.7 ml of 1,2-dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide are reacted with one another. 5.6 g of 1-(2-methoxy-phenyl)-cyclopropyl-carbonitrile, boiling point 104-115° C./0.1 mbar, which was also reacted as described for 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, is obtained. 3-[1-(2-Methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid is thus obtained as an oil.
Reaction SMILES: C(OC(=O)[N:7]([CH:10]([CH3:33])[CH2:11][C:12]1[CH:32]=[CH:31][C:15]2[O:16][CH:17]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[O:18][C:14]=2[CH:13]=1)[CH2:8][CH3:9])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH:17]1[O:16][C:15]2[CH:31]=[CH:32][C:12]([CH2:11][CH:10]([NH:7][CH2:8][CH3:9])[CH3:33])=[CH:13][C:14]=2[O:18]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.58 g (3.3 mmol) of 2G in 10 mL of dichloromethane (distilled over CaH2) was added trifluoroacetic acid at room temperature, and the mixture was allowed to stir at room temperature for 30 minutes. The resulting reaction mixture was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to give 1.6 g (3.3 mmol, 98%) of 2H as a colorless gum (M+H, 371).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[N-:35]=[N+:36]=[N-:37].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]3[NH:37][N:36]=[N:35][N:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1(c2nnn[nH]2)CCCCC1)c1cnn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a solution of the compound obtained in Example A1 (106 mg) in toluene (4 mL) and dimethylformamide (1.5 mL) were added sodium azide (86 mg) and triethylamine hydrochloride (183 mg), and the mixture was stirred at 120° C. for 24 hours. To the reaction mixture were further added sodium azide (90 mg) and triethylamine hydrochloride (183 mg), and the mixture was stirred for 21 hours. After cooling to room temperature, the reaction mixture was filtered through Celite to remove precipitates, and the filtrate was concentrated in vacuo. The resultant crude product was purified successively by column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 95/5) and gel-permeation chromatography (solvent; chloroform) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(1,2,3,4-tetrazol-5-yl)cyclohexyl]carbamoyl]-pyrazolo[1,5-a]pyrimidine (95 mg, yield: 83%) as a powder.