Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:10][CH:11]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[Na]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:11][CH2:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(CC=O)(C(=O)c1ccccc1)c1ccccc1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)c2ccccc2)c2ccccc2)CC1
Yield: 23.4 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-benzoyl-3-phenylbutyraldehyde (0.32 g) and 1-(2-methoxyphenyl)piperazine (0.23 g) with sodium triacetoxyboranehydride (0.33 g) gave pure product 1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine (0.12 g). The oxalate salt was prepared as described above.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].O1CCCC1>O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCCCC2)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCNS(=O)(=O)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
7.8 g of 4-piperidinylbenzenesulphonyl chloride are added to a solution comprising 3.51 g of 5-aminovaleric acid and 3.6 g of sodium hydroxide dissolved in 35 cm3 of water, followed by the addition of 35 cm3 of tetrahydrofuran in order to obtain a solution. The temperature rises to 35° C. The mixture is kept stirring for 4 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid, diluted with 100 cm3 of water and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 5.8 g of expected product are obtained. M.p. 115°-120° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 120°-122° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:17])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([C:33](O)=[O:34])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH:5][CH2:4][CH:3]([CH3:17])[CH2:2][NH:1][C:33]([C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:34])(=[O:8])=[O:7])=[CH:14][CH:13]=1)#[N:16]
Reactant: CC(CN)CNS(=O)(=O)c1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CNS(=O)(=O)c3ccc(C#N)cc3)ccc21
Yield: 65.4 %

Procedure:
A solution of the compound obtained in Step 2 (65.7 mg, 0.26 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (62.1 mg, 0.26 mmol), HATU (128 mg, 0.34 mmol) and TEA (0.108 mL, 0.78 mmol) in DMF (1.25 mL) was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give the title compound (81 mg, 0.170 mmol, 65.7%) as a white powder.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.CCN(C(C)C)C(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:3][C:4]1[C:8]([N:9]([CH2:10][CH3:11])[C:39]([CH:36]2[CH2:37][CH2:38][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])[CH2:35]2)=[O:41])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)C1CCN(C(=O)OC(C)(C)C)C1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (0.20 g, 0.68 mmol) in CH2Cl2 (1.4 mL) were added DIPEA (0.35 g, 2.7 mmol) followed by 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.22 g, 1.0 mmol) and EDCI (0.20 g, 1.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated. The residue was purified by silica gel chromatography eluting with 0%-50% acetone/hexanes to afford a colorless oil (0.14 g, 49%).
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.O.CCOC(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>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=2)[C:8]([CH3:9])=[CH:7][C:5]=1[NH2:6]
Reactant: COc1cc(Br)c(C)cc1N
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnn(C)c2)c(C)cc1N
Temperature: 80 °C
Yield: 39.8 %

Procedure:
To a solution of 4-bromo-2-methoxy-5-methylaniline (Preparation 39, 350 mg, 1.620 mmol) in EtOH (2.5 mL), toluene (2.5 mL) and water (2.5 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (404 mg, 1.944 mmol), sodium carbonate (343 mg, 3.24 mmol) and Pd(PPh3)4 (225 mg, 0.194 mmol). The reaction mixture was heated to 80° C. for 2.5 hours, under nitrogen. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL), washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to give the title compound (140 mg, 36%). 1H NMR (500 MHz, CDCl3): δ 7.56 (d, J=0.5 Hz, 1H), 7.39 (s, 1H), 6.75 (s, 1H), 6.63 (s, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.76 (br s, 2H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].Cl[C:24]1[CH:29]=[C:28]([O:30][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH3:32])[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:24]1[CH:29]=[C:28]([O:30][CH:31]([CH3:32])[C:33]([O:35][CH3:36])=[O:34])[N:27]=[CH:26][N:25]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Oc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)ncn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
338 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 216 mg of 4-chloro-6-[1-(methoxycarbonyl)ethoxy]pyrimidine were dissolved in 2 ml of N,N-dimethylformamide, to this solution was added 150 mg of potassium carbonate, and the mixture was stirred for 2 hours at 60° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 101 mg of methyl 2-([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidin-6-yl]oxy)propionate [present compound 3-12].
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:28])[CH:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:35](OC=O)(=[O:37])C>ClCCl>[CH:35]([NH:1][C:2]1([NH:7][C:8](=[O:28])[CH:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:37]
Reactant: CC(=O)OC=O
Reactant: NC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CNC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CNC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CNC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
The amine (42) (490 mg) in dry dichloromethane was cooled to 0° C. and treated with pyridine (211 mg) followed by formic-acetic anhydride (117 mg). The mixture was stirred at 0° C. for 5 minutes then allowed to warm to room temperature. After 1/2 hour the solvent was evaporated and the residue dried in vacuo. The solid was triturated with dry ether, filtered off, and washed with more ether before drying in vacuo to give the product (43) (510 mg) as a white solid. νmax (NUJOL) 3250 br, 1780sh, 1760, 1680sh, 1655 and 1345 cm-1.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([Cl:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[Cl:25][C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[CH:6][C:7]([F:8])=[C:2]([N:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])[CH:3]=1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3cc(F)c(N4CCOC4=O)cc3Cl)CC2)c(C)c1
Yield: 58.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-chloro-5-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (851 mg) described in Preparation Example 7 and oxazolidin-2-one (174 mg), the title compound (506 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl-].[NH2:16][C:17]1[CH:39]=[CH:38][C:20]([NH:21][C:22]([C:24]2[CH:37]=[CH:36][C:27]([NH:28][C:29]3[CH:34]=[CH:33][N+:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:19][CH:18]=1.Cl.CO.CCOC(C)=O>CO.CCOC(C)=O>[Cl-:1].[CH3:35][N+:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]([NH:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:39][CH:38]=3)=[O:23])=[CH:37][CH:36]=2)=[CH:34][CH:33]=1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Reactant: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-6-nitroquinoline (70 mg, 0.33 mmol) in MeOH (10 mL) was added compound D5 (100 mg, 0.28 mmol), and the mixture was stirred at 20° C. for 1 h (until a clear solution obtained). A drop of c.HCl was then added, and refluxing was continued for a further 20 h. TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) showed some D5 remained, so more 4-chloro-6-nitroquinoline (35 mg, 0.16 mmol) was added and refluxing was continued for a further 4 h. The reaction mixture was then diluted with EtOAc and the resulted precipitate was filtered and washed sequentially with EtOAc, CH2Cl2 and diisopropylether, and finally crystallized from MeOH EtOAc to give Cpd. N1 (111 mg, 75%), mp (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ14.50 (br, 1 H, N+H); 11,42, (br s, 1 H, NH), 11.10 (s, 1 H, NH), 10.58 (s, 1 H, NH), 9.82 (d, J=2.1 Hz, 1 H, ArH), 8.72 (dd, J=9.3, 2.2 Hz, 1 H, ArH), 8.60 (d, J=7.0 Hz, 1 H, ArH), 8.42 (d, J=7.4 Hz, 2 H, ArH), 8.24 (d, J=8.6 Hz, 1 H, ArH), 8.15 (d, J=8.6 Hz, 2 H, ArH), 8.04 (d, J=8.8 Hz, 2 H, ArH), 7.51 (t, J=8.3 Hz, 4 H, ArH), 7.34 (d, J=7.5 Hz, 2 H, ArH), 6.91 (d, J=7.0 Hz, 1 H, ArH), 4.01 (s, 3 H, N+CH3); LCMS 489+ve.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([O:13][CH3:14])[N:4]=1)[NH2:2].[C:15]1([CH2:21][CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([NH:1][N:2]=[CH:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1
Reactant: COc1cc(C(F)(F)F)cc(NN)n1
Reactant: O=CCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(NN=CCc2ccccc2)n1
Yield: 64.7 %

Procedure:
A mixture of 2-hydrazinyl-6-methoxy-4-(trifluoromethyl)pyridine [261360-23-0] (0.11 g, 0.55 mmol) and 2-phenylacetaldehyde (0.57 g, 0.66 mmol) in toluene (5 ml) was heated at reflux for 6 h using a Dean-Stark apparatus. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (5% EtOAc in hexane) to yield the title compound (0.11 g, 63%). [LCMS RtD=3.75 min; [M+H]+=310.1]
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][N:14]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Clc1ccn2c(Br)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3ccnc(Cl)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo-[1,2-a]-pyridine (1 eq, 6.48 mmol, 1.5 g) and 2-chloro-pyridine-4-boronic acid (1 eq, 6.48 mmol, 1.02 g) are dissolved in DME (6 ml) and water (2 ml) and Na2CO3 (2 eq, 13.0 mmol, 1.61 g) is added. PdCl2(PPh3)2 (0.06 eq, 0.389 mmol, 273 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-chloro-3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridine as an orange solid; [M+H]+=265
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>CO>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCCCNCc1ccc(-n2ccnc2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-imidazol-1-yl-benzaldehyde, of Preparation 43, using the method described in Example 1, Step A except that the mine was formed in MeOH with a reaction time of 1h. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 1H), 7.43 (d, 2H), 7.33 (d, 2H), 7.25 (m, 1H), 7.18 (m, 1H), 3.82 (s, 2H), 3.65 (s, 3H), 2.62 (t, 2H), 2.29 (t, 2H), 1.61 (m, 2H), 1.52 (m, 2H), 1.33 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.[I-:13].[Na+]>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[I:13]
Reactant: Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dichloro-3-nitropyridin-2-amine (15 g, 72.1 mmol) in AcOH (70 mL) was added sodium iodide (43.2 g 149.9 mmol). The mixture was stirred at 90° C. for 2 h, cooled to rt, diluted with water (70 mL) and filtered. The solid residue was washed with water, and then dried under vacuum to afford the desired product as a pale yellow solid, which was used in the next step without further purification. LC-MS: calculated for C5H3ClIN3O2 299.45, observed m/e: 299.94 (M+H)+ (Rt 2.18/5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)[CH3:2].[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([S:16][CH2:29][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:13][C:12]=12)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.05 g, 3.27 mmol) in N,N-dimethylformamide (15 mL) were serially added 2,2-diphenylethyl iodide (1.11 g, 3.60 mmol) and potassium carbonate (500 mg, 3.60 mmol) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl[[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate (1.11 g). To a solution of this compound (1.00 g, 1.99 mmol) in ethanol (45 mL)-water (5 mL) was added sodium periodate (0.51 g, 2.39 mmol) and the mixture was refluxed for 3 hours. To this reaction mixture were added-ethyl acetate and water, and the resulting two layers were separated. The aqueous layer was extracted with ethyl acetate and the pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:8) and recrystallized from ethyl acetate to provide 0.64 g of the title compound. Yield 42%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])=[O:12])=[O:8])=[O:4].[CH3:33][N:34]1[C@@H:51]2[CH2:52][C:39]3[CH:40]=[CH:41][C:42]([O:53][CH3:54])=[C:43]4[O:44][C@H:45]5[C:46]([CH2:48][CH2:49][C@@H:50]2[C@:37]5([C:38]=34)[CH2:36][CH2:35]1)=[O:47].Cl>O1CCOCC1>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])=[O:12])=[O:8])=[O:4].[CH3:33][N:34]1[C@@H:51]2[CH2:52][C:39]3[CH:40]=[CH:41][C:42]([O:53][CH3:54])=[C:43]4[O:44][C@H:45]5[C:46]([CH2:48][CH2:49][C@@H:50]2[C@:37]5([C:38]=34)[CH2:36][CH2:35]1)=[O:47]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)CN)C(=O)O
Reaction time: 18 h

Procedure:
To the Boc-Gly-Gly-Gly-Gly-Leu-Hydrocodone (SEQ ID NO: 1) (0.304 g) was added 25 ml of 4N HCl in dioxane. The resulting mixture was stirred at ambient temperatures for 18 hours. Solvent was removed and final product dried under vacuum. Solid was collected as a slightly yellow solid (0.247 g, 97% yield): 1H NMR (DMSO-d6) δ 0.87 (m, 6H), 1.23 (s, 1H), 1.51-1.86 (m, 4H), 2.18 (m, 1H), 2.71 (m, 2H), 2.77 (s, 3H), 2.96 (m, 2H), 3.17 (m, 2H), 3.61 (s, 3H), 3.81-3.84 (m, 10H), 4.22 (m, 1H), 4.36 (m, 1H), 5.09 (m, 1H), 5.59 (d, 1H), 6.74 (dd, 2H), 8.16 (br s, 4H), 8.38 (br s, 1H), 8.74 (br s, 1H), 11.42 (br s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[C:24]([C:25](=[O:27])[CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]2[C:24]([C:25](=[O:27])[CH2:26][CH:30]([OH:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:28][CH:29]=1
Reactant: CC(=O)c1cccnc1Oc1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CC(O)c1ccccc1)c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A solution of 0.114 mL (111 mg, 1.10 mmol) of diisopropylamine in 8 mL of tetrahydrofuran was cooled to −78° C. and treated dropwise with 0.440 mL (1.10 mmol) of a solution of 2.5 M n-butyllithium in hexane. After stirring for 30 min, a solution of 231 mg (1.00 mmol) 1-[2-(4-Fluorophenoxy)-3-pyridinyl]-ethanone in 2 mL of tetrahydrofuran was added dropwise. After stirring for 30 min, 0.112 mL (1.07 mmol) of benzaldehyde was added dropwise, and stirring was continued for 1 h. The mixture was quenched by the addition of 2 mL of saturated aqueous NH4Cl solution and was allowed to warm to rt. The mixture was partitioned between 50 mL of saturated aqueous NH4Cl solution and 300 mL of EtOAc. The separated organic layer was washed with 50 mL of saturated aqueous sodium hydrogencarbonate solution, 50 mL of brine, dried (Na2SO4), and evaporated to 259 mg of an oil. Purification by flash chromatography using a 40% EtOAc-hexane eluant afforded 211 mg (63% yield) of the title compound as an oil; 1H NMR (CDCl3) d 3.23 (1H, br s), 3.54-3.56 (2H, m), 5.34-5.37 (1H, m), 7.07-7.41 (10H, m), 8.21-8.26 (2H, m); APCI MS (m/e) 338 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[CH:3]=1.[OH-].[K+].Cl>CCO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2ccc(Br)cc12

Procedure:
To a suspensions of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (0.27 g, 1.0 mmol) in EtOH (5 mL) was added 6 N KOH (0.3 uL, 2.0 mmol). The reaction was heated to reflux for 3 hours then cooled to room temperature and neutralized to pH 6 with 1M HCl. The resulting solid was filtered and dried under vacuum to yield 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-25) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=7.6 Hz, 1 H), 8.42 (s, 1 H), 8.21 (d, J=2.4 Hz, 1 H), 7.30 (dd, J=2.0, 7.6 Hz, 1 H). MS m/z 240.9, 242.9 (M+1)+.