Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)O1>>[NH:30]1[C:31]2[C:27](=[C:26]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[CH3:11])=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[N:3]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1cnc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (20 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A and purified via reverse phase HPLC to give 13.8 mg of 129 as a white solid. MS (Q1) 336.2 (M)+
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[I-].[Li+].C1CCN2C(=NCCC2)CC1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C.O>[CH2:21]([CH:2]1[C:3](=[O:6])[CH2:4][CH2:5][C:1]1=[O:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)C1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(=O)C1Cc1ccccc1

Procedure:
To a suspension of 1,3-cyclopentanedione (500 mg, 5.10 mmol) and anhydrous lithium iodide (750 mg, 5.61 mmol) in acetonitrile (10 ml) was added DBU. After 30 min benzyl bromide (1.74 g, 10.2 mmol) was added and the reaction heated for 24 h at reflux. The reaction was poured into water (40 ml), extracted with EtOAc (4×50 ml), dried (MgSO4), the solution concentrated in vacuo and the residue purified by chromatography (SiO2; EtOAc) to give the title compound as an off white solid (222 mg, 23%). δ H (CD3OD) 7.20 (4H, d), 7.10 (1H, m), 3.41 (2H, s), 2.52 (4H, s). m/z (ESI, 70V) 189 (MH+).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].O.[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@H:14]1[O:32][C:33]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][NH2:49])=[CH:41][CH:40]=2)=[C:36]([CH:50]([CH3:52])[CH3:51])[NH:35][N:34]=1)(=[O:11])[CH3:10].C(N(CC)CC)C>C(#N)C.ClCCl>[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@H:14]1[O:32][C:33]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][NH:49][S:2](=[O:4])(=[O:3])[NH2:5])=[CH:41][CH:40]=2)=[C:36]([CH:50]([CH3:52])[CH3:51])[NH:35][N:34]=1)(=[O:11])[CH3:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNS(N)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of chlorosulfonyl isocyanate (0.022 mL) in acetonitrile (1 mL) was added water (0.005 mL), and the mixture was stirred at room temperature for 10 minutes. This reaction mixture was added to a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole (51 mg) and triethylamine (0.052 mL) in dichloromethane (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(sulfamoylamino)propoxy]phenyl}-methyl)-1H-pyrazole (18 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.01 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (3 mg).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.C(O[C:15]([C:17]1([CH3:20])[CH2:19][CH2:18]1)=[O:16])C.[C:21](#[N:23])[CH3:22].[O-]CCCC.O.CC(OC)(C)C.Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[CH3:20][C:17]1([C:15](=[O:16])[CH2:22][C:21]#[N:23])[CH2:18][CH2:19]1
Reactant: CCOC(=O)C1(C)CC1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: CCCC[O-]
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: CO
Product: CC1(C(=O)CC#N)CC1
Reaction time: 0.17 h

Procedure:
Alternatively, to a 5 L three-necked round-bottom flask equipped with overhead stirrer, thermocouple, reflux condenser, and an addition funnel, add potassium tert-butoxide in THF (3.00 L, 3.00 moles). Mix 1-methyl-cyclopropanecarboxylic acid ethyl ester (264.00 g, 2.06 moles) with acetonitrile (123.00 g, 3.00 moles), then add through an addition funnel over 0.5 hour to the butoxide solution. Heat the resulting mixture to reflux. Reflux 2 hours, then cool to <40° C. by adding methanol (96.00 g, 3.00 mL). Stir the mixture 10 minutes, then transfer the contents to a 12 L separatory funnel containing a vigorously stirring mixture of water (3.96 L, 219.81 moles) and MTBE (3.96 L, 33.32 moles). Separate the layers and extract the aqueous layer with MTBE (3.96 L, 33.32 moles). Adjust the pH of the aqueous layer from 12.5 to 3.5 using 5 N HCl (610.00 mL, 3.05 moles). Extract the aqueous layer with MTBE (2×1.32 L, 11.11). Combine the organic layers, dry over sodium sulfate (62.00 g, 436.49 moles), and filter to afford 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile.
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]([OH:43])=O)[CH2:30]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=2)=[CH:46][CH:45]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[O:50]([C:51]1[CH:52]=[CH:53][C:54]([NH:57][C:41](=[O:43])[C@@H:31]2[CH2:30][C@@H:29]([CH2:33][NH:32][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][N:27]2[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:55][CH:56]=1)[C:47]1[CH:48]=[CH:49][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.4 %

Procedure:
N-Methylmorpholine (60 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline (Compound D109 (D), 206 mg), 4-aminodiphenylether (104 mg), and 1-hydroxybenzotriazole (70 mg) in tetrahydrofuran (6 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at room temperature for 13 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium carbonate and then brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated in vacuo. The residue was washed with hexane to give the title compound (182 mg) as colorless plates: 1H NMR (400 MHz, CDCl3) δ 1.44-1.49 (18 H), 1.70 (br s, 1H), 2.54 (br s, 2 H), 3.08 (br s, 1H), 3.20 (br s, 2 H), 3.52 (br s, 1 H), 4.52 (br s, 1 H), 4.64 (br s, 1 H), 6.96 (d, J=7.8 Hz, 4 H), 7.07 (t, J=7.3 Hz, 1H), 7.31 (t, J=7.8 Hz, 2 H), 7.47 (d, J=9.3 Hz, 2 H), and 9.49 (br s, 1 H); mass spectrum (EI+) m/e 511 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:20][CH3:21])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1CC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(OCC)cccc2n1CC
Temperature: 120 °C
Yield: 99.7 %

Procedure:
A mixture of 1-ethyl-4-hydroxy-1H-indole-2-carboxylic acid ethyl ester (100 mg, 0.43 mmol) and NaH (13 mg, 0.52 mmol) was stirred in DMF (3 mL) for 10 min. Ethyl iodide (80 mg, 0.52 mmol) diluted in 1 mL of DMF was added and placed in a sealed tube. The reaction mixture was heated to 120° C. via microwave for a period of 15 min. The reaction mixture was taken up in 100 mL of EtOAc and washed with 100 mL of 0.1N hydrochloric acid, brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed to produce 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (112 mg, 100% yield) as brown oil. This material was diluted in 2 mL of methanol and 2 mL of 1N NaOH and placed in a sealed tube. The reaction mixture was heated to 120° C. via microwave for 15 min. The reaction mixture was diluted in 100 mL of EtOAc and washed with 50 mL of 1N HCl, 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed to afford 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (100 mg, 100% yield) as a white solid. LCMS for C13H15NO3 calcd. (m/e) 233, observed 234 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[CH3:23])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.[OH-:24].[Na+]>O>[NH2:1][C:2]1[N:3]([C:16]2[C:17]([CH3:23])=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:2][CH2:6][C:7]([OH:15])=[O:24])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: [OH-]
Reactant: Cc1c(O)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Agent: [Na+]
Solvent: O
Product: Cc1c(OCCC(=O)O)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-amino-2-(3-hydroxy-2-methylphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg), 1N aqueous sodium hydroxide solution (326 μl) and water (3 ml) was added dropwise γ-propiolactone (25 μl) at 80° C. The mixture was stirred at 80° C. for 2 hours, after stirring, cooled to room temperature, and the insoluble materials were filtered off. pH of the filtrate was adjusted to about 2 by adding 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (8 mg).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:16])[CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[S:27](=[O:30])(=[O:29])[NH2:28].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([N:12]1[C:11]2[CH:10]=[C:9]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[C:19]([S:27]([NH2:28])(=[O:29])=[O:30])[CH:20]=3)=[O:23])[CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:16])[CH3:15]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CC(=O)n1c2ccccc2c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)n1c2ccccc2c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 1-carbazol-9-yl-ethanone and 2.43 g of 4-chloro-3-sulfamoyl-benzoyl chloride in methylene chloride (20 mL) is added 2.55 g of aluminum chloride. The mixture is stirred at 50° C. overnight. The solution is then cooled at −78° C., quenched with a 6 N HCl solution and allowed to warm up to room temperature. Methylene chloride is added to dissolve the precipitate and the solution is extracted, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to afford 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as yellow foam. MS (m/z): 427 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10->100% CH3CN in 5 min) room temperature=5.35 minutes.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([CH3:35])[C@@H:19]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[CH:11][CH:10]=1)=O)CCC.[ClH:36].[OH-].[Na+]>C1(OC)C=CC=CC=1.CC(O)=O>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([CH3:35])[C@@H:19]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[CH:11][CH:10]=1.[ClH:36]
Reactant: CCCCOC(=O)Nc1ccc(CC(=O)N(C)[C@H](CN2CCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: CN(C(=O)Cc1ccc(N)cc1)[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1

Procedure:
The product from Example 59 (2.9211 g, 6.053 mmol) and anisole (2 drops) were mixed in AcOH (10 mL) and 4N HCl (10 mL) and stirred at 25° C. overnight, fitted with a drying tube. The mixture was adjusted to pH 13 with 1N NaOH with stirring in ice-H2O and then extracted with CH2Cl2 (2×70 mL). The combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was gravity column chromatographed eluting with CHCl3:2% NH3 before it was converted to the HCl salt with Et2O—HCl to yield 15 HCl.(0.5531 g, 22%, unoptimized): m.p. (HCl salt) 200° C. (dec); 1H NMR (HCl salt, DMSO-d6) δ1.98 (br s, 4H, —CH2CH2—), 2.86 (s, 3H, —NCH3), 3.2-4.3 (complex, 8H, 4 —CH2—), 7.16 (d, J=7.4 Hz, 2H, aromatic), 7.33 (d, J=7.5 Hz, 2H, aromatic), 7.7 (m, 2H, aromatic), 8.08 (s, 1H, aromatic), 8.23 (m, 1H, aromatic). MS(FAB) m/z 383. Anal. (C, H, N) C21H26N4O30.2HCl.0.75H2O.
Reaction SMILES: C(#N)C.Br[CH2:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH3:21][SH:22].[Na].O>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:9]2[CH:19]=[CH:20][C:6]([CH2:5][S:22][CH3:21])=[CH:7][CH:8]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CSCc1ccc(C(=O)c2ccc(F)cc2)cc1

Procedure:
To an acetonitrile solution (200 ml) of 4-bromomethyl-4'-fluorobenzophenone (20 g), an aqueous 15% sodium methylmercaptan solution (60 ml) was added and the mixture was heated for 6 hours with refluxing. After the reaction mixture was restored to room temperature, water (500 ml) and toluene (300 ml) were added. The organic layer was separated, which was then successively washed with an aqueous 2N sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent n-hexane:ethyl acetate=9:1) to obtain 4-fluoro-4'-methylmercaptomethylbenzophenone (17 g).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[CH:22]=[C:21]([O:24][CH3:25])[CH:20]=[C:19]([C:26]([O:28][CH3:29])=[O:27])[C:18]=2[CH:17]=[CH:16][C:15]1=[O:30]>>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([C:26]([O:28][CH3:29])=[O:27])[C:18]2[CH:17]=[CH:16][C:15](=[O:30])[N:14]([CH2:13][CH:9]=[O:8])[C:23]=2[CH:22]=1
Reactant: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 5 mL of a 90% aqueous trifluoroacetic acid solution, 350 mg of methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylate was dissolved, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resultant solution was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 476 mg of a pale yellow oily substance, methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[CH3:6])[CH3:2].[NH:22]([C:50]([O:52][CH2:53][CH:54]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])[C@H:23]([C:47](O)=[O:48])[CH2:24][C:25](=[O:46])[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:47](=[O:48])[C@@H:23]([NH:22][C:50](=[O:51])[O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:24][C:25](=[O:46])[NH:26][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-3) 13.0 g (45 mmol) and Fmoc-Asn(Trt)-OH 35.1 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 25.8 g, (yield 66%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nsc(CO)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (0.24 g, 0.90 mmol) in MeOH (10 ml) was added sodium borohydride (0.058 g, 1.54 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 2 ml of water and concentrated under vacuum. Added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 20% EtOAc-Hexane) to get the product (0.072 g, 43%) that was carried forward to the next step without further purification.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:7]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:8]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][N:10]=1.ClC(Cl)C(O)=O.ClCCl.C(Br)(Br)[Br:40]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:40][C:6]1[N:7]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:8]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][N:10]=1
Reactant: BrC(Br)Br
Reactant: COC(=O)CSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Solvent: ClCCl
Product: COC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Sodium nitrite (2.76 g, 40 mmol) was added to a solution of methyl 2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (0.71 g, 2 mmol) and benzyltriethylammonium chloride (1.63 g, 6 mmol) in bromoform (10 mL). Dichloroacetic acid (0.33 mL, 4 mmol) was then added and the reaction mixture stirred at room temperature for 3 h. The mixture was directly loaded onto a 7-inch column of silica gel, packed with dichloromethane (DCM). The column was first eluted with DCM until all bromoform eluted, then eluted with acetone/DCM (5:95) to give methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (713 mg, 85%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:25][CH3:24])[N:7]3[N:8]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Reactant: CN
Product: CNc1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Yield: 77.3 %

Procedure:
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (25 mg, 0.077 mmol) and excess of methylamine in alcohol (1 mL) in sealed tube was heated at 120° C. for overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give 2-(4-fluorophenyl)-N-methyl-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine a peach solid in 77.3% yield. 1H NMR (CDCl3): δ 8.59 (d, 2H, J=5.4 Hz), 7.58–7.62 (m, 2H), 7.28–7.30 (m, 3H), 7.07–7.14 (m, 3H), 6.11 (bs, 1H), 6.00 (d, 1H, J=7.4 Hz), 3.16 (d, 3H, J=5.0 Hz); MS (ES+ve): 320 (18, M+2), 319 (20, M+1), 318 (100, M+).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[CH:33]([CH2:34][S:35][C:36](=[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][NH:47]3)[C:37](=[O:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:32][C:31]2=[O:52])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.Cl>C(Cl)Cl.CCOCC>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[C:31](=[O:52])[N:32]3[CH:33]2[CH2:34][S:35][CH:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[C:37]3([OH:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C(C(=O)NC1C(=O)NC1CSC(C(=O)C(=O)OC(C)(C)C)=C1C=CC=CN1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C1CSC(c1ccccn1)C2(O)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
3.053 g of the product of Step B and 1.3 g of triethylene diamine were dissolved in 30 ml of methylene chloride and the mixture was stirred for 1 hour and 30 minutes. Then 28 ml of N hydrochloric acid were added and extraction was effected with methylene chloride. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and ethyl acetate. The fraction rich in the expected product were recovered, the solvents were expelled and the crystals formed were taken up in ether to obtain 1.885 g of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-2-hydroxy-3-(2-pyridyl)-4-thia-1-azabicyclo[4,2,0]octane-2-carboxylate.