Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[N:13]2)=[C:10]([Cl:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:11]([N:12]2[C:16](=[O:17])[N:15]([CH3:21])[N:14]=[N:13]2)=[C:10]([Cl:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(-n2nn[nH]c2=O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)c(-n2nnn(C)c2=O)c1Cl
Temperature: 60 °C
Yield: 98.5 %

Procedure:
Methyl 2,4-dichloro-3-(4,5-dihydro-5-oxo-1H-tetrazol-1-yl)benzoate (4.00 g), methyl iodide (2.36 g) and potassium carbonate (2.29 g) were suspended in N,N-dimethylformamide (30 ml) and stirred at 60° C. After reaction, cold water was added to the reaction mixture and the mixture was extracted with ethyl acetate (150 ml) and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective methyl 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoate (4.13 g, yield 98%) was obtained. mp: 135-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].BrC[CH2:22][CH2:23][O:24][CH3:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[O:1][CH2:22][CH2:23][O:24][CH3:25])[C:8](=[O:11])[CH2:7][CH2:6]2
Reactant: COCCCBr
Reactant: COc1cc2c(cc1O)C(=O)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: COCCOc1cc2c(cc1OC)CCC2=O

Procedure:
To a mixture of 6-Hydroxy-5-methoxy-indan-1-one (10.5 g, 59 mmol), K2CO3 (16 g, 118 mmol), tetrabutyl-ammonium iodide (2 g, 5.9 mmol) suspended in actone (200 ml), 1-Bromo-3-methoxy-propane (8.5 ml, 88.5 mmol) was added, and then the mixture was heated to reflux for 4 hs under N2. The solid was filtered off and washed by actone (50 ml×3), the filtrate was concentrated to give the crude product which was used directly for next step without purification. LC-MS: m/e 237 (MH+)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[CH:4][N:3]=1.C(C1C=CC(C2ON=C(C3C=CC(C=O)=NC=3)N=2)=CC=1)C(C)C.C(C1C=CC(C2ON=C(C3N=CC([CH2:67][NH:68][CH:69]4[CH2:72][CH:71]([C:73]([OH:75])=[O:74])[CH2:70]4)=NC=3)N=2)=CC=1)C(C)C>>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:67][NH:68][C@@H:69]4[CH2:72][C@H:71]([C:73]([OH:75])=[O:74])[CH2:70]4)=[N:3][CH:4]=3)=[N:12][N:11]=2)=[CH:14][CH:15]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CNC4CC(C(=O)O)C4)cn3)no2)cc1
Reactant: CC(C)Cc1ccc(-c2nnc(-c3ccc(Cl)nc3)o2)cc1
Agent: CC(C)Cc1ccc(-c2nc(-c3ccc(C=O)nc3)no2)cc1
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)nc3)o2)cc1

Procedure:
The title compound was prepared from 2-chloro-5-[5-(4-isobutylphenyl)-1,3,4-oxadiazol-2-yl]pyridine by procedures analogous to those described in Preparations (5C-5D) and Examples (1A-1B) for the preparation of 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine-2-carbaldehyde and 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cyclobutanecarboxylic acid, respectively.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: NCc1ccccc1F
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccccc1F)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-fluorobenzylamine (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 48 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1OCCOC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:19]1[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)Cc1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 118.7 %

Procedure:
A mixture of methyl (2-bromophenyl)acetate of Step A (20.0 g, 87.3 mmol), 4-carboxybenzeneboronic acid (14.5 g, 87.4 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium [II] (3.6 g, 4.4 mmol) and potassium phosphate (55.6 g, 262 mmol) in dry 4-dioxane (ca. 400 mL) was heated at 100° C. with vigorous stirring for 17 hours. The cooled mixture was then filtered through Celite and washed with 1,4-dioxane (ca. 200 mL). The filtrate was concentrated in vacuo to give a tacky brown solid (28.0 g). Purification by flash chromatography using a solvent gradient of 320:1:1 to 80:1:1 dichloromethane/acetic acid/methanol afforded an impure tacky orange solid (11.9 g). The solid product was dissolved in ethyl acetate (300 mL), filtered from insoluble material, and the filtrate washed with water (2×150 mL) and brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a light orange solid (7.3 g). Recrystallization from diethyl ether provided the title compound (5.2 g, 22%) as pale orange needles.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[C:14]1[NH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[C:17]([CH3:19])[N:18]=1.O>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[C:14]1[NH:15][C:16]([S:20]([NH2:1])(=[O:22])=[O:21])=[C:17]([CH3:19])[N:18]=1
Reactant: N
Reactant: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(N)(=O)=O
Reaction time: 3 h

Procedure:
Aqueous ammonia solution (approximately 33% w /w, 1.2 ml) was added dropwise with stirring to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylimidazole-5-sulphonyl chloride (2.0 g, 0.005 mol) in dioxane (15 ml) and the mixture was stirred for 3 hours. It was poured into water (50 ml) and extracted with diethyl ether (3×25 ml). The combined extracts were washed with water (2×50 ml) dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (1:2). Recrystallization from a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:3) gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylimidazole-5-sulphonamide (0.45 g), m.p. 266°-267° C., as an off-white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:12]([CH2:13][CH3:14])[CH2:11][C:10](=O)[C:9]2[S:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:24][NH2:25].C([BH3-])#N.[Na+].[BH4-].[Na+].[OH-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:4][C:5]([N:7]1[CH:12]([CH2:13][CH3:14])[CH2:11][CH:10]([NH:25][CH2:24][C:23]2[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:21]([C:20]([F:19])([F:33])[F:34])[CH:22]=2)[C:9]2[S:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CCC1CC(=O)c2sccc2N1C(=O)OC(C)C
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2sccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Inject titanium(IV)isopropoxide (0.372 ml, 1.26 mmol) to a mixture of 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4-carboxylic acid isopropyl ester (0.225 g, 0.842 mmol), 3,5-bis(trifluoromethyl)benzylamine (0.211 g, 0.842 mmol), and then stir at room temperature for 4 h. Inject a solution of sodium cyanoborohydride (0.212 g, 3.37 mmol) in methanol (8 ml) to the reaction mixture and continue to stir at room temperature overnight. Add another portion of solution of sodium cyanoborohydride (0.212 g, 3.37 mmol) in methanol (8 ml) and continue to stir for 4 h. Add sodium borohydride (0.159 g, 4.21 mmol) and heat the reaction at 60° C. overnight. Treat the mixture with 0.1 N sodium hydroxide (25 ml) for 10 minutes, and then filter through a Celite® pad. Wash the filtered residue thoroughly with ethyl acetate. Separate the organic layer, wash with brine (3×50 ml), dry over Na2SO4, filter and concentrate to provide crude 7-(3,5-bis-trifluoromethyl-benzylamino)-5-ethyl-6,7-dihydro-5H-thieno [3,2-b]pyridine-4-carboxylic acid isopropyl ester (0.315 g) which was elaborated without further purification. MS (ES+): 495 (M+H).
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][NH2:23])=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O.C(N(CC)CC)C>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][NH:23][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[NH2:24])=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ncccc1C(=O)NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of DMSO (3 mL) of (4-benzyloxy-phenyl)-acetic acid hydrazide (130 mg) described in Manufacturing Example 8-1 were added triethylamine (0.21 mL), 2-aminonicotinic acid (70 mg), and BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) (250 mg), which was stirred for 1 hour at the same temperature. Water was added to the reaction solution, and the solids thus precipitated were filtered off to obtain the titled compound (170 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>C(O)C>[C:37]1([NH:36][C:34]([CH2:33][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)=[O:12])[CH2:5][CH2:4]2)=[O:35])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(CNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1)Nc1ccccc1

Procedure:
To a solution of 581 mg (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 759 mg (7.5 mM) of triethylamine in ethanol (30 ml) was added 254 mg (1.5 mM) of chloroacetylaniline at room temperature, and the mixture was refluxed for 18 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate=½) to provide the title compound as red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCc1ccccc1
Product: COC(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-4-phenylbutanoate (prepared from (+)-α-amino-4-phenylbutyric acid (Bachem) using General Procedure AG), the title compound was prepared as a solid (mp=147-149.5° C.). The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using EtOAc/hexanes as the eluent.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.N1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:27]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)[C:28](=[O:30])[CH3:29])=[CH:15][CH:14]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1

Procedure:
A mixture of 4-((quinolin-2-yl)methoxy)benzaldehyde (2.5 g, 9.5 mmol), 1-(pyridin-4-yl)propan-2-one (1.3 g, 9.5 mmol) and piperidine (162 mg, 1.9 mmol) in toluene (50 mL) was heated at reflux for 18 h, concentrated, and the residue chromatographed on silica eluting with a gradient of ethyl acetate in hexanes giving impure title substance (2.4 g) as a yellow solid which was chromatographed again on silica eluted with 1% and 2% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide giving a 3:1 mixture of the title substance contaminated with the pyridyl starting material. Yield 2.0 g, 55%. The title substance appeared to be a 10:1 mixture of two isomers by NMR. 1H NMR (CDCl3, 400 mHz, partial) δ 2.35 (s, 3H, major isomer), 2.23 (s, 3H, minor isomer). HPLC-MS 6.09 min, m/e 381 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([CH2:20][CH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2)([OH:19])=[O:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH2:21][CH2:20][C:17]([OH:19])=[O:18])[CH:23]=2)[NH:27][C:26]1=[O:31])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C(O)CCc1ccc2c(c1)CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(CCC(=O)O)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-(2-carboxyethyl)-2-oxindole to give 0.35 g of 3-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-propionic acid as a yellow-orange solid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]1([Mg]Cl)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>C1COCC1>[CH:5]1([C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C2CCCCC2)CC1

Procedure:
Anhydrous cerium(III) chloride (10.0 g) was added to THF (100 ml) with stirring under ice-cooling and a mixture was stirred at ambient temperature overnight and then cooled in an ice bath. A solution of cyclohexyl magnesium chloride (2M solution in diethyl ether) (20.3 ml) was dropwise added to the mixture with stirring on ice bath (keeping the temperature below 6° C.). To the mixture was added dropwise a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.38 g) in THF (25 ml) and the mixture was stirred at 0-6° C. for 1 hour. 10% aqueous acetic acid (100 ml) was added to the reaction mixture and extracted twice with ethyl acetate (100 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-cyclohexyl-4-hydroxy-1-piperidinecarboxylate (7.27 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:28][B:27](B2OC(C)(C)C(C)(C)O2)[O:26]1.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)=[CH:3][C:2]([B:27]([OH:28])[OH:26])=[CH:7]1
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 32.9 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stirrer was charged with 5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 125i (1.0 g, 2.64 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.0 g, 7.92 mmol), PdCl2(dppf) (190 mg, 0.26 mmol), potassium acetate (776 mg, 7.92 mmol), and dioxane (40 mL). After bubbling argon into the mixture for 30 minutes, a reflux condenser was attached to the flask and mixture was stirred at 100° C. for 6 h under an argon atmosphere. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by reverse-phase Combiflash eluting with 0.3% NH4HCO3 water/CH3CN to afford 163a as a white solid (300 mg, 33%). MS: [M+H]+ 346.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH:25]=[N:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH:32][CH:11]3[CH2:12][CH2:13][CH2:14][N:9]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[CH:29][CH:30]=2)[CH:25]=[N:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(NC3CCCN(Cc4ccccc4)C3)ccc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A mixture of 1-benzyl-piperidin-3-one hydrochloride (116 g, 0.52 mol, 1.2 eq) and TEA (43.5 g, 0.43 mol, 1.0 eq) in DCE (800 mL) was stirred at 30° C. for 1 hour. Then 5-amino-indazole-1-carboxylic acid tert-butyl ester (100 g, 0.43 mol, 1.0 eq) and CH3COOH (25.8 g, 0.43 mol, 1.0 eq) were added and the reaction mixture stirred for 30 min. NaBH(OAc)3 (273 g, 1.29 mol, 3.0 eq) was then added in one portion and the mixture stirred at 30° C. for 16 hours. LC-MS showed complete conversion. The reaction mixture was diluted in DCM (1 L) and the organic layer washed with saturated NaHCO3 (800 mL×3) and H2O (500 mL×3), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using (DCM:MeOH=60:1) to give the 5-(1-benzyl-piperidin-3-ylamino)-indazole-1-carboxylic acid tert-butyl ester (131 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[C:17]([C:19]1([CH2:32][CH2:33]OS(C)(=O)=O)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.CN(C)C=O>[C:17]([C:19]1([CH2:32][CH2:33][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([CH3:14])=[CH:8][C:9]2=[O:13])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2c(C)cc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 5 mL of an N,N-dimethylformamide solution containing 0.19 g of 7-methoxy-4-methylquinolin-2(1H)-one, 47 mg of a 60% aqueous sodium hydride solution was added at 50° C., and the mixture was stirred at the same temperature for 40 minutes. Thereto was added dropwise 4 mL of an N,N-dimethylformamide solution containing 0.36 g of tert-butyl 4-cyano-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate at 50° C., and the mixture was stirred at 50 to 55° C. for 3 hours. Thereto was added 0.27 g of potassium carbonate at the same temperature, and the mixture was further stirred for 3 hours and 10 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [hexane:gradient elution of ethyl acetate=75:25 to 50:50] to obtain 70 mg of a colorless oily substance, tert-butyl 4-cyano-4-(2-(7-methoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidine-1-carboxylate.