Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH:6]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([N+:19]([O-])=O)[CH:11]=2)[CH2:5][C:4]([CH3:24])([CH3:23])[NH:3]1.[H][H]>C(O)C.[Pd]>[NH2:19][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([NH2:16])[CH:13]=1)[C:9]([NH:8][CH:6]1[CH2:5][C:4]([CH3:24])([CH3:23])[NH:3][C:2]([CH3:1])([CH3:25])[CH2:7]1)=[O:22]
Reactant: [H][H]
Reactant: CC1(C)CC(NC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC(C)(C)N1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(NC(=O)c2cc(N)cc(N)c2)CC(C)(C)N1
Yield: 79.6 %

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidyl)-3,5-dinitrobenzamide (1.0 g.) is dissolved in ethanol (50 ml.) and 10% palladium on charcoal (.1 g.) is added. The reduction is carried out in a Parr apparatus for 2 hours at 40 psi of hydrogen. The catalyst is removed by filtration, washed with a few ml. of ethanol and the filtrate taken to dryness under reduced pressure leaving a tan solid. Recrystallization from ether gives a cream colored product (6.6 g., m.p. 188°-190°C., 79.6% yield).
Reaction SMILES: [CH2:1]([C:3]1([C:12](Cl)=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].S(=O)(=O)(O)O.[CH3:20]COCC>>[CH2:1]([C:3]1([C:12](=[O:13])[CH3:20])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)Cl)Cc2ccccc2C1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Product: CCC1(C(C)=O)Cc2ccccc2C1

Procedure:
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole with 10% palladium on carbon.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[N:14][N:13]2[CH:16]=[CH:17][N:18]=[C:12]2[CH:11]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:9][C:10]1[CH:15]=[N:14][N:13]2[C:16]([I:1])=[CH:17][N:18]=[C:12]2[CH:11]=1
Reactant: Clc1cnn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cnn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
N-Iodosuccinimide (2.17 g, 9.65 mmol) was added to a solution of 7-chloroimidazo[1,2-b]pyridazine (0.988 g, 6.43 mmol) in N,N-dimethylformamide (25 mL). The reaction mixture was stirred at r.t. overnight. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (gradient: 0-50%) to afford the desired product (1.40 g, 77.9%). LCMS (M+H)+: m/z=279.9/281.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:37]=[CH:36][C:25]3[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 38.4 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (114 mg, 0.336 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (80 mg, 0.344 mmol), 4 N HCl in dioxane (103 ul) and 2-methoxyethanol (5 mL). Heated reaction to 120° C. for 2.5 hours. Evaporated off solvent and purified with normal phase chromatography to yield a white solid, N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (69 mg, 38%). LCMS: m/z=535.34 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.65 (dd, 1H, J=8.6, 1.3 Hz), 7.36 (d, 1H, J=2.3 Hz), 7.21 (d, 1H, J=8.6 Hz), 6.91 (s, 1H), 5.44 (d, 1H, J=7.6 Hz), 5.36 (d, 1H, J=6.8 Hz), 3.87 (m, 3H), 3.24 (m, 1H), 2.82 (s, 3H), 2.17 (m, 6H), 1.84 (m, 2H), 1.37 (m, 13H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([CH2:31][C:32]([O:34]CC)=[O:33])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[N:20]=1)=[O:14])(=O)C.[OH-].[Na+]>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([CH2:31][C:32]([OH:34])=[O:33])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[N:20]=1)=[O:14]
Reactant: CCOC(=O)Cc1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(NC(=O)c3cc4ccccc4[nH]3)sc2CC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-[(1-acetyl-2-indolyl)carbonylamino]-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole, prepared above according to Example 10, is dissolved in 10 ml of 95° ethanol and then 1.5 ml of 2N NaOH are added. The reaction mixture is stirred,overnight at room temperature and then concentrated under vacuum. The residue is taken up in a buffer solution, pH=2, a precipitate is separated by filtration, washed with water, filtered and then rinsed with ether.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Cc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC(=O)C(F)(F)F)n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cc1
Yield: 22.5 %

Procedure:
A mixture of 7-[2-[2-(2,2,2-trifluoroacetamido)-thiazol-4-yl]-2-(4-methylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 4.5 g.), sodium acetate 3 hydrate (12.5 g.), water (250 ml.) and tetrahydrofuran (20 ml.) was treated in a similar manner to that of Example 16-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.84 g.), m.p. 135°-155° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([OH:13])[CH2:7]2.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)C>[CH3:21][S:22]([O:13][C@@H:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCc2c(F)cc(F)cc2C1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)O[C@@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (59.0 g, 0.32 mol), prepared as in Example 3, and triethylamine (13.8 M, 74.2 mL, 0.53 mol) in 1.78 L of diethyl ether was cooled using a methanol/ice bath. Methanesulfonyl chloride (12.9 M, 37.2 mL, 0.48 mol) was added under argon over 5-10 minutes and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and ether and the ether layer was separated and the aqueous layer was extracted with ether. The combined ether layers were washed once with each of 1N hydrochloric acid, saturated sodium bicarbonate solution and brine and then dried over magnesium sulfate. Evaporation gave crude (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate as an off-white solid (87.12 g), m.p. 79°-80° C. [α]D25 =+16.77° (c=2.0, CHCl3).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][C:3]=1[C:9]#[N:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)CC.O>[CH3:7][N:6]1[C:2]2[C:37]3[CH:36]=[N:35][CH:34]=[CH:33][C:32]=3[N:31]=[C:9]([NH2:10])[C:3]=2[N:4]=[C:5]1[CH3:8]
Reactant: Cc1nc(C#N)c(Br)n1C
Reactant: Nc1ccncc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Cc1nc2c(N)nc3ccncc3c2n1C
Temperature: 100 °C
Yield: 40.6 %

Procedure:
5-Bromo-1,2-dimethyl-1H-imidazole-4-carbonitrile (2.00 g, 10.0 mmol), palladium (II) acetate (112 mg, 0.499 mmol), triphenylphosphine (393 mg, 1.50 mmol), and water (3.5 mL) were added to a solution of 4-aminopyridin-3-ylboronic acid hydrochloride salt (3.5 g, 0.020 mol), aqueous sodium carbonate (17.5 mL of 2 M), and n-propanol (17.5 mL). The vessel was evacuated and filled with nitrogen three times. The reaction was sealed and heated under a nitrogen atmosphere at 100° C. for two hours and allowed to cool to room temperature. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material, and additional aqueous sodium carbonate (2.5 mL of 2M), palladium (II) acetate (56 mg), triphenylphosphine (197 mg), and 4-aminopyridin-3-ylboronic acid hydrochloride salt (872 mg) were added. The reaction was heated again at reflux for two hours, allowed to cool to room temperature, and further cooled with ice. A precipitate was present and was isolated by filtration and washed with water to provide 865 mg of 1,2-dimethyl-1H-imidazo[4,5-c][1,6]naphthyridin-4-amine. The product was purified by column chromatography on silica gel (eluting with 25% to 40% CMA in chloroform) to provide an analytically pure sample, mp 330-335° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:5][CH:4]=1.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13][NH:28][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Sc2cccc(C=O)c2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 72A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1](NN)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.I(O)(=O)(=O)=[O:19]>OCC(CO)O>[OH:19][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)=[O:15]
Reactant: NNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: [O-][I+3]([O-])([O-])O
Solvent: OCC(O)CO
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
An aldehyde was introduced into the monoclonal antibody 22-1-1 obtained in Example 1 by oxidation with sodium metaperiodate, which was bound with biotin hydrazide to obtain a biotinated antibody. Specifically, 1 ml of an ice-cooled metaperiodic acid solution was added to 1 ml of the ice-cooled monoclonal antibody 22-1-1, which was mixed well and subjected to an oxidation reaction in the dark place at 0° C. for 30 minutes. Thereafter, glycerol was added thereto to the final concentration of 15 mM, which was incubated at 0° C. for 5 minutes to stop the oxidation reaction. This solution was dialyzed against a 0.1M sodium acetate buffer (pH5.5) overnight, and biotin hydrazide was added to the final concentration of 5 mM to stir at room temperature for 2 hours. The unreacted molecules were removed from this by dialysis to obtain a biotin-labeled antibody.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(O)(=O)C>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
196 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 5 ml of glacial acetic acid and after the addition of 0.1 g (1 mmol) of acetic anhydride stirred for 3 hours at ambient temperature. Then 15 ml of water are added, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1ccccc1

Procedure:
Following a procedure similar to that described in Example (1b), 710 mg of isomer B of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-phenylethyl]amine [prepared as described in step (a) above], 920 mg of nickel chloride hexahydrate and 293 mg of sodium borohydride were reacted and purified, to obtain 620 mg of isomer B of the title compound as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:33])[C:24]4[C:29]([CH:30]=3)=[C:28]([C:31]#[CH:32])[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:31]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH:30]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][CH:17]=1)[NH:22][C:23]2=[O:33])#[CH:32]
Reactant: C#Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Yield: 34.3 %

Procedure:
4-[4-(5-Ethynyl-1-oxo-1,2-dihydroisoquinolin-3-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester (60.3 mg, 0.136 mmol) and 4M HCl/dioxane (3 mL) in CH2Cl2 (3 mL) were stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude material was purified by reverse phase preparative HPLC-MS to obtain 5-ethynyl-3-(4-piperazin-1-ylmethylphenyl)-2H-isoquinolin-1-one as an off-white solid (16.0 mg, 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]([CH2:30][C@@H:31]([O:33][C:54](=[O:55])[C@@H:52]([NH:51][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH3:53])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), (S)—N-Cbz-alanine (1.647 g, 7.36 mmol, Shanghai Hanhong Chemical CO., LTD.) and DMAP (0.90 g, 7.36 mmol, Aladdin) in 30 mL of CH2Cl2 at 0° C. was added EDC solid (2.116 g, 11.04 mmol, Aladdin) in portions. The mixture was continued to stir at 0° C. for 2 hrs, and then the reaction mixture was warmed up to room temperature, and stirred at rt for 20 hrs. The mixture was diluted with 180 mL CH2Cl2, and the result solution was washed with 0.1 N HCl (10 mL×3), followed by 50 mL saturated NaHCO3. The aqueous phase was extracted with EtOAc (50 mL×3), the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired compound as a pale yellow solid (2.1 g, 73%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[N+:1]([C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N+:8]([O-:39])[CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 61.7 %

Procedure:
To a mixture of tert-butyl [(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (179.2 mg, 0.4163 mmol) and mCPBA (210.6 mg, 0.9397 mmol) was added DCM (2.00 mL). The reaction mixture was stirred at room temperature for 13 h. The mixture was diluted with DCM (30 mL), washed with 1 M NaOH aqueous solution. The separated aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound (114.7 mg, 62%). LCMS calc. for C19H26F3N4O5 (M+H)+: m/z=447.2. found 447.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:9]1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:9]1[C:31]1[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:29]([C:28]([F:27])([F:43])[F:42])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(Br)c(CCOC2CCCCO2)c2ccccc21
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(CCOC2CCCCO2)c2ccccc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a degassed solution of 1-tert-butoxycarbonyl-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (2.0 g), 3,5-bis(trifluoromethyl)phenylboronic acid (2.43 g) and Na2CO3 (aq., 2N, 8.8 ml) in tetrahydrofuran was added tetrakis(triphenylphosphine)-palladium(0) (0.55 g). The resulting solution was then warmed to reflux for 18 h, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (SiO2; 3-5% ethyl acetate/hexanes) to afford the title compound (2.1 g). 1H NMR (CDCl3) δ1.23 (s, 9H), 1.45-1.71 (br m, 6H), 2.82 (t, 2H, J=7.2 Hz), 3.37 (m, 1H), 3.61 (m, 2H), 3.98 (m, 1H), 4.50 (t, 1H, J=3.5 Hz), 7.30 (t, 1H, J=7.0 Hz), 7.41 (t, 1H, J=7.0 Hz), 7.60 (d, 1H, J=10.0 Hz), 7.89 (s, 1H), 7.91 (s, 2H), 8.27 (d, 1H, J=10.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[C:30]([O:33][CH2:34][C:35](Cl)=[O:36])(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[C:30]([O:33][CH2:34][C:35]([N:1]([C:35](=[O:36])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc(CSc2ncccc2C(=O)Nc2ccc(OC(F)(F)F)cc2)ccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)N(C(=O)COC(C)=O)c1cc(CSc2ncccc2C(=O)Nc2ccc(OC(F)(F)F)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Compound No. 3-11, 800 mg, 1.9 mmol) was dissolved in pyridine (10 mL), and acetoxyacetyl chloride (0.66 mL, 6.1 mmol) was added thereto under ice-cooling, and the mixture was stirred for 18 hours at room temperature. The mixture was diluted with ethyl acetate (100 mL), and the whole was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and 1 N hydrochloric acid (50 mL) twice successively. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) again and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from ethyl acetate-hexane to give 300 mg of the target compound as a colorless solid. (Yield 30%)