Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH3:21][C@H:22]([C@H:26]([CH3:30])[CH2:27][CH2:28][CH3:29])C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C@H:22]([CH3:21])[C@H:26]([CH3:30])[CH2:27][CH2:28][CH3:29])[CH3:9]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a solution containing 1.0 g (6.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 10 mL of dichloromethane was added 1.1 g of chloromethylene dimethyl-ammonium chloride (8.3 mmol). The resulting solution was stirred under nitrogen for 1.5 hours. The solvent was subsequently evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. To a solution containing 2.5 g (14.6 mmol) of potassium monoethyl malonate in 50 mL of acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and 1.2 g (11.4 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was cooled to 0° C. and a solution of the (2R,3R)-2,3-dimethyl-hexanoyl chloride in acetonitrile (20 mL) was slowly added followed by the addition of triethylamine (0.4 g, 0.4 mmol). The reaction was heated to 40° C. and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25° C., quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 1.3 g (87.8% yield) of the titled compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:54][C:55]1[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:24][CH2:25]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:54][C:55]1[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(O)c(Cl)c4)c23)CC1
Reactant: OCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccncc5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 21A (0.047 g, 0.1 mmol), triphenylphosphine (79 mg, 0.3 mmol), and 4-hydroxymethylpyridine (22 mg, 0.2 mmol) in dry THF was added diethyl azodicarboxylate (0.047 ml, 0.3 mmol). The mixture was stirred at room temperature overnight and purified by preparative HPLC to give Compound 21B as a colorless semi-solid (TFA salt). Analytical HPLC retention time=2.303 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=564+.
Reaction SMILES: [CH2:1]([N:7]1[C:12]2=[N:13][C:14]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:16]=[C:11]2[CH2:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(=O)([O-])O.[K+].[Br:36][C:37](Br)=[N:38][OH:39]>CCOC(C)=O>[Br:36][C:37]1[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][CH2:1][N:7]2[C:12]3=[N:13][C:14]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[N:16]=[C:11]3[CH2:10][CH2:9][CH2:8]2)[O:39][N:38]=1
Reactant: C=CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCC2CC(Br)=NO2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 5-(hex-5-enyl)-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate H) (3.98 g, 10 mmol) and potassium hydrogen carbonate (5.01 g, 50.0 mmol) in EtOAc (50 ml) was treated dropwise with dibromoformaldoxime (6.08 g, 30.0 mmol) in EtOAc (50 ml) over 2 hours. The mixture was stirred at room temperature overnight and then filtered. The filtrate was washed with 1H HCl, water, brine and dried by passing through a phase separator. The solvent was removed under reduced pressure to afford the titled compound which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:28])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:27])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-(4-fluorophenyl)-5-(1-heptenyl)pyridine (Example 32) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.13 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.22 (sept, J=6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.22 (m, 3 H), 1.11 (m, 8 H), 0.85 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C25H36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.86; H, 9.66; N, 3.59. mp 73-75° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[Na+].[Na+].[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[N:26][C:27]=3[NH:37][NH2:38])[N:22]=2)=[CH:17][CH:16]=1>CCO>[O:12]1[CH2:13][CH2:14][O:10][CH:11]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:29][C:28]3[C:27]4=[N:37][N:38]=[C:2]([NH2:1])[N:26]4[CH:25]=[CH:24][C:23]=3[N:22]=2)=[CH:17][CH:16]=1
Reactant: N#CBr
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Reaction time: 3 h

Procedure:
To dry EtOH (1 mL) was added cyanogen bromide (0.104 mL, 0.52 mmol, 5M in MeCN) followed by sodium carbonate (96 mg, 0.91 mmol). [2-(4-[1,3]Dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 100 mg, 0.26 mmol) was added and the mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo and the resulting solid was used without further purification. LRMS m/z (M+1) Calcd: 410.2. Found 410.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Methyl 4-hydroxybenzoate (Fluka) (1.52 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) in DMF (10 mL) was treated with 2-chloro-N,N-dimethylacetamide (Merck) (1.03 ml, 10 mmol) and the mixture was stirred at RT overnight. The reaction mixture was worked up by partitioning between ethyl acetate and 2M hydrochloric acid, washing with HCl, brine, dried (MgSO4) and evaporating to dryness. The residue was dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and 2-chloro-N,N-dimethylacetamide (Merck) (1.03 ml, 10 mmol). The mixture was stirred at RT over the weekend, and then worked up. Partitioned between ethyl acetate and 2M HCl and the organic solution was washed with HCl (X2), brine (X3), dried (MgSO4), and evaporated to give the title compound (1.62 g, 68%) as a white solid. LCMS (System A) RT=0.73 min, ES+ve m/z 238 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:18])[Cl:17])[CH2:12][F:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(O)(C)(C)C.O>[NH2:24][CH2:21][C:22]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:17])[Cl:18])[CH2:12][F:13])=[CH:6][CH:5]=2)[CH:23]=1
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: C#CCN
Solvent: O
Solvent: CC(C)(C)O
Product: NCc1cn(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
To the solution of ((N-[(1S,2R)-2-(4-Azido-phenyl)-1-fluoromethyl-2-hydroxy-ethyl]-2,2-dichloro-acetamide (150 mg, 0.465 mmol) in tert-butylalcohol: water (1:1, 3 mL) is added Na-ascorbate (12 mg, 0.060 mmol), CuSO4.5H2O (3 mg, 0.012 mmol), propargyl amine (26 mg, 0.472 mmol) resulting reaction mixture stirred at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 25-40% methanol in dichloromethane and washed with diethyl ether and dried under vacuum to afford the title compound (25 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 3.84 (s, 2H), 4.23-4.29 (m, 1H), 4.30-4.34 (m, 0.5H), 4.42-4.46 (m, 0.5H), 4.58-4.61 (m, 0.5H), 4.69-4.73 (m, 0.5H), 4.93 (bs, 1H), 6.07 (d, 1H, J=4.28 Hz), 6.49 (s, 1H), 7.54 (d, 2H, J=8.48 Hz), 7.81 (d, 2H, J=8.52 Hz), 8.57 (s, 1H), 8.61 (d, 1H, J=5.6 Hz). LC-MS (m/z): [M+H]=376.2.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCc2cc(C)ccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)c(COc2ccc(C(=O)CCC(=O)O)cc2)c1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(4-(2,5-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step B, 2.62 g, 7.7 mmol) in abs ethanol (30 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred for 3 hours and then acidified with 1M HCl. The occurring white precipitate was filtered, washed with water and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[OH:14])=[O:8].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([CH:9]1[CH:13]([O:14][C:1](=[O:3])[CH3:2])[CH:12]=[CH:11][S:10]1)=[O:8]
Reactant: COC(=O)c1sccc1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1SC=CC1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
8.6 Parts of acetyl chloride are added in the course of 10 minutes to a solution, cooled to 0° C., of 16 parts of 3-hydroxy-thiophene-2-carboxylic acid methyl ester and 15.3 parts by volume of triethylamine in 100 parts by volume of chloroform. The solution is stirred for 4 hours at 0° C. After the reaction, the mixture is poured into 100 parts by volume of ice water and the organic phase is separated off, dried and concentrated. The residue is distilled. 19.4 parts (96% of theory) of 3-acetoxydihydrothiophene-2-carboxylic acid methyl ester of boiling point 82°-84° C./0.08 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:25]1[CH2:30][CH2:29][CH:28]([C:31](=O)[CH3:32])[CH2:27][CH2:26]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:31]([CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[CH3:32])[CH:3]=1
Reactant: CC(=O)C1CCOCC1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Temperature: 22 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
A solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (130 mg, 0.4 mmol), 1-(tetrahydro-2H-pyran-4-yl)ethanone (52 mg, 0.4 mmol) and AcOH (0.1 mL) in MeOH (10 mL). The mixture was stirred at 22° C. for 1 h, then NaBH3CN (76 mg, 1.2 mmol) was added. The mixture was stirred at 22° C. for 4 h. The reaction mixture was concentrated and quenched with water. The mixture solution was extracted with DCM, the combined organic layers were concentrated and the residue was purified by prep-TLC to give the desired compound (14.0 mg, Yield 8%). 1H NMR (CD3OD, 400 MHz): δ 6.90-7.07 (m, 6H), 6.81 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.03 Hz, 1H), 3.98-4.04 (m, 1H), 3.87 (d, J=11.3 Hz, 2H), 3.70 (s, 2H), 3.28-3.45 (m, 5H), 2.82 (brs, 4H), 2.56-2.65 (m, 2H), 1.70 (d, J=13.8 Hz, 1H), 1.57 (brs, 1H), 1.17-1.37 (m, 3H), 1.04 (d, J=6.3 Hz, 3H). LCMS (m/z): 438.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[NH:11][C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2ccc(OC)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)c2cc(OC)ccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a mixture of (S)-2-(6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (100 mg, 0.31 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added K2CO3 (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (143 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:6]([CH:14]=1)[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8].Cl.[C:26](=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:6]([CH:14]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:26])=[O:12])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)NCC(O)COc1ccc(N)cc1C(=O)CCC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCC(=O)c1cc(N)ccc1OCC(O)CNC(C)(C)C

Procedure:
3-[5-Amino-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionic acid was esterified with hydrogen chloride in methanol. Evaporation of the solution under reduced pressure gave a residue which was dissolved in the minimum of water and the solution was neutralised with sodium carbonate and extracted with dichloromethane. The combined extracts were washed with saturated brine, dried, and evaporated to give methyl 3-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 97.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.256 mmol) was dissolved in acetonitrile (8 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (133 mg, 1.02 mmol), acetic acid (0.307 mL, 5.12 mmol) and sodium triacetoxyborohydride (218 mg, 1.02 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methyl-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (126 mg, yield 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12](N(CC)CC)C.CI>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN(CC)CC
Reactant: Sc1nc2cc(Br)ccc2s1
Solvent: CI
Solvent: CCO
Product: CSc1nc2cc(Br)ccc2s1
Yield: 78.4 %

Procedure:
To a solution of 5-bromobenzo[d]thiazole-2-thiol (24 mg, 0.098 mmol) in EtOH (1.5 mL) was added triethylamine (10 mg, 0.098 mmol) and methyliodide (14 mg, 0.098 mmol). The mixture was heated at reflux for 1.5 h. Then the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 5-bromo-2-(methylthio)benzothiazole 20 mg (80%).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]([F:20])([F:19])[F:18])[CH:14]=3)[NH:9][C:8]2=[O:21])[C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[F:1][C@H:2]1[CH2:6][N:5]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]([F:20])([F:19])[F:18])[CH:14]=3)[N:9]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=3[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:8]2=[O:21])[C@H:4]([C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[CH2:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N2C[C@H](F)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(OC(F)(F)F)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(OC(F)(F)F)ccc32)c(OC(F)(F)F)c1
Yield: 51.7 %

Procedure:
With 200 mg of the compound obtained in Step 20-1 (Isomer B) and 133 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 158 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([NH:22][C:23]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([O:45][C@@H:46]3[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:80])[C:76]([CH3:79])([CH3:78])[CH3:77])[C@@H:63]([O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])[C@H:55]([O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@H:47]3[O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])=[N:39][NH:40]4)=[CH:30][CH:29]=2)=[O:24])([CH3:21])[CH3:20])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[N:14]1([C:17]([C:19]([NH:22][C:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([O:45][C@@H:46]3[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:80])[C:76]([CH3:79])([CH3:78])[CH3:77])[C@@H:63]([O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])[C@H:55]([O:56][C:57](=[O:62])[C:58]([CH3:59])([CH3:60])[CH3:61])[C@H:47]3[O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:52])[CH3:53])=[N:39][NH:40]4)=[CH:32][CH:33]=2)=[O:24])([CH3:21])[CH3:20])=[O:18])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#Cc4ccc(/C=C/CC(=O)NC(C)(C)C(=O)N5CCN(C(=O)OCc6ccccc6)CC5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(CCc4ccc(CCCC(=O)NC(C)(C)C(=O)N5CCNCC5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 4-[2-(4-{(E)-3-[1-{[4-(benzyloxy-carbonyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]prop-1-enyl}phenyl)ethynyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (34 mg) in methanol (3 mL) was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-{2-[4-(3-{1-[(piperazin-1-yl)-carbonyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]ethyl}-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (30 mg). This material was dissolved in methanol (3 mL). To the solution was added lithium hydroxide monohydrate (6 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added acetic acid (0.1 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (17 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[N:18]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:2]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[NH2:18]
Reactant: Nc1cccc(CCNC(=O)C(F)(F)F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(CCNC(=O)C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
N-(3-aminophenethyl)-2,2,2-trifluoroacetamide hydrochloride (0.27 g, 1.0 mmol) was suspended in 6M HCl (2.0 mL) and cooled thoroughly in an ice bath. This was rapidly stirred while a solution of NaNO2 (73 mg) in H2O (1.0 mL) was added slowly. The mixture was stirred at 0-5° C. for 45 min and was then treated with SnCl2.2H2O (1.3 g, 5.8 mmol) in 6N HCl (4.0 mL). The resulting suspension was stirred at 0-5° C. for 3 h and then carefully quenched with 3N NaOH (15 mL) to pH 7-8. The mixture was diluted with Et2O, filtered through Celite® and the filter cake was washed with H2O and Et2O. The layers of the biphasic filtrate were separated and the aqueous extracted with Et2O (2×). The combined organics extracts were washed with brine (1×), dried (Na2SO4), filtered and evaporated to provided N-(3-hydrazinophenethyl)-2,2,2-trifluoroacetamide as a pale yellow oil (0.18 g, 72% yield), which was used without further purification. MS (ESI) m/z: 248.0 (M+H+).