Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:48])[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:47])[CH2:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.CCOCC>[OH:39][CH2:38][CH2:37]/[CH:36]=[CH:35]/[CH2:34][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:24](=[O:48])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.3 %

Procedure:
A TBAF (4.46 g, 17.06 mmol) in THF was added to a solution of (E)-tert-butyl2-(6-(tert-butyldimethylsilyloxy)hex-3-enamido)phenylcarbamate (6.17 g, 14.2 mmol) in THF (180 mL) at 0° C. for 0.5 hour, then the mixture was stirred at RT for 12 hours. The reaction mixture was diluted with ether (500 mL) and washed with brine (3×200 mL), the organic layer was dried over Na2SO4, filtered and concentrated to give the desired compound of (E)-tert-butyl 2-(6-hydroxyhex-3-enamido)phenylcarbamate (10) (2.38 g, 52%) as a yellow oil after purification by column chromatography on silica gel (eluent: PE:EA=1:1). 1H NMR (300 MHz, CDCl3): δ 1.475 (S, 9H), 2.292 (q, 2H), 3.096 (d, 2H), 3.652 (t, 2H), 5.655-5.701 (m, 2H), 6.996-7.124 (m, 2H), 7.310-7.380 (m, 2H), 7.482 (d, J=7.8 Hz, 1H), 8.652 (s, 1H); LC-MS found 321 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36]C(S(Cl)(=O)=O)=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:22]([C:25]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(OS(C)(=O)=O)c(F)cc3c1=O)CCN2C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
304 mg of the compound (168) obtained in Example 45 was added to 2 ml of pyridine, and 260 mg of p-toluene-sulfonyl chloride was added to the solution. The solution was stirred for 2 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with water and aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 220 mg of the subject compound (169).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([I:18])[NH:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([I:18])[N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(I)[nH]c2CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(I)n(COCC[Si](C)(C)C)c2CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-iodo-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 28, 2.2 g, 6.06 mmol) in THF (35 mL) was added NaH (60% in paraffin oil, 254 mg, 6.36 mmol) and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0° C. and SEM-Cl (1.13 mL, 6.36 mmol) was added dropwise.
Reaction SMILES: [Cl-].[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][N+:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]2[C:17]([CH3:20])=[CH:18][S:19][C:9]=12.[CH3:30][O-:31].[Na+]>CO>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:6]([CH:5]=[C:4]([C:3]([F:29])([F:28])[F:2])[CH:23]=1)[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10](/[C:17](/[CH3:20])=[CH:18]\[S:19][CH3:9])[C:30]1=[O:31]
Reactant: Cc1csc2n1c1ccccc1[n+]2Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Yield: 74.8 %

Procedure:
285 mg of 9-[3,5-bis(trifluoromethyl)benzyl]-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride (0.632 mmol) were solubilised in methanol (40 mL), then 274 mg (8 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-[3,5-bis(trifluoromethyl)benzyl]-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a white powder (211 mg, 77%). Mp 148° C.; Rf=0.72 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=2.18 (3H, d, J=1.1, CH3), 2.26 (3H, s, SCH3), 5.20 (2H, brs, CH2), 6.31 (1H, q, J=1.1, H5), 6.82-7.15 (4H, m, Ar), 7.75 (3H, brs, Ar); 13C NMR (75 MHz, CDCl3) δ=16.79, 20.45, 43.95, 107.84, 109.41, 121.88, 121.88 (1C, sept, J=3), 122.00, 123.07 (2C, q, J=272), 126.34, 127.50 (2C, q, J=3), 127.94, 128.36, 128.78, 132.17 (2C, q, J=34), 139.07, 152.19; HRMS m/z C20H17F6N2OS [M+H]+ calcd: 447.0960, found: 447.0959.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)=[CH:6][C:5]=1[Cl:34].O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:34][C:5]1[CH:6]=[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:35])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
To a solution of 130 mg (0.254 mmol) 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid methyl ester (Example 65) in 2 mL dioxane was added 2 mL water and 13 mg (0.317 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred at room temperature for 4 hours and then poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate The layers were separated and the aqueous layer was extracted with 20 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give 125 mg (98.9%) of the title compound as a light yellow solid. MS (ESI): m/z=498.098 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([O:35]C(=O)OCC2C=CC=CC=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[H][H].[CH2:48]([OH:50])[CH3:49]>[Pd]>[CH2:1]([C:3]1([OH:35])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:48](=[O:50])[C:49]2[CH:7]=[CH:8][CH:3]=[CH:1][CH:2]=2)=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2]
Reactant: [H][H]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Reactant: CCO
Agent: [Pd]
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccccc1

Procedure:
A mixture of Compound 53 (20 mg, 0.027 mmol), 10% palladium on carbon (4 mg, 20%) in 1 mL of ethanol was hydrogenated for 17 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([Cl:16])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Cl-:16].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([S:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Reactant: SCc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(N)[n+](CCCC)c(SCc2ccccc2)c1C#N
Temperature: 100 °C
Yield: 49.4 %

Procedure:
3.15 gms (0.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano pyridinium chloride (compound 6 - Table 1), 1.24 gms (0.01 mole) of benzyl mercaptan and 1.0 gm (0.01 mole) of triethylamine was dissolved in dimethylformamide and heated at 100°C for 1 hour. The dimethylformamide was evaporated off, ethanol added and 2.0 gms (50% yield) of 2-amino-6-benzylmercapto-1-n-butyl-4-n-butylamino-5-cyano pyridinium chloride (compound 75 - Table 5) crystallised out and was recrystallised from ethanol (MPt 145° - 147°C).
Reaction SMILES: C(C1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#N.[CH3:15][Mg+].[Br-].[OH-].[Na+].CCO[C:23]([CH3:25])=[O:24]>C1COCC1.CCCCCC>[C:23]([C:25]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)(=[O:24])[CH3:15]
Reactant: CCOC(C)=O
Reactant: C[Mg+]
Reactant: N#Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cc([N+](=O)[O-])cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a solution of 7-cyano-5-nitroindole (0.7 g, 4.4 mmol) in 20 mL of THF was added 5.0 mL of MeMgBr (3.0 M) and the resulting reaction mixture was stirred for 12 h at 25° C. Reaction was quenched by adding 10 mL of 1.0 N aqueous HCl. Reaction mixture was basified with 3 N aqueous NaOH and aqueous solution was extracted with EtOAc several times. Organic extracts were dried over MgSO4 and concentrated in vacuo to provide oily residue which was subjected to column chromatography (50% EtOAc/Cy.hexane) to yield 0.20 g (1.2 mmol, 26%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]CS([O-])(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+]=[N-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCOCCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCN
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To 146 g of [2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate was dissolved in 500 ml DMF, was added 134 g of sodium azide. The reaction mixture was stirred at 70° C. for 20 h, and then concentrated under reduced pressure. The resulting residue was dissolved in 1,200 ml water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine. The reaction mixture was stirred at RT for 2 h, after which was added 200 ml water. The reaction mixture was stirred at RT for 18 h and concentrated to 500 ml under reduced pressure. Then the resulting precipitate was filtered off. The filtrate was further concentrated under reduced pressure to remove THF, and washed with MC. The aq layer was concentrated to obtain 86.2 g of compd 42 as a liquid. 1H NMR (400 MHz; CDCl3) δ 4.96 (br s, 1H), 3.54-3.48 (m, 4H), 3.34 (q, 2H), 2.88 (t, 2H), 1.48-1.46 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:29][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(N2CCOCC2)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 55.3 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Chloro-4-morpholin-4-yl-benzaldehyde (42.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 46.98 mg (45%) of the title compound. (300 MHz, DMSO-d6) 12.89 (s, 1H), 7.95 (s, 1H), 7.72 (m, 2H), 7.21 (s, 1H), 7.09 (m, 3H), 6.30 (s, 2H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 3.75 (s, 4H), 3.27 (s, 4H), 2.87 (s, 1H), 2.78 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz). MS=499 (M+H), HPLC: 2.47 min. (G Method).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][NH2:20])[C:14]=2[C:21]([F:24])([F:23])[F:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]([F:38])([F:37])[CH2:33][C:34](Cl)=[O:35]>CCOC(C)=O.C1COCC1>[F:31][C:32]([F:38])([F:37])[CH2:33][C:34]([NH:20][NH:19][C:15]1[C:14]([C:21]([F:24])([F:22])[F:23])=[C:13]([NH:12][CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][N:16]=1)=[O:35]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(F)(F)F)NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
A mixture of N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-3-(trifluoromethyl)pyridin-4-amine (0.38 g, 1.117 mmol) in EtOAc (3 mL) and THF (3 mL) and sat'd aqueous sodium carbonate (3 mL) was stirred as 3,3,3-trifluoropropanoyl chloride (0.213 g, 1.452 mmol) was added slowly. The mixture was stirred for 10 min. The reaction was diluted with EtOAc, washed with aqueous sodium bicarbonate, dried with brine, and concentrated. The crude product was purified by silica gel chromatography using 0-100% ethyl acetate/hexane as the eluent to give 3,3,3-trifluoro-N′-(4-((((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide as an off-white solid (0.4 g, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) d 7.87 (d, J=6.3 Hz, 1H), 7.08-6.92 (m, 4H), 6.23 (d, J=6.3 Hz, 1H), 5.35 (d, J=3.8 Hz, 1H), 3.35-3.12 (m, 4H), 1.89 (dt, J=9.1, 4.9 Hz, 1H), 1.44-1.31 (m, 1H), 1.07 (dt, J=8.4, 5.5 Hz, 1H), 0.98 (dt, J=8.9, 5.5 Hz, 1H). LCMS M+1=451.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[NH2:22][C:23]1[S:24][C:25]([S:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:27]=1.Cl.NC1SC(Cl)=CN=1.Cl[C:44](OC)=[O:45]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:44](=[O:45])[NH:22][C:23]3[S:24][C:25]([S:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@]2(CNc3ccc(Br)cc32)C1
Agent: Cl
Agent: Nc1ncc(Cl)s1
Product: CCOC(=O)CSc1cnc(NC(=O)N2C[C@]3(CCN(C(=O)OC)C3)c3cc(Br)ccc32)s1

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that (S)-t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that the ethyl 2-((2-aminothiazol-5-yl)thio)acetate synthesized by a method described in the known methods (International Publication WO2005/066145 etc.) was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CN1CCCC1=O.[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:22]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][CH2:18][CH2:19][CH2:20]1)=[O:33]
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CCCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
3-Dimethylamino-propan-1-ol (346 uL, 2.92 mmol) was dissolved in N-methylpyrrolidinone (25.0 mL, 259 mmol) and sodium hydride 60% dispersion in mineral oil (93.5 mg) was added. The reaction was stirred for 5 minutes and then 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one (500 mg, 1.95 mmol) was added. The reaction was stirred at room temperature for 4 hours and then partitioned between ethyl ether (100 mL) and water (50 mL). The layers were separated and the organic layer was washed twice with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 3-nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester as a yellow oil (437 mg, 69%). LCMS (m/e) 324 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.80 (m, 2H), 7.53-7.36 (m, 1H), 4.29-4.17 (m, 4H), 3.89-3.17 (m, 2H), 2.39-2.08 (m, 4H), 2.19 (s, 6H), 1.88-1.73 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C)CC5)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 53.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(4-methylpiperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (74 mg, 0.119 mmol) was hydrolyzed by lithium hydroxide (50 mg, 1.19 mmol), THF/Methanol/water (12/6/3 ml) to yield 8 mg (30 mg 53.9% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.4 (b, 1H), 8.566-8.559 (d, 1H), 8.185-8.178 (d, 1H), 7.874 (s, 1H), 7.706 (s, 1H), 7.451-7.443 (d, 1H), 7.413-7.3 (m, 2H), 7.2-6.956 (m, 5H), 5.392 (s, 2H), 3.340-3.307 (m, 4H), 2.669-2.636 (m, 4H), 2.401 (s, 3H). MS: m/z=467.4 (M+1); HPLC: 98.239% in method B.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:23]([OH:25])=[O:24])[CH2:4][C:5]1[CH:12]=[C:10]([I:11])[C:9]([O:13][C:14]2[CH:21]=[C:19]([I:20])[C:18]([OH:22])=[C:16]([I:17])[CH:15]=2)=[C:7]([I:8])[CH:6]=1.[CH2:26](N(CC)CC)C.[C:33]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][O:35][CH2:34]1>C1COCC1.C(Cl)(Cl)Cl>[CH3:26][O:24][C:23](=[O:25])[C@H:3]([CH2:4][C:5]1[CH:6]=[C:7]([I:8])[C:9]([O:13][C:14]2[CH:15]=[C:16]([I:17])[C:18]([OH:22])=[C:19]([I:20])[CH:21]=2)=[C:10]([I:11])[CH:12]=1)[NH:2][C:33](=[O:40])[CH2:34][O:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: CCN(CC)CC
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)O

Procedure:
To a solution of 1.65g of the methyl ester of thyroxine hydrochloride in 80ml of dry THF and 30ml of chloroform in a flask protected from light was injected 300μl of triethylamine while the mixture was agitated. Diglycolic anhydride (255mg, 0.0022 mole) was then added and the mixture stirred overnight. The solution was then washed 3 times with water, dried over sodium sulphate and the volatiles removed in vacuo. The residue was purified on a 30g Sephadex LH-20 column, using a solution of 20% methanol in dichloromethane as eluent. The clear fractions were collected, the solvent removed and the residue precipitated from methanol with water, yielding 1.53g, 84 percent.
Reaction SMILES: Cl[S:2][N:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[P:4](=[S:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[CH3:18][NH:19][C:20](=[O:32])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([CH3:31])[CH3:30].CN(C)C=O>C(OCC)C.O>[CH2:6]([O:5][P:4]([N:3]([S:2][CH2:18][NH:19][C:20](=[O:32])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([CH3:30])[CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:8][CH2:9][CH3:10])=[S:11])[CH3:7]
Reactant: CCOP(=S)(OCC)N(SCl)c1ccccc1
Reactant: CNC(=O)Oc1ccccc1OC(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOP(=S)(OCC)N(SCNC(=O)Oc1ccccc1OC(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The O,O-diethyl N-(chlorothio)phenylphosphoramidothioate as a yellow oil obtained in Part A, above, is dissolved in a minimal amount of diethyl ether (about 5 ml) and the ether solution is added to a cooled (0° C.) solution consisting of 6.34 gm (0.030 mole) of 2-isopropoxyphenyl methylcarbamate and 20 ml dimethylformamide. This reaction mixture is stirred as it is permitted to warm to 25° C., and stirring is continued for four hours. The mixture is then diluted with 100 ml water and extracted with diethyl ether. The ether phase is recovered, washed with water, and dried over anhydrous sodium sulfate. The ether is removed by evaporation under reduced pressure. The oily residue thus obtained is chromatographed through a column of silica gel. Development is with methylene chloride. After removing the methylene chloride by evaporation under reduced pressure, there is obtained 1.02 gm. of the crude product as an amber oil which is crystallized from petroleum ether having a boiling range between 30° and 60° C. to give 2-isopropoxyphenyl [[(diethoxyphosphinothioyl)anilino]thio]methylcarbamate as colorless crystals having a melting point at 69° to 70.5° C.