Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.C(N(CC)CC)C>CS(C)=O>[CH:2]([CH2:3][N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:1]
Reactant: COc1cccc(C(=O)N(CCO)c2ccccc2OC)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N(CC=O)c2ccccc2OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
In an atmosphere of argon, N-(2-hydroxyethyl)-3-methoxy-N-(2-methoxyphenyl)benzamide (339 mg, 1.12 mmol) was dissolved in DMSO (4 ml) to which were subsequently added dropwise triethylamine (0.724 ml, 5.20 mmol) and a DMSO solution (8 ml) of a sulfur trioxide-pyridine complex (844 mg, 5.20 mmol) at room temperature. After 20 minutes of stirring at the same temperature, this was mixed with ice water (40 ml) and extracted with ethyl acetate, and then washed with water and saturated brine. The resulting organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by evaporation to obtain 220 mg (65.6%) of the title compound the form of light yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1.[C:26]([Li])(C)(C)C.CI>>[C:22]([Si:19]([CH3:21])([CH3:20])[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:6]=2)[C:2]([CH3:26])=[CH:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1
Solvent: CI
Product: Cc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12

Procedure:
In analogy to the procedure described in example 27 c], 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole was treated with tert-butyllithium and methyl iodide to yield 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indole as red crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[C:5]([F:14])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[S:27][C:26]([N:28]3[CH2:34][CH2:33][CH2:32][NH:31][C:30](=[O:35])[CH2:29]3)=[N:25][CH:24]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:5]1[C:6]([O:8][CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)=[N:7][C:2]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[S:27][C:26]([N:28]4[CH2:34][CH2:33][CH2:32][NH:31][C:30](=[O:35])[CH2:29]4)=[N:25][CH:24]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: Fc1cnc(Cl)nc1OC1CCOC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2ncc(F)c(OC3CCOC3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 90 °C
Yield: 71.9 %

Procedure:
2-Chloro-5-fluoro-4-(tetrahydrofuran-3-yloxy)pyrimidine (70 mg, 0.32 mol), 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 97 mg, 0.32 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), XPhos (76 mg, 0.16 mmol) and potassium carbonate (89 mg, 0.64 mmol) were added to a flask. The flask was purged and flushed with argon (3×). Degassed tert-amyl alcohol (1.1 ml) was added, the reaction mixture was purged with nitrogen for 5 min, and then heated to 90° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, treated with water, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash (methanol/dichloromethane eluant) to provide 109 mg (0.23 mmol, 70% yield) of 4-[5-(3-{[5-fluoro-4-(tetrahydrofuran-3-yloxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one. MS APCI: [M+H]+ m/z 485.1. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.30 (d, J=2.9 Hz, 1H), 7.59 (t, J=4.8 Hz, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 5.64 (t, J=4.9 Hz, 1H), 4.16 (s, 2H), 3.97-3.73 (m, 6H), 3.21 (m, 2H), 2.32 (m, 1H), 2.26 (s, 3H), 2.10 (m, 1H), 1.77 (s, 2H). rhSyk=++
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](SC)=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.O.[NH2:18][NH2:19]>CO>[NH2:12][C:11]1[NH:19][N:18]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[C:13]#[N:14]
Reactant: CSC(Nc1cccc(Cl)c1)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N

Procedure:
A mixture of 15 g (60.1 mmol) of 3-(3-chloro-phenylamino)-2-cyano-3-methylmercapto-acrylonitrile [for preparation see: EP 0 010 396 A1], 3.13 ml (63.2 mmol) of hydrazine hydrate and 100 ml of methanol is heated under reflux for 3 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethyl acetate/hexane yields the title compound; m.p. 195-200° C.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:22]1[CH:29]2[CH:23]1[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=12.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][Si](C)(C)C)=[N:39][CH:40]=1>O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38](=[O:41])[N:39]([C@@H:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][CH2:25][CH2:24][C@H:23]2[OH:22])[CH:40]=1
Reactant: c1ccc2c(c1)OCCC1OC21
Reactant: C[Si](C)(C)Oc1ccc(Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=c1ccc(Cl)cn1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 90 °C

Procedure:
22.7 g (72 mmol) of tetrabutylammonium fluoride trihydrate are added to a mixture of 10.54 g (65 mmol) of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin and 19.4 g (96 mmol) of 5-chloro-2-trimethylsilyloxy-pyridine, and the mixture is heated at 90° C. for 3 hours. The mixture is stirred into water and extracted several times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, and the solvent is evaporated off in vacuo. The residue is crystallized in n-butyl acetate. Crystals of melting point 175.5°-177.5° C. are obtained.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1>O1CCCC1>[CH:13]1([CH:17]([OH:18])[C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=CC1CCC1
Reactant: CCOC(=O)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 51.6 %

Procedure:
To a solution of ethyl 4-iodobenzoate (1.45 mL, 8.69 mmol) in anhydrous tetrahydrofuran (14.5 mL) at −40° C. was added isopropyl magnesium chloride lithium chloride complex (8.0 mL, 10.4 mmol) dropwise. The resulting brown solution was stirred for 40 min at −40° C. The crude cyclobutanecarbaldehyde (1.8 g, approximately 10.5 mmol pure) was added and the reaction was warmed to room temperature and stirred for 18 h. The reaction is then quenched with 1 N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 2.0 g of crude material. Purification by silica gel flash chromatography (0-20% ethyl acetate in heptane) afforded ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (1.05 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 4.64 (d, J=7.6 Hz, 1H), 4.47-4.25 (m, 2H), 2.73-2.47 (m, 1H), 2.13-1.94 (m, 2H), 1.95-1.70 (m, 4H), 1.55 (br. s., 1H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Si]([NH:8][C:9]1[N:10]=[C:11]([Cl:21])[C:12]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=1)(C(C)(C)C)(C)C.I[CH2:23][CH2:24][CH3:25].[H-].[Na+].Cl>CN(C=O)C.CCOCC.O>[CH2:23]([NH:8][C:9]1[N:10]=[C:11]([Cl:21])[C:12]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=1)[CH2:24][CH3:25]
Reactant: CC(C)n1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Reactant: CCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc(Cl)c2ccn(C(C)C)c2n1
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, 2-(t-butyl-dimethylsilanyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (5.7 g, 17.6 mmol) and 1-iodopropane (4.5 g (26.4 mmol) were dissolved in DMF (20 mL). The reaction mixture was cooled to 0° C. with vigorous stirring, and NaH (1.06 g of a 60% dispersion in mineral oil, 26.4 mmol) of (60%) was added. The mixture was stirred for 10 min, and then water (50 mL) was slowly added to quench the reaction. The mixture was extracted with EtOAc (300 mL) and the organic layer was washed with water (50 mL) and then with a brine solution (50 mL), and lastly, dried over anhydrous Na2SO4. After evaporation of the solvents, a yellow oily residue was isolated (6.5 g). The residue was dissolved in Et2O (50 mL), concentrated hydrochloric acid (10 mL) was added at 0° C. with stirring, and the mixture was stirred for an additional 10 min. After the reaction was completed, the solution was extracted with EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was washed with H2O (150 mL) and then with a brine solution (150 mL) and dried over Na2SO4. The solvents in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to yield 2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIV, 4.5 g, !00%) as a yellow solid. LCMS (ESI) m/z=253 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N=[N+]=[N-])C.O>O=S(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: CCN=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 3,5-dibromobenzoic acid (26 g, 93 mmol) in SOCl2 (100 mL) was heated at reflux for 2 h, concentrated, diluted with dry DCM (300 mL) and added slowly to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (9.75 g, 100 mmol) and EtN3 (28 g, 277 mmol) in dry DCM (300 mL) at 0° C. The solution was stirred for 1 h at rt, poured into water and the organic layer was separated. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to give crude compound P37a (28 g, 93%) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].CO.O.O[Li].O>C1COCC1>[CH3:35][C:31]1([CH3:34])[CH2:30][CH2:29][CH:28]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:21][CH2:22][C@H:23]([O:26][CH3:27])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@H]1CC[C@H](N(c2cc(C3CCC(C)(C)CC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-(4,4-Dimethylcyclohexyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (890 mg, 1.76 mmol) was dissolved in a 3:2:1 mixture of THF:methanol:H2O (50 mL) and treated with a 1N solution of LiOH.H2O (5.29 mL, 5.29 mmol). After stirring for 2 h at 60° C., the reaction mixture was evaporated to dryness and suspended in water. The reaction mixture was acidified to pH 3. After extraction with EtOAc, the organic fraction was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2:MeOH (90:10) as eluent affording the 5-(4,4-dimethyl-cyclohexyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methylcyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid (535 mg, 58%) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].C(Cl)Cl>>[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCNCC1)c1ccc2ccccc2n1

Procedure:
A solution of compound 41e (0.50 g, 0.93 mol) in TFA/DCM (1:3, 10 mL) was stirred at rt for 2 h. The resulting mixture was concentrated under reduced pressure to obtain compound 41f as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H26N6O: 439.2 (M+H). found: 439.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(=O)O[CH2:16][CH2:15][O:14]1>[I-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:16][CH2:15][OH:14])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CCOC(C)=O
Product: O=C(OCCO)c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
A mixture of p-nitrobenzoic acid (33.4 g, 0.2 mole), ethylene carbonate (19.4 g, 0.22 mole) and tetraethylammonium iodide (9.6 g, 0.036 mole) was heated at 140° C. for 45 minutes. On cooling, the mixture was dissolved in ethyl acetate (500 ml) and washed with water (3×) and saturated sodium chloride. The organic solution was dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was shown to be a mixture of the desired product and a small amount of the diester product, bis-(4-nitrobenzoyl)-ethylene glycol, by TLC (silica gel, ethyl acetate as mobile phase; Rf 's=0.5 and 0.7, respectively). The mixture was therefore chromatographed on silica gel, eluting first with benzene and then with chloroform to give hydroxyethyl p-nitrobenzoate (31 g) as a pale yellow solid, m.p. 77°-78° C., which was homogeneous by TLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[F:25][C:26]([F:40])([F:39])[CH:27]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:28][C:29](O)=[O:30].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:25][C:26]([F:39])([F:40])[CH:27]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:28][C:29]([NH:24][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=4)[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)=[O:30]
Reactant: O=C(O)CC(Nc1ccccc1)C(F)(F)F
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(Nc5ccccc5)C(F)(F)F)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
To a stirred solution of compound 12 (scheme 3) (100 mg, 0.29 mmol), compound 327 (103 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.03 mmol) in dry N,N-dimethylformamide (3 mL) at 0° C. was added HATU reagent (335 mg, 0.88 mmol). The mixture was stirred at room temperature for 16 h. A saturated aqueous solution of sodium bicarbonate was added and the aqueous solution was extracted twice with EtOAc, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 15:85). The resulting solid was triturated in methanol, filtered off and dried under reduced pressure to afford title compound 324 (81 mg, 0.15 mmol, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.50 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.81 (dd, J=13.2, 2.0 Hz, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.45 (t, J=8.8 Hz, 1H), 7.37 (dd, J=8.8, 1.6 Hz, 1H), 7.10 (dd, J=8.4, 7.2 Hz, 2H), 6.75 (d, J=8.0 Hz, 2H), 6.61 (t, J=7.2 Hz, 1H), 6.55 (d, J=5.6 Hz, 1H), 6.13 (d, J=9.2 Hz, 1H), 4.75-4.65 (m, 1H), 3.72 (s, 3H), 2.94 (dd, J=15.6, 3.6 Hz, 1H), 2.78 (dd, J=15.9, 9.6 Hz, 1H). LRMS (M+1) 556.0 (100%).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1>C(O)C>[CH3:4][N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:13])[CH2:9][CH2:10]1
Reactant: CC(=O)Nc1ccc(C(=O)CN2CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(CC(=O)c2ccc(N)cc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
1.8 g of sodium hydroxide dissolved in 10 ml of ethanol and 10 ml of water were added to 4.0 g of 2-(4-methylpiperazin-1-yl)-1-(4-acetylamino-phenyl)-ethanone which was obtained in the same manner as in Example 1, and stirred at 85° C for 2 hours in a nitrogen atmosphere. Then, ethanol was distilled off, the deposited oily product was extracted with chloroform, washed with water, dried over anhydrous sodium sulfate and further concentrated to solid to obtain 2.7 g of 2-(4-methylpiperazin-1-yl)-1-(4-amino-phenyl)-ethanone.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].O[N:18]=[C:19]([NH2:35])[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=2[O:26][C:25]1=[O:34].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[O:14]=[C:13]1[NH:12][C@H:11]2[CH2:10][S:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([O:1]/[N:18]=[C:19](\[NH2:35])/[CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[O:26][C:25]3=[O:34])=[O:3])[C@H:16]2[NH:15]1
Reactant: Cc1ccc2oc(=O)n(CCCCC(N)=NO)c2c1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(CCCC/C(N)=N/OC(=O)CCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
To a suspension of biotin 7 (23 mg, 0.092 mmol) and compound 13 (22 mg, 0.083 mmol) in anhydrous DMF (0.5 ml) was added EDCl (16 mg, 0.10 mmol) and DIPEA (13 mg, 0.10 mmol) and stirred under a nitrogen atmosphere at ambient temperature for 12 h. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml) and brine (25 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 19:1 dichloromethane/methanol to give a yellow oil (21 mg, 51%).
Reaction SMILES: C([O:9][C:10]1[CH:11]=[C:12]([Cl:32])[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[C:14]([I:16])[CH:15]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:32][C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)=[C:14]([I:16])[CH:15]=[C:10]([OH:9])[CH:11]=1
Reactant: O=C(Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(I)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.12 g of 5-benzoyloxy-3-chloro-1-iodo-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzene were dissolved in 16 ml of tetrahydrofuran and 7.8 ml of methanol, and 3.9 ml of 2N aqueous sodium hydroxide solution were added. After 30 minutes of stirring at room temperature. 3.9 ml of 2N hydrochloric acid were added, and the reaction mixture was concentrated under reduced pressure. Saturated sodium chloride solution and ethyl acetate were added to the residue, and the mixture was shaken. The ethyl acetate phase was isolated, dried and concentrated. The resulting crude product was purified chromatographically. Yield: 2.03 g (80%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:21][N:19]([CH3:20])[C:17](=[O:18])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:24])[NH:1]3)[CH:11]=1
Reactant: CCO
Reactant: CN(C)C(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CN(C)C(=O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of 2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide (1.6 g, 5 mmol) in t-BuOH: ethanol: acetic acid (332 mL: 20 mL: 24 mL) was added pyridinium tribromide (5 g, 15 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (22 mL). Water (0.7 mL) and zinc dust (5 g) were added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with 0.5 N HCl (2×), 10% Na2CO3 (2×), brine (2×), water, dried over Na2SO4, concentrated and triturated with ether to give N,N-dimethyl-2-[3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetamide.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29].Cl>CN(C)C=O>[CH2:27]([NH:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 111.2 %

Procedure:
To 50.0 g (0.269 mole) of 4-hydroxy-3-nitroquinoline in 300 ml of N,N-dimethylformamide in a 500 ml erlenmeyer flask was added, gradually, 44.3 g (0.2892 mole) of phosphorus oxychloride. The resulting mixture was heated on a steam bath for about 15 minutes, and was then poured onto ice with stirring. After neutralization with saturated sodium bicarbonate solution, the resulting light-colored solid was separated by filtration and washed sequentially with a saturated sodium bicarbonate solution and water. The solid was dissolved in methylene chloride and the solution obtained was dried over sodium chloride, filtered and transferred to a 2 l erlenmeyer flask. Triethylamine (159.6 g, 1.577 moles) was added at one time, followed by the slow addition of 21.2 g (0.2892 mole) of isobutylamine. After the isobutylamine had been added, the mixture was heated on a steam bath for about 30 minutes. The methylene chloride was removed by rotary evaporation. Water was added to the residue obtained, and concentrated hydrochloric acid was subsequently added to dissolve the residue. The solution was filtered, and the filtrate was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting yellow solid was filtered, washed with water, and dried to provide 73.4 g of crude 4-isobutylamino-3-nitroquinoline, m.p. 114°-118° C. The product was further purified by recrystallization from ethanol.