Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][OH:48])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][OH:48])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCO)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCO)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-2-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-ethanol as a light yellow oil; MS: 561 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[O:16])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[O:16])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nc(C(=O)NC(C)(C)C(=O)O)cs1
Temperature: 25 °C
Yield: 100 %

Procedure:
Methyl 2-(2-((tert-butoxycarbonylamino)methyl) thiazole-4-carboxamido)-2-methylpropanoate (2.4 g, 6.7 mmole) was dissolved in 10 mL methanol and 3 mL water. To the mixture, lithium hydroxide monohydrate (0.56 g, 13.4 mmole) was then added. The reaction was stirred at room temperature until TLC indicated complete consumption of starting material. To the mixture, water and EtOAc were added, and the aqueous layer was acidified with 2 N HCl to about PH 7. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product as a white solid (2.3 g, quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1>ClCCl>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[O:25])[CH:19]=1
Reactant: Cc1cc(O)ccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 4-amino-m-cresol (Fluka, 4.17 g, 33.9 mmol) and triethylamine (23.6 mL, 0.170 mol) in dry dichloromethane (100 mL) was treated with 6-chloropyrimidine-4-carbonyl chloride, obtained as described above for Intermediate 7, step 1 (6.0 g, 34 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were dried on magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as yellow solid.
Reaction SMILES: BrC1C=CC(C[O:7][C:8]2[N:12]([C:13]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:11]=[CH:10][CH:9]=2)=CC=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:7][C:8]1[N:12]([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(-n2nccc2O)c1
Temperature: -78 °C
Yield: 60.2 %

Procedure:
A solution of methyl 2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate (765 mg, 1.97 mmol, EXAMPLE 68) in DCM (8 mL) was purged with nitrogen and cooled to −78° C. BBr3 (6 mL, 5.93 mmol, 1M in DCM) was added at this temperature. Thereto, the mixture was stirred at the same temperature for an hour, methanol was added until no gas released, and then the above mixture was basified with NaHCO3 aq (pH=3). Extracted with ethylacetate three times, and the organic phase was washed with brine and dried with Na2SO4, concentrated and the residue was washed with ethylacetate to give 260 mg of the title compound (60%). 1H NMR (400 MHz, CD3OD): δ 4.02 (3H, s), 7.91-7.97 (2H, m), 8.69-8.70 (2H, m). [M+H] Calc'd for C10H9N3O3, 220; Found, 220.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[CH3:12][S:13]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:39])[F:38])[CH:32]=3)=[C:27]([CH3:40])[NH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:38])[F:39])[CH:32]=3)=[C:27]([CH3:40])[N:26]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=3)[CH:25]=2)=[O:23])=[CH:41][CH:42]=1)(=[O:15])=[O:14]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)F)c1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)c(F)c1

Procedure:
Example 39 is prepared as described for example 2.1, substituting benzyl bromide with 4-bromomethyl-2-fluoro-benzonitrile and substituting preparation 5 with preparation 39a. ESI mass spectrum: [M+H]+=580; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24])([O-:20])=[O:19]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:24][C:23]([C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[N+:18]([O-:20])=[O:19])=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2ccccc2[N+](=O)[O-])[nH]c1-c1ccc(C)cc1
Yield: 18.3 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (12.8 g) and 2-nitrobenzylamine (8.6 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(2-nitrophenyl)imidazole-4-carboxylate(3.5g). 3.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (20 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(2-nitrophenyl)imidazole-4-carboxyic acid (2.4 g), melting point 144° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=2[CH3:29])=[C:5]2[N:6]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:9]([NH2:10])[N:4]2[N:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C=O)C>[CH3:1][C:2]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[C:20]=2[CH3:29])=[C:5]2[N:6]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:9]([NH:10][C:30](=[O:32])[CH3:31])[N:4]2[N:3]=1
Reactant: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(N2CCOCC2)nc2c(Cc3cccc(C(F)(F)F)c3C)c(C)nn12
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a solution of 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 0.3 mmol), prepared as described in Example 17, in DMF (1 mL) was added acetic anhydride (30 mg, 0.3 mmol). Reaction mixture was stirred overnight. Reaction mixture was concentrated to dryness and dissolved with DMSO (1 mL). The crude product was purified by reversed phase HPLC to provide the titled compound (15 mg, 11%); LC/MS: MS (ES+) m/e 448 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 2.30 (s, 3H) 2.44-2.48 (m, 3H) 3.38-3.50 (m, 4H) 3.61-3.70 (m, 4H) 3.95 (s, 2H) 7.20 (s, 1H) 7.28 (d, J=7.83 Hz, 1H) 7.37 (d, J=7.07 Hz, 1H) 7.51 (d, J=7.83 Hz, 1H) 10.60 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1>>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-methoxy-benzene following the procedure of Example 478: MS (ESI) m/z 514.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:19])(=[O:20])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 65 °C
Reaction time: 40 h
Yield: 80.5 %

Procedure:
Into a solution of methyl 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.53 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.6 ml), and the resulting mixture was stirred at 65° C. for 40 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(3-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (412 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[N:13]([CH3:19])[CH:12]=2)=O)=[C:4]([NH:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH3:22])[CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[N:13]([CH3:19])[CH:12]=3)[N:20]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH3:22])[C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)Nc2cnc(Cl)cc2NC(C)c2ccccn2)cn(C)c1=O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc3cnc(Cl)cc3n2C(C)c2ccccn2)cn(C)c1=O
Temperature: 150 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid [6-chloro-4-(1-pyridin-2-yl-ethylamino)-pyridin-3-yl]-amide II-21″ (900 mg; 2.26 mmol) is dissolved in acetic acid (10 ml) and stirred at 150° C. for 1 h in a microwave reactor. The volatiles are removed in vacuo and the residue purified by silica gel chromatography using a DCM/Methanol gradient. The product containing fractions are combined and concentrated under reduced pressure. The product is then lyophilized to afford the desired compound.
Reaction SMILES: O[C:2]1([C:14]2[NH:15][CH:16]=[N:17][CH:18]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:12]([C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([S:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:11][CH2:10][CH2:9]2)#[N:13]
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cnc[nH]1
Reactant: CCOC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CSC1(c2c[nH]cn2)CCCc2cc(C#N)ccc21
Temperature: 25 °C

Procedure:
A solution of 1.00 mmol of 5-hydroxy-5-(3H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (Example 2c1) and 10 mmol of ethyl mercaptoacetate [623-51-8] in 2 ml of trifluoroacetic acid is stirred at 70° C. for 24 hours. The reaction mixture is cooled to room temperature, poured into ice-water and neutralized with 4M sodium hydroxide solution. The mixture is extracted with ethyl acetate, and the combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of t-butylamine (1.3 mL, 13 mmol) in DMSO (15 mL) was added sodium hydride (60% wt. in mineral oil, 0.53 g, 14 mmol) at RT. After the reaction mixture was stirred for 10 min, it was treated with 1-bromo-4-fluoro-3-nitrobenzene (2.0 mL, 9.1 mmol). The reaction mixture was stirred at RT for 1 h the 70° C. for 3 h. After cooling to RT, it was quenched with 50 mL of water and extracted with DCM (3×40 mL). The combined organic phases were washed with 2 N HCl followed by brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give 4-bromo-N-tert-butyl-2-nitrobenzenamine as a red crystalline solid. The crude product was used without further purification. MS (ESI, pos. ion) m/z: 273.9 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][C@@H:9]([OH:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].F[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:20]=1)[C:16]#[N:17].[OH-].[Na+]>O.C1(C)C=CC=CC=1.CN1C(=O)CCC1>[C:3]([O:7][CH2:8][C@H:9]([CH3:10])[O:11][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:20]=1)[C:16]#[N:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](O)COC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(F)cc(C#N)c2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](COC(C)(C)C)Oc1cc(C#N)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.02 %

Procedure:
To a 3-necked round-bottomed flask (100 ml with condenser, septum thermometer and magnetic follower) was charged sodium hydride (32.96 mmol, 1.32 g). The flask was placed under an inert atmosphere and dry NMP (80 ml) was charged. To the resulting suspension was charged (S)-1-tert-butoxy-2-propanol (30.21 mmol; 3.99 g; added in 0.2 ml aliquots with temperature control to control H2 evolution). Once gas evolution had ceased 3-fluoro-5-(4-methanesulfonyl-phenoxy)benzonitrile (see Example 1, 27.46 mmol, 8.0 g) was added in one portion. The reaction mixture was heated to 70° C. for 3 hours. The reaction was cooled to room temperature and toluene (240 ml) was added followed by water (240 ml). The contents were stirred at room temperature for 30 minutes and then transferred to a separating funnel. The two layers were separated and the aqueous layer was further extracted with toluene (240 ml). The organic extracts were combined and washed once with sodium hydroxide (160 mmol, 160 ml) and then with water (4×160 ml). The toluene was removed in vacuo to leave an oil that slowly solidified (9.20 g; 83.02% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C.CCOC(C)=O>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([NH:32][C:29]2[CH:30]=[C:31]3[C:26]([CH:25]=[N:24][N:23]3[CH3:22])=[CH:27][CH:28]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Cn1ncc2ccc(N)cc21
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Cl)nc32)cc1
Yield: 81.5 %

Procedure:
A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.585 mmol), 1-methyl-indazol-6-ylamine (86 mg, 0.585 mmol) and DIEA (0.250 mL, 1.44 mmol) in dioxane (5 mL) was stirred at 110° C. for 20 h. EtOAc and H2O were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-(1-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (216 mg).
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[Br:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[C:31](O)([C:39]1[C:40]([OH:48])=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=1)[C:32](=[O:38])[NH:33]2>>[Br:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]([C:39]1[C:40]([OH:48])=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=1)[C:32](=[O:38])[NH:33]2
Reactant: O=C1Nc2cccc(Br)c2C1(O)c1cc2c(cc1O)OCC2
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (62%) as a solid: MS (ES+) m/z 346.5 (M+1), 348.5 (M+1).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1)[CH3:3].[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:11](=[O:13])[CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:2][CH3:3])[CH2:9][CH2:8]1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCN1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCN1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 48.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-ethylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 114, (S)-3-(benzyloxy)-2-(2-(4-ethylpiperazin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (20.6 mg, 48.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.60 (d, 2H), 7.31-7.25 (m, 5H), 7.21 (t, 2H), 7.04-6.99 (m, 4H), 4.69 (m, 1H), 4.51 (s, 2H), 3.76 (m, 1H), 3.71 (m, 1H), 2.97 (s, 2H), 2.46 (m, 3H), 2.38 (m, 3H), 2.33-2.28 (m, 4H), 0.98 (t, 3H). MS (EI) for C30H35FN4O4. found 535.6 (MH+).
Reaction SMILES: O[Li].O.O.O.O.O.O.[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:36]([O:38]CC)=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([Br:35])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[NH:11]1>O.C1COCC1>[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:36]([OH:38])=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([Br:35])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[NH:11]1
Reactant: CCOC(=O)[C@@H](Cc1ccc(Br)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cc1ccc(Br)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 210 mg (9 mmol) LiOH.6H2O in 40 mL water was added at RT to a solution of 3.64 g (5.83 mmol) of (R)-2-(3,4-dibromo-phenyl)-1-ethoxycarbonylethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 70 mL THF and the reaction mixture was stirred for 7 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 100 mL water, 1 M HCl was added until an acid reaction was obtained, the precipitate was filtered off and dried in the vacuum drying chamber at 50° C. The product was reacted further without purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:11][C:10]=1[N+:22]([O-])=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[NH2:22][C:10]1[CH:11]=[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cc1cc(-c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(O)c(N)c2)ccn1
Yield: 115.5 %

Procedure:
Nitroarene 64.A (2.65 g, 8 mmol) was hydrogenated (10 psi) with Pd/C (500 mg, 10% Pd/C, 50% water) in EtOAc. The reaction mixture was filtered and concentrated to yield crude 64.B (1.85 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19](F)[CH:20]=3)[N:15]=[CH:14][C:13]2=[O:23])[CH2:6][CH2:5]1.[CH3:24][O-:25].[Na+]>CO.[Cl-].[NH4+]>[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:25][CH3:24])[CH:20]=3)[N:15]=[CH:14][C:13]2=[O:23])[CH2:6][CH2:5]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: C[O-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-2(1H)-quinoxalinone dihydrochloride (0.363 g, 1 mmol) in dry MeOH (5 ml) was added a 25 wt. % solution of sodium methoxide in MeOH (0.87 ml, 4 mmol). After heating under reflux overnight, a further portion of sodium methoxide solution (0.22 ml) was added and heating was continued for 24 h. Aqueous ammonium chloride 96 drops) was added and the mixture was evaporated to dryness. The residue was extracted several times with 10% MeOH/DCM, and the extracts were filtered and evaporated. The residue was chromatographed on silica, eluting with 0-20% (2M ammonia/MeOH)/DCM to give the product (0.20 g, 66%).
Reaction SMILES: CC[N:3]([C:9]1[CH:14]=[CH:13][C:12]2[C:15]([NH:17][NH:18][C:19](=[O:20])[C:11]=2[CH:10]=1)=[O:16])CCCCN>C(Cl)Cl>[CH:14]1[C:9]([NH2:3])=[CH:10][C:11]2[C:19]([NH:18][NH:17][C:15](=[O:16])[C:12]=2[CH:13]=1)=[O:20]
Reactant: CCN(CCCCN)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Solvent: ClCCl
Product: Nc1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 100 mg activated ester-terminated dendrimer (e.g., PAMAM-CONHS) in 15 ml CH2Cl2 with 0.1 ml triethylamine is added N-(4-aminobutyl)-N-ethylisoluminol (ABEI, 1.01 eq isoluminol per activated ester end group). The reaction is stirred overnight at room temperature, diluted with CH2Cl2 to 75 ml and washed with water (3×30 ml) and saturated Na2CO3 (3×30 ml). The organic layer is dried over Na2SO4 and stripped of solvent to yield the dendritic isoluminol conjugate.