Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[C:42]2[CH:43]=[CH:44][C:45](B(O)O)=[CH:46][C:41]=2[O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:44]=[CH:43][C:42]3[O:37][CH2:38][CH2:39][O:40][C:41]=3[CH:46]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c(C(=CC2CCCC2)c2ccc3c(c2)OCCO3)cc2cccnc21
Yield: 95.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 1,4-benzodioxane-6-boronic acid (0.13 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 96%) as a white solid: LC/MS m/e calcd for C28H26N2O4S [M+H]+ 487.59, observed 487.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:42].O1CCOCC1>ClCCl>[ClH:42].[CH2:36]([O:35][CH2:34][CH2:33][N:32]1[C:31]2[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=2[N:29]=[C:28]1[N:24]1[CH2:25][CH2:26][CH2:27][N:21]([CH2:20][CH2:19][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:22][CH2:23]1)[CH3:37]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reaction time: 8 h

Procedure:
Combine 1-t-butoxycarbonyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (5.0 g) and dichloromethane (50 mL). Add a solution of hydrochloric acid in dioxane (10 mL, 4 M, 40 mmol). After 8 hours, evaporate in vacuo to give 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(methylsulfonyl)phenyl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC the target compound. LC-MS (conditions E): tR=0.65 min.; [M+H]+: 404.07 g/mol.
Reaction SMILES: CC1C=CC(S(Cl)(=O)=[O:9])=CC=1.[Cl:12][C:13]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:14]=1[CH2:15][N:16]([CH3:35])[C:17]([N:19]1[CH2:24][CH2:23]/[C:22](=[N:25]/O)/[CH2:21][C@@H:20]1C1C=CC(F)=CC=1C)=[O:18]>CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:12][C:13]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:14]=1[CH2:15][N:16]([CH3:35])[C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:9])[NH:25][CH2:21][CH2:20]1)=[O:18]
Reactant: Cc1cc(F)ccc1[C@H]1C/C(=N\O)CCN1C(=O)N(C)Cc1cc(Cl)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(Cc1cc(Cl)ccc1Cl)C(=O)N1CCNC(=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 117.3 %

Procedure:
A solution of p-tosyl chloride (28 mg) in acetone (0.5 mL) was added drop-wise to a mixture of intermediate 25b (43 mg) in acetone (1 mL) and 5% sodium carbonate solution (1 mL) under a Nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, then it was heated to reflux for 45 minutes. The mixture was allowed to cool to r.t., and the aqueous residue was extracted with DCM. The organic layer was washed with a 5% sodium hydrogen carbonate solution (10 mL). The aqueous phase was re-extracted with DCM (3×20 mL). The combined organic extracts were dried and concentrated in vacuo to give the crude 7-(R)-4-fluoro-2-methyl-phenyl)-5-oxo-[1,4]-diazepane-1-carboxylic acid, (2,5-dichloro-benzyl)-methylamide (38 mg).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:28][C:29]1[N:30]=[CH:31][N:32]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 4 h

Procedure:
A mixture of trityl chloride (17 g), triethylamine (8.5 ml), 4-methylimidazole (5 g) and toluene (40 ml) was stirred at 80° for 4 h and filtered, and the solid material was washed with toluene. It was then partitioned between water and chloroform, and the chloroform solution was separated, dried and combined with the dried toluene filtrate. The combined organic solutions were evaporated to dryness under reduced pressure, and the residue was triturated with diethyl ether to give 4-methyl-1-tritylimidazole, mp. 214°-216°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([O:15][CH3:16])[CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([O:15][CH3:16])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CO[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1

Procedure:
With the exception that N-t-butoxycarbonyl-cis-4-methoxy-L-prolinol, instead of N-t-butoxycarbonyl-L-prolinol, was used, the same procedure as in Preparation Example 1-1 was repeated to afford the title compound. 6.94 g (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=O>>[CH3:18][O:17][C:12](=[O:16])[C@H:13]([CH3:15])[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: COC(=O)C(C)=O
Product: COC(=O)[C@H](C)Nc1ccc2ccccc2c1

Procedure:
Following reductive amination General Procedure AA above and using 2-aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by silica gel tlc (Rf=0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:21][CH:20]=1
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Reactant: Sc1ccc(Cl)cc1
Product: O=c1ccc2cc(OCCCCSc3ccc(Cl)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-chlorobutoxy)-carbostyril (m.p. 206°-208° C.) and 4-chlorothiophenol.
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH:9]=[CH:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)#[CH:2].N1C(C)=CC(C)=CC=1C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:23][C@@:3]1([C:1]#[CH:2])[CH:9]=[CH:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)(=[O:35])[CH3:34]
Reactant: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reactant: CC(=O)OC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2.0 g. of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one in 40 ml. of collidine and 13 ml. of acetic anhydride is heated to boiling for 5 hours under nitrogen. After cooling, the solution is poured into ice/water. The reaction product is extracted with methylene chloride, washed in succession with 2N hydrochloric acid, sodium bicarbonate solution, and water, and dried over sodium sulfate. The crude product is chromatographed on silica gel. With 25-30% ethyl acetate-hexane, 950 mg. of 17β-acetoxy-17β-ethynyl-18-methyl-4,15-estradien-3-one is eluted which melts, after recrystallization from acetone/methanol, at 163°-164°.
Reaction SMILES: O.O.O.O.C([NH:8][C:9]12[CH2:22][C:13]3([NH:23]C(=O)C)[CH2:14][C:15]([NH:18]C(=O)C)([CH2:17][C:11]([NH:27]C(=O)C)([CH2:12]3)[CH2:10]1)[CH2:16]2)(=O)C.[ClH:31]>>[ClH:31].[ClH:31].[ClH:31].[ClH:31].[NH2:8][C:9]12[CH2:16][C:15]3([NH2:18])[CH2:17][C:11]([NH2:27])([CH2:12][C:13]([NH2:23])([CH2:14]3)[CH2:22]1)[CH2:10]2
Reactant: CC(=O)NC12CC3(NC(C)=O)CC(NC(C)=O)(C1)CC(NC(C)=O)(C2)C3
Agent: Cl
Solvent: O
Product: NC12CC3(N)CC(N)(C1)CC(N)(C2)C3
Yield: 82 %

Procedure:
1,3,5,7-Tetraacetamidoadamantane tetrahydrate (2.0 g=4.6 mmoles) was dissolved in 18% hydrochloric acid (30 ml of concentrated hydrochloric acid diluted with 30 ml of water) and the solution was refluxed for three hours. The crystalline product thus obtained was separated from the mixture by filtration, washed with acetone and dried. 1.29 g of product, mp 360° C. (lit.>360° C., H. Stetter and C. Wulff, Chem. Ber. 93, 1366 (1960)), corresponding to an 82.0% yield, were obtained.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([OH:22])[CH2:19][C:20]#C>>[F:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([C:20]#[C:19][CH2:18][OH:22])=[CH:3][C:4]=2[O:16][CH3:17])[CH:12]=[CH:11][CH:10]=1
Reactant: C#CCCO
Reactant: COc1cc(Br)ccc1Oc1cccc(F)n1
Product: COc1cc(C#CCO)ccc1Oc1cccc(F)n1

Procedure:
According to the procedure of example 11 (a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.98 mmol; 300 mg) and 3-butyn-1-ol by propargylic alcohol (2.50 mmol; 150 μL), the title compound was obtained as a yellow solid (71%, 191 mg) after purification on silica gel (cyclohexane/ethyl acetate gradient).
Reaction SMILES: C(#N)C.[NH2:4][CH:5]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7].C1OC1C.[O:37]=[C:38]1[N:42]([C:43](Cl)=[O:44])[C:41]2[CH:46]=[CH:47][CH:48]=[CH:49][C:40]=2[NH:39]1>C(Cl)Cl.CC(C)=O>[O:37]=[C:38]1[N:42]([C:43]([NH:4][CH:5]([C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)[C:6]([NH:8][CH:9]2[C:24](=[O:25])[N:11]3[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]23)=[O:7])=[O:44])[C:41]2[CH:46]=[CH:47][CH:48]=[CH:49][C:40]=2[NH:39]1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(O)cc3)[C@H]2SC1
Reactant: O=C(Cl)n1c(=O)[nH]c2ccccc21
Agent: CC1CO1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)[nH]c4ccccc43)c3ccc(O)cc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To 8 ml. of dry acetonitrile were added 422 mg. (1 mmole) of 7-(α-amino-4-hydroxyphenylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. The mixture was stirred in a bath comprising acetone and wet ice, and 1.62 grams (8 mmoles) of N,O-bis-trimethylsilylacetamide were added. Solution was complete within about 5 minutes. The mixture was stirred for an additional 5 minutes, and 0.7 ml. of propylene oxide was added followed, after an additional 5 minutes, by 197 mg. (1 mmole) of 2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride. The mixture was stirred for 105 minutes and then was rotary evaporated to about one-half volume. The concentrated reaction mixture was slowly added to rapidly-stirred ice water, and the pH of the resulting mixture, containing a percipitated gum, was adjusted from 3.8 to 1.6. The resulting mixture then was sonicated, with hardening of the gum. The resulting hard lumps were broken, sonicated, filtered, washed with dilute hydrochloric acid (pH 1.8), and air-dried to give 251 mg. of a buff powder. The filtrate was concentrated to remove acetonitrile and was filtered to afford an additional 20 mg. of a buff-colored powder. The solids were combined and added to 40 ml. of methylene chloride. The mixture was sonicated and filtered to recover 210 mg. of solid. The solid was added to 100 ml. of methylene chloride, sonicated, and filtered to obtain 200 mg. of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38]([O:41][CH2:42]Br)(=[O:40])[CH3:39].[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[C:38]([O:41][CH2:42][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18])(=[O:40])[CH3:39]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Reactant: CC(=O)OCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added bromomethyl acetate (76 mg, 503 μmol), NaI (101 mg, 670 μmol), and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1) to yield the title compound as a white solid (15 mg). LC-MS: 597.7 [M+H]+. 1H NMR (CDCl3, 400 MHz,) δ 2.02 (s, 3H), 3.37 (br, 2H), 4.22 (br, 2H), 4.38 (br, 1H), 5.78-6.02 (m, 2H), 7.15-7.20 (m, 1H), 7.40-7.45 (m, 2H), 7.50-7.91 (m, 7H), 8.15-8.17 (m, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[Br:29]Br>O>[Br:29][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:7](=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:17][CH:16]=3)[CH2:8][C:9]=2[CH:10]=1
Reactant: CC(=O)Oc1ccc2c(c1)Cc1ccccc1-2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c(c1)Cc1cc(Br)ccc1-2
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 72.9 %

Procedure:
2-Acetoxyfluorene (70 g) was added to a mixture of acetic acid (330 mL) and acetic anhydride (110 mL) and heated up to 65° C. to obtain a homogeneous solution. Bromine (125 g) was dropwise added thereto in 40 minutes and stirred for further one hour. The reaction solution was poured into water (1 L) to obtain deposited crystals by filtration under reduced pressure. The dried crystals were ecrystallized from a mixed solution of ethanol (400 mL) and ethyl acetate (300 mL) to obtain colorless needle-shaped 2-bromo-7-acetoxyfluorene (69 g). The melting point of this compound was 130° C.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9](N)=[C:8]([CH3:13])[CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N([O-])=O.[Na+].C(N)CN.[BrH:22]>[Cu]Br>[Br:22][C:9]1[CH:11]=[CH:12][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][C:8]=1[CH3:13]
Reactant: Cc1cc(-n2cncn2)ccc1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: NCCN
Product: Cc1cc(-n2cncn2)ccc1Br
Reaction time: 0.25 h

Procedure:
4-(1,2,4-Triazol-1-yl)-2-methylaniline (D62, 0.55 g) in 48% HBr (10 ml) at -5° C. was stirred while sodium nitrite (0.3 g) was added portionwise over approximately 5 minutes to give a brown sludge which was left for a further 15 minutes. During this time, copper (1) bromide (0.63 g) was heated under reflux in 48% HBr (2 ml) under argon. The brown sludge was added to it portionwise over 5 minutes and the resulting black reaction mixture heated under reflux for a further 1 minute. After cooling slightly, the mixture was poured gently into 10% aqueous ethylenediamine solution to give a purple solution. Ethyl acetate extraction gave the title compound which was purified by chromatography on silica using 4-10% pentane/ethyl acetate as eluant (0.77 g, 73%) Mass spec (CI) MH+ 238, 240.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([OH:15])=[O:14])[O:12][C:7]=2[CH:6]=1.S(Cl)(Cl)=O.[CH:33]1C=CC=CC=1>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([O:15][CH3:33])=[O:14])[O:12][C:7]=2[CH:6]=1
Reactant: c1ccccc1
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) (0.4 g) was dissolved in benzene (10 ml), and thionyl chloride (2 ml) was added thereto, followed by heating under reflux for 3 hours. The solvent was then evaporated under a reduced pressure, methanol (5 ml) was added thereto, and the mixture was stirred at room temperature for one hour. The solvent was then evaporated under a reduced pressure, and the residue was purified by use of silica gel chromatography (eluant: n-hexane/ethyl acetate= 3/1) to give 0.2 g of the title compound (colorless crystals).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].[O:34]1CCC[CH2:35]1.CN(CCS(O)(=O)=O)C.[OH-].[Na+]>C(Cl)Cl>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([CH:35]=[O:34])[C@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C1CCOC1
Agent: CN(C)CCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C=O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1.17 h
Yield: 93 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (109.5 mg, 0.24 mmol) was added to a tetrahydrofuran solution (7.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (39.6 mg, 0.24 mmol) at room temperature and the resulting mixture was stirred for 70 minutes. Methylene chloride was added to the reaction mixture and the resulting mixture was poured into a 2 N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (107.9 mg, 93%) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[NH:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[N:9][C:10]([O:13][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:12]=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2ccccc2)c2ccc(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3)nn(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
NaH (0.115 g, 2.886 mmol) was added to an ice cold solution of 1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (0.325 g, 1.443 mmol) in DMF (5.0 mL) and stirred at ambient temperature for 30 min. Ethyl bromoacetate (0.482 g, 2.886 mmol) was added to the reaction mixture dropwise and stirring was continued for 2 h. After completion of the reaction, the excess of NaH was quenched by the addition of ice cold water. Diethyl ether was added and the mixture was extracted with water and brine. The organic layer was dried over Na2SO4 and filtered. Concentration of the organic layer furnished the title compound as a white solid (0.353 g, 79%). [1H-NMR (CDCl3, 300 MHz) δ 8.2 (d, 1H), 7.94-7.87 (m, 2H), 7.54-7.36 (m, 3H), 6.79 (d, 1H), 5.0 (s, 2H), 4.29 (q, 2H), 4.05 (s, 3H), 1.30 (t, 3H); HPLC RtA=5.555 min (95%); LCMS RtC=1.967 min; [M+H]+=312.1]
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:46])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:45])[C:33]([N:36](C)[C:37](=O)OC(C)(C)C)([CH3:35])[CH3:34])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:46])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:45])[C:33]([CH3:35])([NH:36][CH3:37])[CH3:34])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)(C)C(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Yield: 80.7 %

Procedure:
A solution of the carbamate (6) (25 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to SCX capture and release to afford the title compound (Example 8) as a pale brown solid (20 mg, 89%): m/z 620 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (6H, s), 1.27 (9H, s), 2.20 (3H, s), 2.39 (3H, s), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, overlapping m), 7.93 (1H, m), 8.29-8.34 (3H, overlapping m), 8.59 (1H, br s), 8.79 (1H, br s).