Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (see US2004/0082553, page 67 (page 68 of pdf version)) (1000 mg, 2.45 mmol) in CH2Cl2 (25 mL) at 5° C. is treated with pyridine (0.23 mL, 2.95 mmol) and methanesulfonylchloride (0.19 mL, 2.45 mmol) then stirred for 1 hour, washed with saturated aqueous sodium bicarbonate, concentrated and used as is (1130 mg). m/z (Cl) 485 [M+H].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH2:22])=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2)=[O:12].C(OCC)(=O)C>C(O)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH2:22])=[C:15]2[C:19](=[C:20]([Br:1])[CH:21]=1)[CH2:18][CH2:17][CH2:16]2)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2c(c1N)CCC2
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c2c(c1N)CCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add N-bromosuccinimide (1.99 g, 11.2 mmol) to 4-Amino-indan-5-carboxylic acid methyl ester (2.15 g, 11.2 mmol) in acetic acid (13 mL). Stir the mixture at room temperature for 48 h. Pour the mixture into ice-water and add ethyl acetate. Separate the layers and wash the organic phase with sat NaHCO3 and brine and dry over sodium sulfate. Remove the solvent under reduced pressure to afford the title compound (3.10, quantitative). MS (ES+): 271 (M+H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]2[N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:39]=4[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]5)[C:22]=3[Cl:41])[CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.[CH2:45]([N:47]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:22]1[C:23]([CH2:28][O:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:39]=2[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[N:9][C:4]([C:1](=[O:2])[NH:47][CH3:45])=[CH:5][CH:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 2-[(E)-3-(6-carboxypyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (60 mg) and methylamine hydrochloride (7.59 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg) and 1-hydroxybenzotriazole (20.7 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-[6-(methylcarbamoyl)pyridin-3-yl]acryloylaminomethyl]pyrrole (58 mg) as amorphous powder.
Reaction SMILES: Br[C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>CO>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Sc1ccccc1Br
Reactant: COC(=O)C1(Br)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C1(Sc2ccccc2Br)CCCCC1
Temperature: 65 °C

Procedure:
To a solution of 715 mg (3.2 mmol) of methyl 1-bromocyclohexane-1-carboxylate (J. Med. Chem. 1970, 13, 317) in MeOH (5 mL) was added diisopropylethylamine (0.9 mL, 5.2 mmol) and 2-bromobenzenethiol (0.55 mL, 4.7 mmol). The solution was heated to 65° C. under nitrogen for 2 h, then cooled and partitioned between ethyl acetate and 1 M HCl. The organic phase was washed twice with 1 M NaOH and brine, then dried over MgSO4 and concentrated. Purification by flash chromatography (10% EtOAc/hexanes) gave methyl 1-[(2-bromophenyl)sulfanyl]cyclohexanecarboxylate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)=[CH:13][C:12]([C:31]1[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].O.Cl>C1COCC1>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-butyryl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (36 mg, 0.065 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated. The resultant residue was triturated with diethyl ether. The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (21.1 mg, 71%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.15 (s, 1H), 8.47 (s, 1H), 8.28 (dd, J=8.7, 1.8 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J=11.4 Hz, 1H), 4.55 (br s, 1H), 3.13 (t, J=7.2 Hz, 2H), 2.53-2.49 (m, 2H), 2.26 (d, J=12.1 Hz, 2H), 1.94-1.74 (m, 4H), 1.68-1.62 (m, 2H), 1.06 (t, J=7.4 Hz, 3H). ESI MS m/z 456 [C25H27ClFN3O2+H]+; HPLC>99% (AUC), tR=10.83 min.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:12]([I:25])=[C:13]([C:23]=1[I:24])[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:43](Br)[CH:44]=[CH2:45].Cl>CS(C)=O>[CH2:45]([N:8]([C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:9]1[C:10]([I:31])=[C:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:12]([I:25])=[C:13]([C:23]=1[I:24])[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])[CH:44]=[CH2:43]
Reactant: CC(=O)OCCNC(=O)c1c(I)c(COC(C)=O)c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c1I
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C=CCN(C(=O)C(COC(C)=O)OC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCCOC(C)=O)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(2,3-Diacetoxypropionylamino)-3-acetoxymethyl-N-(2-acetoxyethyl)-2,4,6-triiodobenzamide (8.65 g, 10.3 mmol) was dissolved in dimethyl sulfoxide (10 ml) at room temperature. Cesium carbonate (3.88 g, 11.8 mmol) was added and after stirring at room temperature for 15 min, the mixture was cooled in an ice bath. Allyl bromide (2.10 g, 17.3 mmol) was added dropwise and the mixture was then stirred for 17 h at room temperature. The reaction mixture was transferred onto aqueous hydrochloric acid (0.1 M, 300 ml). The formed precepitate was filtered off, redissolved in methylene chloride (150 ml) and washed with water (5×100 ml). The organic phase was dried (Na2SO4), and the solvent evaporated. Yield: 8.73 g (96%).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])[CH3:24]>CN1C(=O)CCC1.O>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]2[N:9]=[C:8]([C:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]4=[N:12][CH:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(C(C)(C)O)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.19 g), 4-amino-cyclohexanecarboxylic acid ethyl ester (0.31 g) in NMP (2 mL) was stirred at 100° C. for 3 h. The reaction mixture was cooled to RT, and diluted with water. The resulting solid was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. Fractions were collected, concentrated, and titurated with EtOAc/hexane. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.215 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
Add Pd/C (10%, 0.46 g) to a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylic acid methyl ester (0.462 g, 1.1 mmol) in MeOH (10 mL) and dichloromethane (10 mL). Bubble nitrogen for 15 minutes. Connect the hydrogen balloon to the reaction flask and stir overnight. Filter through celite and wash the celite pad with dichloromethane (50 mL). Remove the solvent. Chromatograph the residue (elute with 2% MeOH in dichloromethane) to give the desired product as a pale yellow solid 0.27 g (59%).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]([CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:22]([F:31])[CH:21]=2)[CH2:15]1)[C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O>C(O)(=O)C.O.[Zn]>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:13][C@@H:14]2[O:18][C:17](=[O:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[C:22]([F:31])[CH:21]=3)[CH2:15]2)=[N:9]1
Reactant: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Reaction time: 0.33 h
Yield: 41.8 %

Procedure:
5(R)—(N-(2,2,2-Trichloroethyloxycarbonyl)-isoxazol-3-ylaminomethyl)-3-(4-imidazol-1-yl-3-fluorophenyl)oxazolidin-2-one (crude, 1.7 g, ˜2.5 mM), was stirred in a mixture of acetic acid (40 ml) and water (18 ml) under nitrogen at ambient temperature. Zinc dust (824 mg, 12.5 mM) was added, the mixture stirred 20 minutes, a further portion (200 mg) of zinc added, and stirring continued for 1 hour. The mixture was filtered through celite, and the filter pad washed well with a mixture of acetic acid and water (5:1). The filtrates were evaporated, and the residue partitioned between hydrochloric acid (0.5M, 200 ml) and dichloromethane (150 ml). The aqueous phase was washed with dichloromethane (100 ml), then made basic with the minimum quantity of concentrated ammonia solution, re-extracted with dichloromethane (2×150 ml), dried (magnesium sulfate), and evaporated. Recrystallisation from isopropanol (40 ml) gave the desired product (470 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1S(C)(=O)=O

Procedure:
To 4-bromo-2-methanesulfonylbenzoic acid (5 g) were added methanol (45 mL) and concentrated sulfuric acid (1.8 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, the solvent was evaporated, and the residue was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g). To a mixture of the obtained methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (295 mg), 2-(dicyclohexylphosphino)biphenyl (399 mg), tripotassium phosphate (3.39 g) and benzophenonimine (2.5 mL) was added 1,2-dimethoxyethane (25 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran (26 mL), 1N hydrochloric acid (100 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-amino-2-methanesulfonylbenzoate (1.46 g). Using the obtained methyl 4-amino-2-methanesulfonylbenzoate (1.46 g) and 3-chloropropane-1-sulfonyl chloride (1.03 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (0.53 g) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:4]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>C(O)(C)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][N:33]1[C:9](=[O:11])[C:8]2[C:3](=[N:4][C:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:6][C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:2]1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1CBr
Solvent: CC(C)O
Product: CN(C)CCN1Cc2nc(-c3ccccc3)cc(-c3cccc([N+](=O)[O-])c3)c2C1=O
Yield: 35.8 %

Procedure:
A mixture of ethyl 2-bromomethyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (1.5 g) and 2-dimethylaminoethylamine (0.6 g) is isopropyl alcohol (15 ml) was refluxed for 1 hour. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (20 ml) and chloroform (40 ml). The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off. The residue was subjected to a column chromatography on silica gel, eluting with a mixture of chloroform and methanol (50:1 V/V). The fractions containing the desired compound were combined and evaporated in vacuo. The crystalline residue was recrystallized from ethanol to give 6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-5-oxo-2-phenyl-5,7-dihydro-(6H)-pyrrolo[3,4-b]pyridine (0.49 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][O:3]1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=1.CN(C=O)C.Cl>[Fe]>[CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[C:8]([O:11][C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2ccc(O)cc21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Fe]
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)OCc2ccc(Oc3ccc(N)cn3)cc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a solution of 3,3-dimethyl-1H-isobenzofuran-5-ol (Intermediate 18, 30 mg, 0.18 mmol) and 2-chloro-5-nitro-pyridine (27.5 mg, 0.1736 mmol) in DMF (1 mL) dipotassium carbonate (37.8 mg, 0.2741 mmol) was added and the reaction mixture was stirred for 1.5 hours at 80° C. After cooling the reaction was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was dissolved in ethanol (3 mL)/water (1 mL). Iron (61.2 mg, 1.1 mmol) and an aqueous 6M solution of hydrogen chloride (0.03 ml, 0.18 mmol) were added and the reaction mixture was stirred for 4 hours at 50° C. The catalyst was filtered off and the resulting solution was diluted with a saturated solution of NaHCO3 (15 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 80:20 to 30:70 as eluent affording the title compound (20 mg) as colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][C:15]=1[Cl:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[Cl:16])[NH2:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1Cl
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(N)ccc1Cl

Procedure:
Prepared from 3-(tert.butyloxycarbonylaminomethyl)-4-chloro-nitrobenzene by hydrogenation in methanol at ambient temperature in the presence of platinum on charcoal, melting point: 75–77° C.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[C:8]([CH3:30])[N:7]=1.[CH3:31]O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([O:29][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[C:8]([CH3:30])[N:7]=1
Reactant: CO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of boron tribromide (13.95 ml, 1M in DCM) was added portionwise over 30 min to a stirred suspension of the product from example 83 step (iv) (1 g) in DCM (15 mL) at 0° C. The suspension was allowed to warm to rt and stirred for 5 h. The suspension was cooled to 0° C. and then MeOH (10 mL) and 4M HCl in dioxane (2 mL) were added and the mixture stirred for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by flash silica chromatography (5% MeOH/DCM) to give the title compound (minor product) as a white solid, 51 mg.
Reaction SMILES: Cl[Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16].CC[N:21]([CH2:24][CH3:25])CC>CCCCCC>[CH:24]1([NH:21][Si:2]([CH3:18])([CH3:17])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([CH3:15])=[C:4]2[CH3:16])[CH2:25][CH2:5][CH2:4][CH2:3][CH2:14]1
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Reactant: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(C)C([Si](C)(C)NC2CCCCC2)c2cc3c(cc21)CCC3
Reaction time: 16 h
Yield: 181 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl)silane (5.00 g, 0.01806 moles) was stirred in hexane (80 mL) as NEt3 (3.29 g, 0.03251 moles) and t-cyclohexylamine (1.81 g, 0.01824 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.55 g, 90.9 percent).
Reaction SMILES: [NH2:1][C:2]1([CH2:6][C:7]([O:9]CC)=O)[CH2:5][O:4][CH2:3]1.[CH3:12][NH:13][CH3:14].O>C1(C)C=CC=CC=1>[NH2:1][C:2]1([CH2:6][C:7]([N:13]([CH3:14])[CH3:12])=[O:9])[CH2:5][O:4][CH2:3]1
Reactant: CNC
Reactant: CCOC(=O)CC1(N)COC1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)CC1(N)COC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 87 %

Procedure:
In a microwave tube was added ethyl 2-(3-aminooxetan-3-yl)acetate (CAN 1207175-54-9, 470 mg, 2.95 mmol). Toluene (7.0 ml) and 40%-dimethylamine solution in water (8.9 g, 10.0 ml, 79.0 mmol) were added. The tube was sealed and the reaction mixture was stirred vigorously at room temperature for 7 days. The reaction mixture was concentrated in vacuo and azeotroped several times with 30 mL toluene. The crude solid was dried under high vacuum at 40° C. for 3 hours to yield the title compound (405 mg, 87%). MS (ESI, m/z): 159.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.2 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A), morpholine-3-carboxylic acid hydrochloride (1 g, 6 mmol) and triethylamine (1.21 g, 12 mmol) in ethanol (40 mL) was stirred at 25° C. for 12 hours under N2. The mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (1.5 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[C:36]3[O:35][CH2:34][CH2:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)O1>>[O:35]1[C:36]2[C:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=4)[N:3]=3)=[CH:29][CH:30]=[CH:31][C:32]=2[CH2:33][CH2:34]1
Reactant: CC1(C)OB(c2cccc3c2OCC3)OC1(C)C
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OCC4)n2)c1

Procedure:
Example 13 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran (ChemBridge Corporation). The batch was purified by preparative HPLC: