Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6](Cl)=[O:7])[CH3:2].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.O>N1C=CC=CC=1>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:6](=[O:7])/[CH:5]=[CH:4]/[O:3][CH2:1][CH3:2])=[C:12]([CH3:17])[CH:11]=1
Reactant: CCO/C=C/C(=O)Cl
Reactant: Cc1cc(Br)ccc1N
Solvent: O
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc(Br)cc1C

Procedure:
Trans-3-Ethoxypropenoyl chloride (0.74 g) was added at 0° to a stirred solution of 4-bromo-2-methylaniline (0.93 g) in pyridine (10 cm3). After 0.5 hours water (40 cm3) was added, the solid material was filtered off, washed with water (30 cm3) and dried. The product was recrystallised from ethyl acetate to afford trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenamide, m.p. 163°-164°, (1.3 g).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=3)[N:19]([CH3:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C([O:46][N:47]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NO>CN(C=O)C>[OH:46][NH:47][C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:29])[CH:18]=[C:17]2[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)=[O:27]
Reactant: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)NO)ccc21
Yield: 34.4 %

Procedure:
A solution of 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid (64 mg, 0.16 mmol), DIPEA (0.14 mL, 0.8 mmol), HATU (68 mg, 0.18 mmol), hydroxylamine hydrochloride (56 mg, 0.8 mmol) and DMF (4 mL) was stirred for 19 hr at room temperature. The reaction mixture was then subjected to HPLC purification to provide 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid hydroxyamide (22 mg, 34% yield). 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 10.18 (s, 1H), 7.99 (s, 1H), 7.93 (d, 2H, J=7.2 Hz), 7.67 (d, 2H, J=8.7 Hz), 7.57 (m, 2H), 7.53 (d, 2H, J=7.7 Hz), 7.43 (d, 1H, J=8.2 Hz), 7.27 (d, 2H, J=8.2 Hz), 7.19 (s, 1H), 4.03 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:32])(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A solution of 4-(benzyloxycarbonylaminomethyl)-1-Boc-piperidine (0.360 g, 1.03 mmol) in DMF (10 mL) was treated with sodium hydride (60%, 0.050 g, 1.25 mmol). After 0.5 h, methyl tosylate (0.18 mL, 1.20 mmol) was added and the mixture heated to 6° C. After 12 h, the mixture was poured into EtOAc and saturated aqueous sodium bicarbonate. The combined extracts were washed with water, brine and concentrated to afford 0.300 g (79%) the title compound which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22]N(C)C=O.P(OC)(OC)(OC)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:22])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: CN(C)C=O
Solvent: O
Solvent: COP(=O)(OC)OC
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 20 ml of dimethylformamide was added 4.2 g of trimethyl phosphate and the whole was refluxed for 5 hours. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. To the residue thus obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.4 g of 1-(m-nitrophenyl)-3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 241°-242° C.
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:34]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]1[O:36]C(=O)C)(=O)C>C(#N)C>[C@@H:34]1([N:1]2[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]1[OH:36]
Reactant: Nc1nc[nH]c(=O)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
A mixture of 5-azacytosine, HMDS, and TMSC1 in acetonitrile is heated to reflux for 20 hours under an inert atmosphere. TMS-triflate and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose are then added directly to the silylated 5-azacytosine in acetonitrile. The addition is performed at ambient temperature and under an inert atmosphere. The reaction mixture is maintained under stirring for 20 hours, then the acetonitrile is removed under vacuum. The solids are then dissolved in dichloromethane, and the mixture is poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10%). The resulting mixture is extracted with dichloromethane. The combined organic extract is washed with cooled (0-5° C.) 10% sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam is dissolved in methanol and treated with a solution of 25% sodium methoxide in methanol. The suspension is stirred at ambient temperature for 15 hours, then the solid is filtered off, washed with methanol and anhydrous ether, then dried in vacuum. The crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH3:15]O>>[CH3:15][O:11][C:10]([C:8]1[S:7][C:6]2[CH:13]=[CH:14][C:3]([CH3:2])=[CH:4][C:5]=2[CH:9]=1)=[O:12]
Reactant: Cc1ccc2sc(C(=O)O)cc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2cc(C)ccc2s1

Procedure:
Hydrogen chloride gas was passed into a solution of 5-methylbenzo[b]thiophene-2-carboxylic acid (7.50 g.) in methanol (250 ml.) until the solution was saturated. The solution was heated under reflux for 1 hour and then evaporated. The residue was washed with water and crystallized from methanol to give 5-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (7.80 g.) m.p. 78°-79°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])[CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:11](=[O:12])[CH:9]([CH3:10])[NH:8]2
Reactant: C[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1Nc2cc(Br)ccc2NC1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)-alanine (22 g, 76 mmol) in acetic acid (300 ml) was added iron powder (10 g, 180 mmol), and the mixture was stirred for 2 hours at 90° C. The reaction mixture was cooled and filtered, and the acetic acid was evaporated. The remaining slurry was extracted with methylene chloride (3×200 ml). The combined extracts were combined, dried over magnesium sulfate, filtered, and evaporated to afford 6-bromo-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (9.4 g, 51%). A sample was recrystallized from ethanol: m.p. 133-135° C. 1H-NMR (DMSO-d6) δ 1.23 (d, J=6.81 Hz, 3H), 3.80 (q, J=6.81 Hz, 1H), 6.27 (bs, 1H), 6.63 (d, J=8.35 Hz, 1H), 6.72 (dd, J=8.35, 1.76 Hz, 1H), 6.80 (d, J=1.76 Hz, 1H), 10.29 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N12CCCC=C1CCNC[CH2:14]2.S(OC)(OC)(=O)=O.Cl>C(#N)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: C1=C2CCNCCN2CCC1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of 2-amino-5-chloro-3-methylbenzoic acid (i.e. the product of Step A) (92.8 g, 500 mmol) in acetonitrile (500 mL) at 0-5° C. was added 1,4-diaza-bicyclo[5.4.0]undec-7-ene (DBU, 90 mL, 92 g, 600 mmol), and then dimethyl sulfate (57 mL, 76 g, 600 mmol) was added dropwise at 0-5° C. After stirring 3 h at this temperature, additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 3 h at this temperature, more additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 2 h at this temperature, concentrated hydrochloric acid (60 mL, 720 mmol) was added dropwise at 0-10° C. The resulting suspension was stirred for 30 minutes at 0-5° C., then filtered, and the solids were washed with ice-cold 2:1 water-acetonitrile (3×100 mL), and dried under nitrogen. The crude product was suspended in methanol (250 mL), water (1000 mL) was added, and the mixture was stirred at room temperature for 1 h. Then the solids were filtered, washed with 4:1 water-methanol (100 mL), then with water (3×100 mL), and dried under nitrogen to afford the title compound as a low-melting white solid, 87.6 g (87.8% yield). HPLC of the solid product showed 99.7 area % of the title ester.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[S:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[S:37][CH:38]=3)=[N:8][N:9]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2nn(C3CCOCC3)c3ccnc(OC)c23)cs1
Yield: 68.2 %

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (250 mg) obtained in Step A of Example 15, methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (264 mg), tetrakis(triphenylphosphine)palladium(0) (76.0 mg) and 2M aqueous sodium carbonate solution (1.60 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (167 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:14]([C:21]1[C:22]([NH2:33])=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[NH:26][C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][N:23]2[C:10](=[O:12])[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[N:33][C:22]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized using method A with 3-(4-hydroxyphenyl)-2-oxopropanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. Exact mass calculated for C26H22N3O2+ m/z+ 408.17, found m/z+ 408.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].N1C=CC=C[CH:22]=1.O=S(Cl)Cl>CC#N>[Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH2:18][CH3:22])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O

Procedure:
The procedure was the same as reported above for 3a using 2b40 (1.28 g, 4.33 mmol), pyridine (685 mg, 0.70 mL, 8.65 mmol), CH3CN (10 mL), and SOCl2 (2.57 g, 1.58 mL, 21.60 mmol): yield 498 mg (37%); MS m/z 314 (M+H)+; 1HNMR (DMSO-d6) δ 8.09 (bs, 1H, H-2), 7.14 (bs, 2H, 6-NH2), 5.80 (d, 1H, H-1′, J1′,2′=5.7 Hz), 5.48 (d, 1H, 2′-OH, J2′-2′OH=6.1 Hz), 5.45 (d, 1H, 3′-OH, J3′-3′OH=5.4 Hz), 5.20 (ddd, 1H, H-2′, J1′,2′=5.7 Hz, J2′,3′=4.6 Hz, J2′-2′OH=6.1 Hz), 4.30-4.37 (bm, 1H, H-3′), 4.03-4.10 (bm, 1H, H-4′), 3.94-4.0 (m, 1H, 5′-CH2), 3.83-3.89 (m, 1H, 5′-CH2), 2.89 (q, 2H, 8-CH2CH3), 1.31 (t, 3H, 8-CH2CH3).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[S:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22].C(O[C:29]([F:32])([F:31])[F:30])(=O)C.[Na].[OH2:34]>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[C:4]([O:34][C:11]([N:8]1[CH2:9][CH2:10][C:4]2[C:3]([S:19][C:20](=[O:24])[N:21]([CH3:22])[CH3:23])=[C:2]([C:29]([F:30])([F:31])[F:32])[CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7]1)=[O:16])([CH3:10])([CH3:5])[CH3:3]
Reactant: O
Reactant: CN(C)C(=O)Sc1c(Br)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: CC(=O)OC(F)(F)F
Agent: [Cu]I
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Sc1c(C(F)(F)F)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Temperature: 180 °C
Yield: 74 %

Procedure:
To a stirred solution of 7-bromo-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.383 g, 3.254 mmol), in NMP (40 ml) add sodium trifluoromethyl acetate (3.54 g, 26.03 mmol), copper(I) iodide (2.47 g, 13.0 mmol) and heat the mixture at 180° C. for 4 h. Cool to ambient temperature. Dilute with EtOAc, water and remove the copper solid residue by filtration. Separate the layers of filtrate and extract the aqueous layer three times with EtOAc. Dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give the desired intermediate as a yellow oil (882 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.N[CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CC[N:42](C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:42][C:35]4([OH:39])[CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: NC1CCCC(O)C1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4(O)CCCCC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (1.09 g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) in THF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heated at 130° C. in microwave for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to afford 550 mg of the desired product, 27a.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C([Li])CCC.CCCCCC.Cl[Si](C)(C)C.[CH3:23][C:24](=[O:26])[CH3:25]>O1CCCC1>[NH2:6][C:2]1[S:1][C:5]([C:24]([OH:26])([CH3:25])[CH3:23])=[CH:4][N:3]=1
Reactant: Nc1nccs1
Reactant: CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cnc(N)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of thiazol-2-amine (7.0 g, 69.9 mmol) in tetrahydrofuran (200 ml) was added a 10.0 M solution of butyllithium in hexane (14 mL, 140 mmol). The mixture was stirred at −78° C. for 1 hour and chlorotrimethylsilane (15.2 g, 140 mmol) was added dropwise. The mixture was allowed to warm up to −40° C., cooled to −78° C. and a 10.0 M solution of butyllithium in hexane (7.0, 70 mmol) was added After 10 minutes, propan-2-one (8.12 g, 140 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.61 (s, 6H) 5.04-5.19 (brs, 2H) 6.89 (s, 1H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[CH3:13][NH:14][CH3:15].CN.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]2[C@@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([N:14]([CH3:15])[CH3:13])=[O:12])[C:28]3=[O:36])[CH2:26]2)=[CH:23][CH:24]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CNC
Agent: CN
Product: CN(C)C(=O)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-bromomethyl-benzoic acid methyl ester, dimethylamine, methylamine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C29H27ClN2O2: 470, observed (M+H)+: 471.2 1H NMR (400 MHz, MeOD-d4) δppm 2.15-2.24 (m, 2 H) 2.90 (s, 3 H) 3.06 (s, 3 H) 3.21-3.35 (m, 1 H) 5.09 (s, 2 H) 6.05 (d, J=7.58 Hz, 1 H) 6.69 (t, J=7.58 Hz, 1 H) 6.89 (d, J=8.08 Hz, 1 H) 7.01-7.10 (m, 1 H) 7.19 (d, J=8.59 Hz, 2 H) 7.25-7.38 (m, 4 H) 7.40-7.49 (m, 2 H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C[Si]([C:20]#[N:21])(C)C>C(O)(=O)C>[C:12]1([CH3:15])[CH:13]=[CH:14][C:9]([NH:8][C:1]2([C:20]#[N:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: O=C1CCCCC1
Reactant: Cc1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Solvent: CC(=O)O
Product: Cc1ccc(NC2(C#N)CCCCC2)cc1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
10 g of cyclohexanone (101.9 mmol, 1 eq.) (starting material 1) are dissolved in 150 ml of acetic acid (15 vol.) in a 500 ml three-necked flask, at room temperature and under nitrogen, the mixture is cooled in an ice bath (10° C.) and followed by portionwise addition of 13.1 g of para-toluidine (starting material 2) (122.3 mmol, 1.2 eq.), and the mixture is then stirred for 15 minutes at 10° C. 15 ml (112.1 mmol, 1.1 eq.) of trimethylsilyl cyanide are then introduced. The reaction medium is stirred overnight at room temperature. It is then poured gently into ice-cold 20% ammonium hydroxide solution (300 ml) until the pH is basic, and extracted with 300 ml of dichloromethane. The aqueous phase is again extracted with 200 ml of dichloromethane. The organic phases are combined and washed with 400 ml of water and then dried over magnesium sulfate. After evaporation, the residue is triturated in heptane, and the product 1-p-tolylaminocyclohexanecarbonitrile is isolated in the form of a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([CH2:36][C:37](O)=[O:38])[N:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[C:37](=[O:38])[CH2:36][C:33]1[NH:34][N:35]=[C:31]([CH3:30])[N:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: Cc1nc(CC(=O)O)n[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)n[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 12 %

Procedure:
Prepared using the same procedure described in Example 189 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (17 mg, 12%). LC/MS (Method B) 3.22 min, [M+1]+ 525.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2SCC2C(F)=CC=C(F)C=2F)=[CH:4][CH:3]=1.CC1N([NH:36][CH2:37][C:38]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=2[F:46])C(C([O-])=O)=CN=1.[Li+].[OH-].[CH2:49]1COCC1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[N:36]([CH3:49])[CH2:37][C:38]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=2[F:46])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: Cc1ncc(C(=O)[O-])n1NCc1c(F)ccc(F)c1F
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1c(F)ccc(F)c1F)c1ncc(C(=O)O)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-(methyl(2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylic acid (71) was prepared in a similar manner as that described for the synthesis of compound 11 using 1-(4-fluorophenyl)-2-(methyl(2,3,6-trifluorobenzylamino)-1H-imidazole-5-carboxylate (70) (24 mg, 0.061 mmol) and 1N LiOH (5 mL) in THF (5 mL) and MeOH (5 mL).