Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][CH2:20][CH2:21][SH:22].CN(C)C=O>O>[CH2:21]([S:22][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:20][CH2:19][CH3:18]
Reactant: CCCCS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-nitrobenzaldehyde (10.0 g), potassium carbonate (10.0 g), n-butylthiol (12.5 ml) and dimethylformamide (12.5 ml) was heated at 100° C. for a period of 16 hours, cooled and poured into water (250 ml). The aqueous mixture was extracted with diethyl ether (4×250 ml) and the combined organic phases were washed with aqueous 2% sodium hydroxide solution (5×100 ml) and finally with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by distillation to give 4-(n-butylthio)benzaldehyde (10.8 g) as a reddish coloured oil. The product was characterized by proton nuclear magnetic resonance spectroscopy. Pmr (CDCl3 ; δ in ppm): 0.97 (3H, t); 1.60 (4H, m); 3.03 (2H, t); 7.32 (2H, d); 7.77 (2H, d); 9.89 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([I:19])C(=O)C1>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([I:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (500 mg, 2.90 mmol) in acetic acid (20 ml) was added NIS (650 mg, 2.89 mmol). The resulting solution was stirred overnight at room temperature and then diluted with water (40 ml). The solids were collected by filtration to afford 5-chloro-4-iodo-2-nitroaniline as a brown solid (800 mg, crude). To a solution of 5-chloro-4-iodo-2-nitroaniline (800 mg, crude) in water (4 ml) and ethanol (20 ml) was added Fe powder (600 mg, 10.74 mmol) and ammonium chloride (430 mg, 8.04 mmol). The resulting solution was stirred overnight at reflux and then cooled to room temperature. The solid was filtered out and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (200 ml) and washed with brine (100 ml), dried over Na2SO4 and concentrated under vacuum to afford 4-chloro-5-iodobenzene-1,2-diamine as a brown solid (600 mg, crude).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH:17]=[O:18])[NH:8][C:7]=1[CH3:19])=[O:5])C.CO.[OH-].[K+]>O>[CH:17]([C:9]1[NH:8][C:7]([CH3:19])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
5-Formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester was dissolved in water (100 mL) and methanol (45 mL) with stirring. Added KOH (2 eq. 1.9 g) and heated in 100° C. After 2.5 h, cooled to room temperature and the remaining ester was removed by extracting into ethyl acetate (200 mL), dried and concentrated. The water layer was acidified to pH=3 using 2N HCl. The white solid was removed by filtration, rinsing with water. The solid was re-concentrated from toluene, triturated with hexanes and dried to afford 2 g (52%) of an off-white solid. 1H NMR (360 MHz, DMSO-d6) δ 12.46 (br s, 1H, CO2H), 11.95 (s, 1H, NH), 9.08 (s, 1H, CHO), 7.36 (s, 5H, ArH), 2.49 (s, 3H, CH3). MS m/z (relative intensity %, ion) found 229 (100, M+); calc. 229.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A mixture of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (1.03 g, 5.07 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.05 g, 5.58 mmol), HOAt (759 mg, 5.58 mmol), 4-methylmorpholine (1.23 mL, 11.15 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g, 5.58 mmol) in DCM (30 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and a saturated solution of NaHCO3. A precipitate was present in the organic fraction which was filtered off to afford the title compound as a pale yellow solid (503 mg). The filtrate was dried (MgSO4) and concentrated in vacuo and the resulting residue was triturated with DCM to afford a second batch of the title compound as a yellow solid (765 mg; 67% yield for the combined batches). LCMS (Method C): RT 2.06 min [M+H]+ 375.3
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOCC>C1COCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: N#CCCN1CCC(C2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 3-(4-cyclohexylpiperidin-1-yl)propionitrile (5.11 g, 23.3 mmol, 1.0 equiv) in anhydrous THF (15 mL) under argon was added a solution of BH3 in THF (1.0M, 82 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6N, 55 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 58 mL, 2.5 equiv). The solvents were removed, ether (40 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×20 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.63 g (88%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(OC(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-dimethylaminocarbonyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:46][N:47]([CH3:49])[NH2:48].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([NH:48][N:47]([CH3:49])[CH3:46])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)N
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 4-benzylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester (0.75 g, 2.35 mmol) (prepared as in Gilligan et al J. Med. Chem. 1994, 364-370) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.32 mg, 2.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol) and the mixture was stirred for 30 min. Then N′,N′-dimethylhydrazine (0.27 ml, 3.53 mmol) and diisopropylethylamine (0.52 ml, 3.06 mmol) was added and the mixture was stirred for 2 days. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with heptane/ethyl acetate (1:2) to give 0.76 g of 4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4].C1C(=O)N([Br:34])C(=O)C1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:34])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a −30° C. solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (1.84 g, 4.89 mmol) in dichloromethane (50 mL) under N2 was added NBS (0.96 g, 5.38 mmol, 1.1 eq.), and the reaction mixture was stirred at −30° C. for 3 h. More NBS (0.96 g, 5.38 mmol, 1.1 eq.) was added, and the reaction mixture was allowed to stand at 0° C. for 18 h. The reaction mixture was diluted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was triturated with methanol to afford the desired product as a yellow solid (1.50 g, 80.1%). LCMS (method C): RT=2.51 min, [M+H]+=383/384.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:13]>CC(C)=O.CO>[NH2:13][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: N
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 216 h
Yield: 148.1 %

Procedure:
Performed in duplicate on identical scales in two pressure vessels, methyl 2,6-dichloronicotinate (4.5 g, 22 mmol) was dissolved in NH3 solution (250 mL, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vessels were sealed and heated at (85±5) ° C. for 9 days. The two reaction mixtures were allowed to cool to 25° C., then combined and concentrated under reduced pressure to yield a white solid. Dissolution of the solid in 1:1 acetone-MeOH (˜500 mL), followed by adsorption onto silica gel (25 g) and then purification by flash column chromatography (25:10:1 hexane-CH2Cl2-Et2O), gave 6.08 g (75%) of methyl 2-amino-6-chloronicotinate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[N:9][CH:10]=1
Reactant: Cc1ccc(F)nc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2C)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Methylimidazole (2.0 g, 24 mmol) and 2-Fluoro-5-methylpyridine (5.41 g, 49 mmol) were dissolved in 40 ml dimethyl formamide. Cesium carbonate (23.8 g, 73 mmol) was added, and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was poured into 100 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The desired compound was obtained as a brown oil (4.0 g, 95%), MS: m/e=174.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH:15]([CH3:20])[C:16](OC)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].Cl>C1C=CC=CC=1>[CH2:25]([NH:29][C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:8][N:7]=2)=[CH:22][CH:21]=1)[CH3:20])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CCCCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
A mixture containing 17.1 g (0.05 mol) of methyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]-propionate and 7.3 g (0.1 mol) of n-butylamine is heated at 80°-85° C. for 6 hours while stirring, then cooled and diluted with 50 ml of benzene. The benzene solution is shaken with 5% aqueous hydrochloric acid solution and then washed with water to acid-free. After separation the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The crude product can be recrystallized from a mixture of benzene with petroleum ether (b.p. 70° C.) The compounds Nos. 1, 6, 7 and 8 are similarly prepared from the corresponding starting materials.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C1(CN)CCCCC1.[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:43])=[CH:45][CH:46]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: NCc1cccs1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1cccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-thiophenemethylamine to replace cyclohexanemethylamine, and 4[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(thiophen-2-ylmethyl)benzamide was obtained (48%) as a colorless solid: mp 167-168° C.; 1H NMR (300 MHz, CDCl3) δ7.81-7.73 (m, 2H), 7.43-7.37 (m, 2H), 7.27-7.16 (m, 3H), 7.07-7.00 (m, 2H), 6.99-6.95 (m, 1H), 6.75-6.70 (m, 1H), 6.48-6.40 (m, 3H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.83-4.78 (m, 2H), 4.59-4.50 (m, 2H), 3.09-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 166.5, 161.9, 161.3, 141.7, 140.6, 139.4, 133.7, 132.6, 128.7, 127.7, 127.5, 126.9, 126.2, 125.3, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 38.8, 29.0; MS (ES+) m/z 509.2 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6].[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:7][C:5]([C:9]1[CH:14]=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
To a dry, round bottom flask was added aluminum chloride (4.402 g, 33.0 mmol). The flask was then cooled to −45° C. After 10 minutes, dry toluene (80 mL) was added followed by dropwise addition of 2-tert-butylphenol (5.00 mL, 32.7 mmol) (commercially available from Aldrich). The mixture was stirred and maintained at −4° C. After 1.5 hours, acetyl chloride (2.40 mL, 33.8 mmol) was carefully added dropwise. The mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After 18 hours, the mixture was slowly poured onto crushed ice. This mixture was stirred at room temperature and the crystals were collected by filtration. The light yellow solid was identified as T5.1 (4.2589 g, 68%). MS ESI (pos.) m/e: 193.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:74][C:75]1[CH:81]=[CH:80][C:78]([NH2:79])=[CH:77][CH:76]=1>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:79][C:78]3[CH:80]=[CH:81][C:75]([F:74])=[CH:76][CH:77]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26.4 mg, 72%). LC-MS m/z 667 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1>>[CH3:3][C@@H:2]([C@@H:24]([OH:25])[C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: O=Cc1cccnc1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)c1cccnc1

Procedure:
Prepared from (4S)-N-propionyl-4-benzyl-2-oxazolidinone and pyridine-3-carboxaldehyde according to the procedure described in Example 1, paragraph A. 13C-NMR (100 MHz, CDCl3): δ 176.40, 152.83, 148.74, 147.85, 136.78, 134.80, 134.04, 129.34, 128.95, 127.45, 123.21, 109.75, 71.46, 66.23, 55.05, 44.28, 37.70, 10.64.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:22]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccccc1C(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O
Yield: 53 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 2-methoxybenzoyl chloride separately prepared according to a conventional method, instead of benzoyl chloride, to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 1.87 g of 4-(2-methoxybenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 53%).
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[S:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>CN1CCCC1=O>[CH3:23][N:20]1[CH2:19][CH2:18][CH:17]([S:16][C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:4]#[N:5])[CH:8]=3)[NH:12][CH:11]=2)[CH2:22][CH2:21]1
Reactant: N#C[Cu]C#N
Reactant: CN1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Solvent: CN1CCCC1=O
Product: CN1CCC(Sc2c[nH]c3ccc(C#N)cc23)CC1
Yield: 5.1 %

Procedure:
A suspension of copper cyanide (17.7 g) and 5-bromo-3-[(1-methylpiperidin-4-yl)thio]-1H-indole (35.5 g, prepared in Example 44) in 1-methylpyrrolidin-2-one (45 ml) is refluxed for 24 hours. After dilution with water, the brown precipitate is separated off and then taken up with a mixture of water (110 ml) and ethylenediamine (170 ml). The blue solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residual oil is chromatographed on silica gel (eluent: AcOEt/iPrNH2 95/5) to give 3-[(1-methylpiperidin-4-yl)thio]-1H-indole-5-carbonitrile (1.5 g), which is converted to the oxalate in ethanol.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[H][H].[ClH:18]>C(O)C.O.[Pd]=O>[ClH:18].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(N)cc1

Procedure:
A suspension of N-methyl-4-nitrobenzenemethanesulphonamide (30 g) in ethanol (150 ml), water (300 ml) and hydrochloric acid (2N, 65 ml) was hydrogenated over 10% palladium oxide on charcoal (7.5 g, 50% paste with water) until hydrogen uptake ceased (9.75 l). The catalyst was removed by filtration through "hyflo" and the filter pad was washed with water (30 ml). The filtrate was evaporated under reduced pressure to give the title compound as a pale yellow powder (28.2 g) m.p. 143°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.333 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.