Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[I:20](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>CO>[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([I:20])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(F)c(I)cc1C(=O)O
Reaction time: 48 h
Yield: 77 %

Procedure:
To a vigorously stirred solution of dichloromethane (700 ml), methanol (320 ml), and 2-amino-4-fluoro-benzoic acid (33.35 grams, 215 mmoles) was added solid sodium hydrogencarbonate (110 grams, 1.31 moles) followed by portion addition of benzyltrimethyl ammonium dichloroiodate (82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours. The mixture was filtered to remove the insolubles. The remaining solid residue was washed with 200 ml of dichloromethane. The filtrate was concentrated and redissolved in a one to one mixture of ethyl acetate (1 liter) and a 0.2 N solution of sodium hydroxide (1 liter), added to a 2 liter separatory funnel and extracted. The organic layer was washed with an additional 200 ml of water. The aqueous layers were combined and acidified with 2N hydrochloric acid. The resulting precipitate was collected by suction filtration, washed with water and dried under vacuum at 60° C. to yield 46.5 grams (77%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (d, 1H), 7.1 (s, broad, 2H), 6.63 (d, 1H). ESI-MS m/z 280 (M−1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][C:12]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:11]2)=[CH:6][CH:5]=1.[CH3:26][N:27]([CH:29]=[O:30])C.C(Cl)(=O)C(Cl)=[O:33]>C(Cl)Cl>[CH:23]([OH:25])=[O:24].[OH:33][N:27]([CH3:26])[C:29](=[O:30])[CH2:22][CH2:21][C:12]1[CH:13]=[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)[N:11]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2cccnc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-n2nc(CCC(=O)N(C)O)cc2-c2cccnc2)cc1
Product: O=CO
Reaction time: 0.5 h

Procedure:
To a solution of compound 31 (0.9 g, 2 5 mM) in CH2Cl2 (25 ml) at RT was added DMF (0.2 ml) and oxalyl chloride (1.26 g, 10 mM). After stirring for 0.5 hr, the reaction mixture was evaporated in vacuo, redissolved in CH2Cl2 (25 ml) and added dropwise to a solution of methylhydroxylamine hydrochloride (0.84 g, 10 mM) and Et3N (3.7 ml) in CH2Cl2 (50 ml) at 0° C. The reaction was stirred for 10 min and poured into a 1:1 stirred mixture of Ch2Cl2 :H2O. The CH2Cl2 layer was separated, washed (H2O and then brine), dried (Na2SO4) and evaporated in vacuo to give a semi-solid which was purified by column chromatography on Silica employing Hexane:40EtOAc:1% MeOH:0.1% HCO2H as eluent. The title compound 35 was obtained as a tan foam as the monoformate salt; MS, m/e 352 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.O>[CH2:7]([N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCOC(=O)CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(=O)N(CC(=O)OCC)Cc1ccccc1
Yield: 85.6 %

Procedure:
Potassium carbonate (110.4 g, 0.97 mol) was added in one portion to a solution of ethyl 2-(benzylamino)acetate (78 g, 0.4 mol) in tetrahydrofuran (500 mL) and water (200 mL). Ethyl 4-chloro-4-oxobutanoate (72.7 g, 0.485 mol) in anhydrous tetrahydrofuran (200 mL) was then added dropwise over a period of 1 hour to the mixture. The mixture was filtered, and the filtrate was washed with ethyl acetate. After the solvent was removed by evaporation, standard extractive workup with ethyl acetate (100 mL) to afford the title product as a yellow oil (110 g; yield=80%). LC-MS: m/z=322 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cc21
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2-(trifluoromethyl)thiazol-4-yl)methanol (80 mg) and toluene (5 ml) was added potassium tert-butoxide (98 mg) at 100° C., and the mixture was stirred at the same temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (29.0 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([OH:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C1C=CN=CC=1)C>[C:26]([O:19][C:5]1[C:6]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:9][CH2:8][C:7]=2[C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N1CCc2c(O)ccc(Br)c2CC1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)c2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Under nitrogen atmosphere, mix 9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (6 g, 17.8 mmol), anhydrous pyridine (0.06 mL, 0.72 mmol), DMAP (222 mg, 1.8 mmol) and acetic anhydride (30 mL). Heat the mixture at reflux for 8 h and then stir at ambient temperature for another 8 h. Concentrate in vacuo, dilute the residue in EtOAc, wash with 1N aqueous HCl, and then with saturated aqueous NaHCO3. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the desired intermediate (5.64 g, 84%) that was used without further purification. MS (ES+) m/z: 380 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.O.CO>[CH3:19][O:18][C:15]1[N:14]=[N:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCN(c2ccc(OC)nn2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(N2CCC(C(=O)O)CC2)nn1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a stirred solution 1-(6-methoxy-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester (3.20 g, 12.06 mmol) in THF (40 mL), H2O (40 mL) and MeOH (4 mL) was added LiOH.H2O (600 mg, 14.3 mmol). Stirring was continued overnight at RT before the organic solvent were removed under vacuo. The pH of the was adjusted to 5 with acetic acid, and the product extracted with EtOAc, dried over Na2SO4. The resulting solid was suspended in heptane, filtered off, washed with cold Et2O to give 1.48 g (61%) of 1-(6-methoxy-pyridazin-3-yl)-piperidine-4-carboxylic acid. ES-MS m/e: 236.2 (M−H+)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Yield: 94.7 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (16.9 g, 49.9 mmol), racemic trans (3-amino-cyclopentyl)-carbamic acid tert-butyl ester (10.0 g, 49.9 mmol: Prepared according to J. Org. Chem. 2004, 69(13), 4538; Tetrahedron 1997, 53(9), 3347; WO94/17090 and Org. Lett. 2000, 2, 4169) and diisopropylethylamine (12.0 mL, 69.9 mmol) in propan-2-ol (175 mL) was heated at reflux for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue triturated (water) to give 23.7 g (94%) of racemic trans [3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT=4.25 min, m+H=502.3; 1H NMR (400 MHz, DMSO) δ: 8.89 (s, 1H), 8.87 (d, 1H), 8.12 (d, 2H), 7.83 (d, 1H), 7.76 (m, 1H), 7.65 (t, 2H), 7.17 (d, 1H), 7.06 (br d, 1H), 4.62 (m, 1H), 3.99 (m, 1H), 2.24 (m, 1H), 1.97 (m, 3H), 1.56 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCCOc1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were initially introduced into 25 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.63 ml (5.5 mmol) of butyl isocyanate was then added dropwise. The mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness, and the residue was crystallized from petroleum ether/diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)[CH3:2].[OH-].[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Nc2ccc(OCC)c(OCC)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(Nc2ncc(C(=O)O)c(=O)[nH]2)cc1OCC
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Ethyl 1,6-dihydro-2-(3,4-diethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (40 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(3,4-diethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3 g). M.p. 243°-245° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[CH:60][C:61]([CH3:74])=[C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=2)[CH:63]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:57][C:58]2[CH:59]=[CH:60][C:61]([CH3:74])=[C:62]([C:64]3[CH:69]=[CH:68][C:67]([C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=3)[CH:63]=2)=[O:8])=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccoc3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
3-Furoic acid (557 mg, 4.97 mmol), HATU (1.89 g, 4.97 mmol), HBTU (560 mg, 4.14 mmol), methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.0 g, 4.14 mmol) and DIPEA (2.17 ml, 12.43 mmol) were mixed in DMF (5 ml) and the reaction stirred at room temperature for 18 h. The DMF was evaporated under vacuum, the residue partitioned between DCM (50 ml) and aqueous sodium carbonate (1M, 50 ml) and the aqueous extracted with DCM (2×30 ml). The combined organics were washed with brine (75 ml), dried (magnesium sulphate) and concentrated under vacuum. The residue was purified on a silica flash column eluting with DCM/ethanol/ammonia (500:8:1), which after evaporation of the solvents under vacuum gave methyl 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylate (800 mg, 58%). LCMS: retention time 3.41 min, MH+336.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[Li]CCCC.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=O.O>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]=[CH:19][C:20]([CH3:24])([CH3:23])[CH3:21]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=CC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Methyl diethylphosphonoacetate (13.35 mL, 73.6 mmol, 1.05 eq.) was dissolved in THF (30 mL) and cooled to −78° C. in an acetone-dry ice bath. n-BuLi (1.6M in hexanes) (45.8 mL, 73.2 mmol, 1.05 eq.) was added slowly over 20 min. Trimethylacetaldehyde (6.0 g, 69.6 mmol, 1.0 eq.), was added to the reaction and allowed to stir at −78° C. for 20 minutes and warmed to room temperature and stirred overnight. Water (30 mL) was added to quench and extracted with ethyl ether (3×100 mL). The combined organics were washed with brine and dried over MgSO4, filtered and evaporated to provide 4,4-Dimethyl-pent-2-enoic acid methyl ester, a colorless liquid (8.52 g, 60.0 mmol, 86%) and was used directly in the next reaction. 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 3.64 (s, 3H), 5.64 (d, 1H, J=16.0 Hz), 6.88 (d, 1H, J=16.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]2=[N:13]O.[H][H].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.[Pt]=O>[NH2:13][CH:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[OH:12])[CH2:4][CH:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc(C)c2c(c1O)C(=NO)C(c1ccccc1)C2
Agent: O=[Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c2c(c1O)C(N)C(c1ccccc1)C2

Procedure:
3.00 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-inden-1-one oxime was dissolved in 55 ml of glacial acetic acid, and this solution was subjected to catalytic hydrogenation in the presence of 0.3 g of platinum oxide at room temperature under 4 atmospheric hydrogen gas pressure. The hydrogenation was terminated at the point when the stoichiometric amount of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate thus obtained was concentrated. The residue thus obtained was dissolved in water and the pH of this solution was adjusted to about pH 8 by adding an aqueous solution of sodium bicarbonate, then extracted with 200 ml of chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated under a reduced pressure. Recrystallized from ethanol to obtain 0.24 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-indene. Colorless needle-like crystals. Melting point: 135°-136° C.
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:3]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(O)(=O)C.[NH2:29][CH2:30][CH2:31][C@H:32]1[O:37]B(C2C=CC=CC=2)[O:35][C@@H:34]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:33]1>C(O)C>[C:12]1([C:11]2[N:29]([CH2:30][CH2:31][C@@H:32]([OH:37])[CH2:33][C@@H:34]([OH:35])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OB(c2ccccc2)O1
Reactant: O=C(NC(C(=O)c1ccccc1)c1ccncc1)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCn1c(-c2ccccc2)nc(-c2ccncc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-(2-oxo-2-phenyl-1-(pyridin-4-yl)ethyl)benzamide, 67 (1.6 g) and acetic acid (1.5 mL) in ethanol (50 mL) is added tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate (7.9 g). Upon heating under reflux for 16 h, the solution is cooled to room temperature and the solvent is evaporated. The residue is partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane, the layers separated and the organic phase washed with brine, dried (magnesium sulfate), filtered and concentrated. Purification of the residue via chromatography affords the title compound, 68 (0.35 g).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=1)[C:17]2=3)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]>S(=O)(=O)(O)O>[C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]=1[N+:1]([O-:4])=[O:2])[C:17]2=3)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1cc2c3c(cccc3c1)C(=O)OC2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1cc2c3c(cccc3c1[N+](=O)[O-])C(=O)OC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Powdered potassium nitrate (0.51 g, 5 mmol) was added to a stirred solution of 3-ethoxalylamino-1,8-naphthalenedicarboxylic anhydride (1.57 g, 5 mmol) in 15 ml of conc. sulfuric acid at 0° C. Stirring was continued for 2 h at the same temperature, then the reaction mixture was poured into 150 ml of ice-water. The separated yellow solid was isolated by filtration and washed with water, ethanol and ether. Trituration with a small amount of ethyl acetate afforded 1.38 g (77%) of the title compound. M.p. 221°-222° C.; 1H-NMR (CDCl3 +DMSO-d6): 1.43 (t,J ™7Hz, 3H, CH3), 4.37 (q,J =7Hz, 2H, CH2), 7.70-8.60 (m, 3H, ArH), 8.82 (s, 1H, H-2), 11.3 (broad s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12]OCN.C(Cl)CCl.C1C=C[C:23]2[N:28]([OH:29])N=NC=2C=1>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]([O:29][CH3:12])[CH3:23])=[O:7])=[CH:4][N:3]=1
Reactant: COCN
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCCl
Solvent: CC#N
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 304.9 %

Procedure:
To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in acetonitrile (400 mL), methoxymethylamine hydrochloride (13.79 g, 141 mmol), EDC (27.1 g, 141 mmol), HOBT (5.2 g, 38.58 mmol) and TEA (53.3 mL, 386 mmol) were added at RT. The reaction mixture was stirred at RT overnight. Solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (300 mL). The reaction mixture was washed with water and brine. The organic layer was dried, filtered and concentrated. Purification of the crude product provided 23.6 g (93%) of compound A as viscous colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][CH3:13])=[S:11])[CH2:5][CH2:4]1.[CH3:15]I.O.[ClH:18]>CO.[Cl-]>[CH3:1][N:2]([CH3:14])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[N:12][CH3:13])[S:11][CH3:15])[CH2:7][CH2:8]1.[ClH:18]
Reactant: CI
Reactant: CNC(=S)NC1CCC(N(C)C)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CN=C(N[C@H]1CC[C@H](N(C)C)CC1)SC
Temperature: 25 °C

Procedure:
A mixture of 0.50 g of 1-(4-dimethylaminocyclohexyl)-3-methyl-thiourea in 10 ml of MeOH, 1.16 ml of 2M HCl (in MeOH) and 0.36 g of methyliodide is stirred at RT. From the mixture obtained solvent is evaporated and the evaporation residue obtained is treated with H2O. 10 ml of a strong basic ion exchanger in chloride form (Amberlite IRA 400 (Cl)R) are added to the aqueous mixture obtained and the mixture obtained is stirred at RT. A precipitate obtained is filtrated off and the filtrate obtained is lyophilized. 1-(trans-4-Dimethylamino-cyclohexyl)-2,3-dimethyl-isothiourea in the form of a hydrochloride is obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1>C(Cl)Cl>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.2 g, 0.66 mmol), N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate (0.28 g. 0.99 mmol) was heated at 100° C. in a sealed reactivial for 20 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (30 mL), the organic extract was washed water (20 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:9 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.08 g).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.[CH3:35][N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[CH2:41][CH2:42][NH2:43]>O.CN(C=O)C.C(N(CC)CC)C>[CH3:35][N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[CH2:41][CH2:42][NH:43][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=1[CH3:20])=[O:23]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CN1CCCC1CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCC1CCCN1C
Temperature: 0 °C
Yield: 50.2 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were sequentially added to DMF (500 mL) with stirring at about 0° C., and stirred for 1.5 hrs, then (1-methylpyrrolidin-2-yl)ethylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 139.1 g (502 mmol) of N-[(1-methylpyrrolidin-2-yl)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 50.2%, m.p. 143-149° C.