Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1
Reactant: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1Cl
Yield: 62 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'-dichlorophenylacetamidine (5.5 g, 27 mmol) to afford 37% of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with POCl3 (14 g, 92 mmol) to afford 62% of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (1 g, 2.8 mmol) with hydrazine (0.27 g, 8.3 mmol) to afford 99% of ethyl 4-hydrazino-2-(3',4'-dichlorophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (0.9 g, 2.7 mmol) with citraconic anhydride (0.49 g, 4.4 mmol) in analogy to Example 21 to afford 47% (0.3 g) of the title compound; m.p. 119-121° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15]CC)=[O:14].[ClH:25].C1(C)C=CC=CC=1>C(O)(=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH2:12][C:13]([OH:15])=[O:14].[ClH:25]
Reactant: CCOC(=O)CC(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CC(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
The solution of ethyl 4-(2-benzimidazolyl)-3-(4-chlorophenyl)butanoate (200 mg) in a mixture of acetic acid (1 ml) and conc. HCl (0.25 ml) was heated at 100° C. for 1 h. Then toluene (30 ml) was added and all volatiles were removed by distillation. Distillation was repeated with further toluene (30 ml). The oily residue is treated with diethyl ether to induce crystallisation, triturated with acetone, and dried in vacuo to leave 4-(2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid•HCl (208 mg) as light red solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:37]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:26][N:36]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2cccc(C(F)(F)F)c2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.26 mmol) of the compound from Example 147A and 60 mg (0.39 mmol) of the compound from Example 73A were reacted according to the General Method 2. Yield: 75 mg (57% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18](C)C)[NH:5][S:6]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11](C)C)(=[O:8])=[O:7].N[C@H](C(OC)=O)C.Cl.S(N)(N)(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH3:18])[NH:5][S:6]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH3:11])(=[O:7])=[O:8]
Reactant: COC(=O)[C@@H](NS(=O)(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Agent: COC(=O)[C@H](C)N
Agent: Cl
Agent: NS(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](C)NS(=O)(=O)N[C@@H](C)C(=O)OC
Yield: 31 %

Procedure:
In a procedure similar to the preparation of sulfamide (8b), H-Ala-OMe.HCl (2.18 g, 15.56 mmol) was subjected to sulfamide formation conditions (SO2Cl2, Et3N, CH2Cl2 0° C., room temperature, 2 hours). Flash chromatography (SiO2, Hexanes/EtOAc) yielded 617 mg (31%) of sulfamide (8a) as a white solid. mp=91-92° C.; TLC Rf=0.40 in (2:1 Hexanes/EtOAc); [α]25D=−75.8 (c=1.003, CHCl3); 1H NMR (CDCl3, 400 MHZ) δ5.24 (d, J=8.0 Hz, 2H), 4.09 (dq, J=7.3.7.3 Hz, 2H), 3.75 (s, 6H), 1.43 (d, J=7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHZ) δ173.7,52.7,51.8,19.2; FTIR (neat) 3273, 1734, 1457, 1378, 1353, 1137 cm−1; HRMS (M+H)+ calculated for C8H17N2O6S 269.0807, found 269.0791.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a degassed solution of 4-nitro-2-fluorophenol (3) (16 g, 102 mmol) in MeOH (150 mL) was added palladium on charcoal (10%) Degussa type (3.0 g, 2.82 mmol). The mixture was stirred at r.t. under hydrogen atmosphere for 3 h, filtered through a celite pad and evaporated under reduced pressure. The residue was triturated with Et2O (50 mL) to afford compound 4 (11.264 g, 87% yield) as a dark-brown solid. MS (m/z): 128.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.57 (s, 1H), 6.62 (dd, J=10.0, 8.4 Hz, 1H), 6.34 (dd, J=13.4, 2.6 Hz, 1H), 6.20 (ddd, J=8.6, 2.6, 1.2 Hz, 1H), 4.67 (s, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:37])[CH3:36]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A174) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12]([N:20]=[C:21]=[S:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:20][C:21]([SH:22])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(S)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of 17 parts of (4-methoxyphenyl)hydrazine hydrochloride, 16.3 parts of benzoyl isothiocyanate, 10 parts of N,N-diethylethanamine and 130 parts of dichloromethane is stirred for 1 hour at room temperature. The mixture is washed with water and the solvent is evaporated. Then there are added 4.5 parts of sodium hydroxide solution 50% and 80 parts of ethanol to the residue and the whole is stirred and refluxed for 30 minutes. The mixture is neutralized with concentrated hydrochloric acid and diluted with water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 13 parts (46%) of 1-(4-methoxyphenyl)-5-phenyl-1H-1,2,4-triazole-3-thiol; mp. 260° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:29])[C@H:6]([C@H:15]1[CH2:19][O:18]C(C)(C)[N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[N+:2]=[N-:3].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCN(C(C)C)C(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CCO>[N:1]([CH2:4][C@H:5]([CH3:29])[C@@H:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10])[C@H:15]([NH:16][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:19][OH:18])=[N+:2]=[N-:3]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (R)-tert-butyl 4-((1R,2S)-3-azido-1-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.) in EtOH (0.1 M) was added PPTS (1.3 equiv.) and the mixture was refluxed for 2 days. The volatiles were removed under vacuo, the residue was dissolved in DCM (0.1 M) and DIEA (1.5 equiv.) and Boc2O (1.0 equiv.) were added to the reaction mixture. The solution was stirred for 3 hours at room temperature. The solvents were removed under reduced pressure and the residue was diluted with ethyl acetate, washed with water, aqueous NaHSO4, aqueous NaHCO3, sat. NaCl, the organic phase was dried with magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:3) to give tert-butyl (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-1-hydroxy-4-methylpentan-2-ylcarbamate as the major isomer (5:2) in 70% yield. LC/MS=289.3 (M+H-Boc), Rt=0.76 min (Frac 65%-95% method).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:24][CH3:25])=[N:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9])C>C(O)C.[OH-].[Na+]>[CH:19]1([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])=[O:9])[CH:18]=3)[C:14]([CH2:24][CH3:25])=[N:15]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)CCNC(=O)c1ccc2c(CC)nn(C3CCCC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)O)ccc12
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 330 mg (0.923 mmol, 1.0 equiv) 3-[(1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl)-amino]-propionic acid ethyl ester in 10 mL ethanol and 4 mL 1N NaOH was heated to reflux for 1 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with 75 mL H2O, acidified to pH 1, and extracted 3×35 mL ethyl acetate. The organic extracts were combined, washed 1×25 mL H2O, 1×25 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate on a rotary evaporator and drying at high vacuum, room temperature gave 297 mg (98%) of white solid: mp 151-153° C.; Anal. calcd for C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.75; H, 7.12; N, 12.91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([O:39]CC)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 52.2 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg), NaOH (80 mg), H2O (5 mL) and THF (2 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 100 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([F:34])[CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[N:27]1[N:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[C:15]([N:12]4[CH2:13][CH2:14][CH:9]([CH2:8][NH2:7])[CH2:10][CH2:11]4)[CH:16]=[C:17]([F:34])[CH:18]=3)[N:23]=2)[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
tert-Butyl(1-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yl)piperidin-4-yl)methylcarbamate (97 mg, 0.204 mmol) was weighed into a flask and dissolved in 10 mL of anhydrous DCM. TFA (314 μL, 4.07 mmol) was added and the reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo, followed by trituration with anhydrous Et2O, affording the desired product (43 mg, 0.114 mmol, 56.1% yield) as a yellow solid. APCI (+) m/z 377 (M+1) detected.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN1C(=O)CCC1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc2sc(Br)nc2c1
Solvent: CN1CCCC1=O
Product: COc1ccc2sc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq), 4-Bromoaniline (2 eq) and disopropylethylamine was subjected to microwave in NMP at 220° C. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product. MS: MH+=335
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=[C:13]([F:23])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:25]([C:28]1[N:33]=[C:32]([Cl:34])[N:31]=[C:30](Cl)[CH:29]=1)(=[O:27])[NH2:26].C(N(CC)C(C)C)(C)C.CCCC(C)C>O.C(O)CCC>[C:25]([C:28]1[N:33]=[C:32]([Cl:34])[N:31]=[C:30]([NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10](=[O:24])[C:11]3[CH:16]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH:14]=[C:13]([F:23])[CH:12]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])[CH:29]=1)(=[O:27])[NH2:26]
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1N
Solvent: O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1cc(C(N)=O)nc(Cl)n1
Yield: 12.1 %

Procedure:
A mixture of N-(3-amino-4-methylphenyl)-3-fluoro-5-morpholinobenzamide (0.33 g), 6-carbamoyl-2,4-dichloropyrimidine (0.212 g), N,N-di-isopropylethylamine (0.53 ml) and n-butanol (5 ml) was stirred and heated to reflux for 36 hours. Water and isohexane were added and the precipitated product was isolated and dried. There was thus obtained the title compound (0.059 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 3.23 (m, 4H), 3.72 (m, 4H), 6.97 (d, 1H), 7.12 (d, 1H), 7.29 (m, 2H), 7.6 (d, 1H), 7.74 (s, 1H), 7.81 (s, 1H), 7.92 (s, 1H), 9.9 (s, 1H), 10.21 (s, 1H); Mass Spectrum: M−H′ 483 & 485.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([OH:28])[C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[CH2:10][C:11](=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([OH:28])[C:7]3[CH2:8][CH:9]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[CH2:10][C:11](=[N:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Solvent: CCO
Product: CN(C)CCCN=C1CC(c2ccc(C(F)(F)F)cc2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Temperature: 25 °C

Procedure:
To 2.3 g of 7-chloro-3,4-dihydro-10-hydroxy-3-[4-(trifluoromethyl)phenyl]-1,9(2H,10H)-acridinedione in 55 ml of ethanol is added 0.70 g of N,N-dimethyl-1,3-propanediamine in 5 ml of ethanol. The solution is heated to reflux and then allowed to cool to room temperature. The solvent is removed in vacuo and the residue is recrystallized from a mixture of benzene and cyclohexane to give 7-chloro-1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro-10-hydroxy-3-[4-(trifluoromethyl)phenyl]9(2H)-acridinone; mp 130°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:38]2[CH2:39][CH2:40][N:35]([C:28]3[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=3)[CH2:36][CH2:37]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc([N+](=O)[O-])c1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Yield: 54.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dinitrophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>O1CCCC1>[F:1][CH:2]([F:13])[C:3]1[C:7]([C:8]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH2:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([CH3:14])[CH:16]=2)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1
Reactant: Cc1cccc(CC2CCCN2)c1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(CC2CCCN2C(=O)c2c(C(F)F)nn(C)c2F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
At ambient temperature, a solution of 267 mg (1.25 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 200 mg (1.14 mmol) of 2-(3-methylbenzyl)pyrrolidine and 127 mg (1.25 mmol) of triethylamine in 5 ml of tetra-hydrofurane. The reaction mixture is stirred for 1 hour at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×150 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and filtered over a Chemelut™ cardridge to yield after concentration 350 mg of a beige oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 300 mg (71% yield) of [3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazol-4-yl][2-(3-methylbenzyl)pyrrolidin-1-yl]-methanone as a colourless oil (M+H=352).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][NH:67][C:66](=[O:70])[CH:65]=1>ClCCCl>[O:70]=[C:66]1[CH:65]=[C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[CH:69]=[CH:68][NH:67]1
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cc[nH]c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.45 g, 0.78 mmol), was reacted with diisopropylethylamine (0.8 g, 6.2 mmol), diphenylphosphinic chloride (0.74 g, 3.1 mmol), then reacted with 4-aminopyridin-2(1H)-one (Molbridge) (0.086 g, 0.78 mmol) in 1,2-dichloroethane at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a off white solid (Yield 28 mg, 6%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31]Cl)[CH2:23][CH2:22]1)[CH3:13]>CN(C=O)C>[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH2:31][N:3]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]3=[O:10])[CH:33]=[CH:34][CH:35]=2)[CH2:23][CH2:22]1)[CH3:11]
Reactant: O=C1CCCC(=O)N1
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CCl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN3C(=O)CCCC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of NaH (0.224 g, 7.48 mmol) and DMF (10 mL) was treated slowly with 2,6-piperidinedione (0.846 g, 7.48 mmol) at room temperature. After the addition was complete, the mixture was cooled to 0° C. and a solution of 3-[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl chloride (2.46 g, 7.12 mmol) and DMF (10 mL) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature overnight. A small portion of water was added and the reaction was concentrated under vacuum. The residue was partitioned between CH2Cl2 /water and the organic layer was separated, dried, and evaporated to give 1-[[3-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione as an oil, 3.25 g. This material was dissolved in i-PrOH (13 mL) and treated with maleic acid (0.83 g, 7.15 mmol). Trituration with ether, filtration, and drying afforded 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione (Z)-2-butenedioate (1:1) as a white solid (2.73 g, 70%), m.p. 103°-105° C. 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[Br:17].C([O:22]O)(C)(C)C.O>C1COCC1>[OH:22][C:15]1[C:10]([F:9])=[C:11]([Br:17])[CH:12]=[CH:13][C:14]=1[F:16]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OO
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Oc1c(F)ccc(Br)c1F
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A quantity of 40.2 ml of 2.0 M lithium diisopropylamine (LDA) is dissolved in 80 ml of THF at −78° C. and 15.4 g of 2,4-difluorobromobenzene is added keeping the temperature below −65° C. The reaction is stirred at −65° C. for 2 hours and 6.6 ml of 6 M anhydrous t-butyl hydroperoxide is added. After warming to room temperature, 100 ml of water is added and the mixture acidified. The solvent is removed by evaporation and the aqueous layer extracted with ether. The extracts are dried and then concentrated to give the desired product.