Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[N:16]=[CH:15][N:14]([CH3:18])[C:13]=3[C:12](=[O:19])[N:11]3[CH2:20][CH2:21][N:22]=[C:10]23)=[CH:4][CH:3]=1.[I:23][CH3:24]>CC(C)=O>[I-:23].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[N:16]=[CH:15][NH+:14]([CH3:18])[C:13]=3[C:12](=[O:19])[N:11]3[CH2:20][CH2:21][N:22]([CH3:24])[CH:10]23)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cn1cnc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: CN1CCN2C(=O)C3=C(N=C[NH+]3C)N(Cc3ccc(Cl)cc3)C12
Product: [I-]
Reaction time: 24 h
Yield: 47.9 %

Procedure:
A suspension of the product of Procedure 67 (1.6 g., 0.005 mole) in acetone (25 ml.) was refluxed overnight with iodomethane (0.7 g., 0.005 mole). Additional iodomethane (0.35 g., 0.0025 mole) was added, and refluxing was continued for 24 hr. The insolubles were collected to give 1.6 g. Recrystallization from MeOH gave analytically pure product 1.1 g., m.p. 188.5°-189.5°.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27].[I-].[K+]>>[C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[O:14][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(=O)c1cc(C(C)=O)c(OCCCCC#N)cc1O
Yield: 24.2 %

Procedure:
A mixture of 582 mg of 4,6-diacetylresorcinol, 460 mg of potassium carbonate, 530 mg of 5-bromopentanenitrile and 0.2 9 of potassium iodide was heated at reflux overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with 40% ethyl acetate in hexane to provide 200 mg of the desired title product, m.p.=105°-106° C.
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=[C:15]1CC(=O)CN(C(OCC2C=CC=CC=2)=O)[CH2:16]1.[CH3:32][N:33]1[CH2:45][C:44]2NC3C=CC=C4C(=O)[NH:47][N:48]=[C:35]([C:36]=2C=34)[CH2:34]1>>[F:13][C:9]1[CH:8]=[C:3]2[C:4](=[O:6])[NH:47][N:48]=[C:35]3[C:36]4[C:2]2=[C:11]([NH:12][C:44]=4[CH2:45][N:33]([CH2:32][CH2:15][CH3:16])[CH2:34]3)[CH:10]=1
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Reactant: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CCCN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 57 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.36 (dd, 1H, J=1.8, 9.0 Hz), 7.19 (dd, 1H, J=1.8, 10.2 Hz), 3.80 (s, 2H), 3.30 (s, 2H), 2.50-2.54 (m, 2H), 1.50-1.54 (m, 2H), and 0.89 (t, 3H, J=7.8 Hz). MS (ESI) m/e [M+1]+ 287.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](Cl)(Cl)Cl)[N:8]=1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:13]([C:9]2[N:8]=[C:7]([Cl:6])[CH:12]=[CH:11][CH:10]=2)=[O:2])=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)c1cccc(Cl)n1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
[A1 is N, A2 is Cl—C, A3, A4 and A5 are CH, R1 is 4-fluorophenyl, X is NR2 and R2 is H in the compound of formula I] Concentrated sulfuric acid (98% by weight, 98.1 g, 1 mol) is added to 2-chloro-6-trichloromethylpyridin (NP, 231 g, 1 mol) over a period of 4 hours. 50% of the sulfuric acid is added at 120° C., 38% at 125° C. and 12% at 130° C. The resulting mixture is stirred for 40 minutes at 130° C. A viscous melted mass is obtained consisting of >90% of a mixture of intermediate IVa1 and Va1 with R1 being H and Hal being Cl. This mass is added to a mixture of 4-fluoroaniline (122.0 g 1.1 mol), triethylamine (202.0 g, 2 mol) and toluene (752 g) at temperatures between 20 and 100° C. within 45 minutes. The resulting reaction mixture is heated to temperatures between 80 and 120° C. and stirred for one hour. The mixture is treated with 500 ml of hydrochloric acid (7.5% by weight) at 80° C. and the phases are separated. The resulting solution of N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarboxamide in toluene is used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6-ylinecarboxamide without further purification.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]2[NH:12][N:1]=[N:13][C:8]=2[CH:7]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of sodium nitrite (284 mg, 4.12 mmol) in water (1 mL) was added to a solution of 4-fluoro-benzene-1,2-diamine (520 mg, 4.12 mmol) in acetic acid (0.50 mL) and water (2.50 mL) at 0° C. The reaction mixture was stirred for few minutes at 50° C. and 1 hour at 0° C. The precipitate was filtered, washed with cold water and dried to yield 5-fluoro-1H-benzo[d][1,2,3]triazole (565 mg, 3.50 mmol, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:37][C@@H:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:25]5[CH2:24]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:37][C@@H:26]5[CH2:27][NH:28][CH2:29][C@@H:25]5[CH2:24]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@H]2CNC[C@H]2C1
Yield: 197.7 %

Procedure:
1,1-Dimethylethyl (3aR,6aS)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclo-penta[c]pyrrole-2(1H)-carboxylate (0.23 g, 0.42 mmol) was taken up in methanol (10 mL) and treated with 4.0M hydrogen chloride in dioxane (excess) and heated briefly to reflux. Concentration in vacuo provided N-(3,4-dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 100%). MS (EI) for C22H22Cl2N4O2: 445 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]([CH3:20])[C:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH3:20])[CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)[OH:11])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(C(=O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
A solution of ethyl 1-[2-(dibenzylamino)propanoyl]cyclopropanecarboxylate (1.31 g) in methanol (60 mL) was cooled to 0° C., 90% sodium borohydride (350 mg) was added, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give the title compound as a colorless oil (yield: 1.31 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=1)=[O:18]
Reactant: COc1ccccc1OC
Reactant: O=C(O)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C(=O)CCCCCBr)cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.1 %

Procedure:
A mixture of 1.0 mL (7.8 mmol) of 1,2-dimethoxybenzene and 2.0 g (10 mmol) of 6-bromohexanoic acid was warmed briefly until homogeneous and stirred while 1.7 mL (11.7 mmol) of trifluoroacetic anhydride was added. The reaction mixture was stirred at room temperature for 17 hours and then was poured into sodium bicarbonate solution. The product was extracted with ethyl acetate and the dried extract was concentrated to an oil which was purified by chromatography on 150 g of silica gel. Elution with 25% ethyl acetate-hexane gave 1.6 g (65% yield) of 1-(6-bromo-1-oxohexyl)-3,4-dimethoxybenzene. The nmr spectrum was consistent with the structure.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:34])[CH:20]([CH:21]=[C:22]([CH3:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]1[C:31](Cl)=[O:32].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][O:12][C:31]([CH:19]1[CH:20]([CH:21]=[C:22]([CH3:30])[C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[C:18]1([CH3:34])[CH3:17])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=CC1C(C(=O)Cl)C1(C)C)c1ccc(Cl)cc1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=CC1C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C1(C)C)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 74.8 %

Procedure:
5.4 g (0.025 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 7 g (0.025 mol) of 2,2-dimethyl-3-(2-methyl-2-(4-chlorophenyl)-vinyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25°-35° C. for a further 3 hours. The reaction mixture was poured into 150 ml of water, to which 5 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.7 g (74.9% of theory) of 2,2-dimethyl-3-(2-methyl-2-(4-chlorophenyl)-vinyl)-cyclopropane-carboxylic acid 3-phenoxy-4-fluoro-benzyl ester were obtained as a yellow viscous oil with the refractive index nD23 : 1.5735.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:1]([O:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:13])[CH3:14])[NH:11][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
According to EP 1714963 4-Bromomethyl-2′-cyanobiphenyl is condensed with L-valinebenzylester tosylate to give (S)-N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester hydrochloride. (S)-N-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester on reaction with valerylchloride yields (S)-N-cyanobiphenyl-4-yl]methyl]-N-valeryl-(L)-valine benzylester further by the reaction of tributyltin chloride and sodiumazide gives benzyl valsartan and debenzylation with Pd/C to give valsartan. Also discloses the process for the recovery of benzyl valsartan substantially free of organo tin impurity.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][CH:13]([F:32])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:22]=[C:21]([S:23][C:24]3[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=3)[NH:20][C:19]=2[CH:31]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:29]([C:27]3[O:28][C:24]([S:23][C:21]4[NH:22][C:18]5[CH:17]=[CH:16][C:15]([O:14][CH:13]([F:12])[F:32])=[CH:31][C:19]=5[N:20]=4)=[CH:25][CH:26]=3)[C:34]3[C:35](=[O:39])[CH2:36][CH2:37][CH2:38][C:33]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1ccc(Sc2nc3ccc(OC(F)F)cc3[nH]2)o1
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(OC(F)F)ccc3[nH]2)o1
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.248 g, 1.61 mmol), 5-(6-difluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.5 g, 1.61 mmol) and 1,3-cyclohexanedione (0.181 g 1.61 mmol) in 5 ml of ethanol is heated at reflux temperature for 2 hours. The reaction mixture is then concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate. The organic phase is washed twice with 2 ml of water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of dichloromethane and methanol (99/1, v/v). The fractions containing the expected products are pooled and concentrated under reduced pressure. The residue is resuspended in 20 ml of acetonitrile, the mixture is heated at reflux temperature for 15 minutes and then let to cool to room temperature. The insoluble material is collected by filtration and dried under vacuum for 1 hour at 30° C. to yield 203 mg of 9-[5-(5-difluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a white powder. Yield=23%. Analytical LC/MS method B: m/z=541 (positive ion mode [M+H]+), m/z=539 (negative ion mode [M−H]−)
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6](C)[CH:7]=1.[CH3:13][C:14]([CH3:16])=[O:15].N1CCC[CH2:18]1.O>C1C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:18])=[CH:6][C:5]2[O:15][C:14]([CH3:16])([CH3:13])[CH2:10][C:9](=[O:11])[C:4]=2[CH:3]=1
Reactant: C1CCNC1
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Reactant: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product of step b (48 g), acetone (31 ml) and pyrrolidine (21 ml) in dry benzene (500 ml) is stirred at room temperature for 3 h and then at reflux for 6 h with water formed being removed via a Dean-Stark apparatus. The cooled mixture is treated with HCl (200 ml, 2M), stirred for 10 min, basified with aqueous NaOH (1M) and extracted with CH2Cl2 (3×300 ml). The combined extracts are dried (K2CO3), filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 50% toluene in hexane) and recrystallized from diethyl ether-pentane to give the title compound, m.p. 95°-96° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(S(C1C2C(=CC=CC=2)NC=1)(=O)=O)C.[Cl:30][C:31]1[CH:48]=[CH:47][C:34]2[N:35]([CH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:36]([CH2:38]Cl)=[N:37][C:33]=2[CH:32]=1>>[Cl:30][C:31]1[CH:48]=[CH:47][C:34]2[N:35]([CH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([CH2:38][N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:8]3)=[N:37][C:33]=2[CH:32]=1
Reactant: O=S(=O)(c1c[nH]c2ccccc12)C1CC1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Agent: CCS(=O)(=O)c1c[nH]c2ccccc12
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(=O)(=O)C3CC3)c3ccccc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 3-(cyclopropylsulfonyl)-1H-indole (prepared in an analogy to 3-ethanesulfonyl-1H-indole) and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-ethylamine, (0.055 g, 0.21 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.046 g, 0.30 mmol) and DIPEA (0.07 mL, 0.38 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give 418 as a white solid (0.060 g, 75%). LCMS (Method K): RT 2.94 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.12 (1H, s), 7.96 (1H, s), 7.70-7.60 (3H, m), 7.25 (2H, s), 7.09 (1H, m), 6.96 (1H, m), 5.46 (1H, m), 3.88 (3H, s), 1.51 (3H, d, J=6.85 Hz)
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:26][C:27]([CH2:35][CH3:36])([CH2:33][CH3:34])[C:28]([O:30]CC)=[O:29])[C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.[OH-].[Na+].Cl.C(Cl)Cl.CO>C(O)C>[CH2:33]([C:27]([CH2:26][N:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:4][N:3]=[N:2][N:1]=2)=[CH:17][CH:16]=1)[C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])([CH2:35][CH3:36])[C:28]([OH:30])=[O:29])[CH3:34]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)CC(CC)(CC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)CC(CC)(CC)C(=O)O
Temperature: 25 °C

Procedure:
1.146 g of ethyl N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-2-aminomethyl-2-ethylbutyrate are dissolved in 10 ml of ethanol, treated with 4.66 ml of 2N NaOH solution and heated to reflux for 20 hours. After cooling to room temperature and addition of 4.66 ml of 2N hydrochloric acid, the mixture is evaporated. The product is isolated by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 --MeOH 80:20, Rf =0.38 (system N8). MS (FAB): m /e 486 (M+ +Na), 502 (M+ +K).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[NH2:24]>>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:28][CH:27]=1)(=[O:25])[NH2:24]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(N)=O)cc3)c(F)cn2c1=O
Yield: 85.9 %

Procedure:
Ethyl 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and (4-carbamoyl-phenyl)-boronic acid (305.7 mg, 1.85 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (540 mg, 85%). ESI-MS m/z: 409 (M+H)+, 453 (M+HCOO)−.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:11](=[O:13])[N:10](COCC[Si](C)(C)C)[N:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:22]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26]([CH3:37])([CH3:36])[O:27]3)[CH2:3][CH2:2]1.[Cl:38]C1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1>>[ClH:38].[CH:1]1([C:4]2[C:12]3[C:11](=[O:13])[NH:10][N:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:22]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26]([CH3:37])([CH3:36])[O:27]3)[CH2:2][CH2:3]1
Reactant: CC1(C)C=Cc2c(-c3[nH]c4cnn(COCC[Si](C)(C)C)c(=O)c4c3C3CC3)ccc(OC(F)F)c2O1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Product: CC1(C)C=Cc2c(-c3[nH]c4cn[nH]c(=O)c4c3C3CC3)ccc(OC(F)F)c2O1
Product: Cl

Procedure:
Reaction was carried out in the same manner as in Example 6-(c) except for using 900 mg (1.70 mmol) of 3-cyclopropyl-2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 55-(b) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one. After completion of the reaction, the solid obtained from the reaction suspension by filtration was washed with 1,4-dioxane and dried under reduced pressure to obtain 739 mg of the title compound as a white solid substantially quantitatively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:29]([CH2:28][CH2:27][O:26][CH3:25])[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COCCC(=O)Cl
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Product: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(6-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C. The crude product obtained in Part D was recrystallized from acetonitrile. The crystals were washed with cold acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.CS(O[C@@H:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27])(=O)=O.CCN(C(C)C)C(C)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C@H:22]3[CH2:26][CH2:25][NH:24][C:23]3=[O:27])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CS(=O)(=O)O[C@@H]1CCNC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)C2CCN([C@H]3CCNC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To a suspension of (4-methoxyphenyl)(piperidin-4-yl)methanone (34 g, 155 mmol) and (R)-2-oxopyrrolidin-3-yl methanesulfonate (34.7 g, 194 mmol) in acetonitrile (388 mL) at room temperature was added DIPEA (108 mL, 620 mmol) and the reaction was heated to 60 C for 29 h then allowed to cool to room temperature and stirred for an additional 24 h. The reaction mixture was concentrated in vacuo to afford a waxy solid which was taken up in ethyl acetate (300 mL) and sonicated. The mixture was filtered and the resulting white solid was washed with ethyl acetate (200 mL) to yield 21.05 g. The combined filtrates were concentrated and purified via silica gel chromatography (330 g isco 0.01% NH4OH 5-10% MeOH/ethyl acetate). Pure fractions were combined, concentrated in vacuo and then taken up in ethyl acetate (80-100 mL) and stirred. A white precipitate formed that was collected by filtration. The filtrate was concentrated to a gold oil, taken up in ethyl acetate to afford a white precipitate that was collected by filtration. A total of 27.7 g of the title material was obtained as a white solid. Calculated MS=302.4. found MS (ESI) m/e 303.4 (M+H+)