Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH2:15].C(OCC)(=O)C.O>O1CCCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:15][CH3:14])=[O:8]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 5-chloroisatoic anhydride (10.0 g, 51 mmol) in tetrahydrofuran (100 ml) at ambient temperature was added a 40% w/w aqueous solution of methylamine (19.80 g, 255 mmol) dropwise. The mixture was stirred at an ambient temperature for 1 hour. Ethyl acetate (100 ml) and water (100 ml) were added and the phases separated. The aqueous layer was back extracted with ethyl acetate (100 ml) and the combined organics were evaporated under reduced pressure to afford a white solid, which was recrystallised from toluene (60 ml) to afford the title compound as a white solid (8.15 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:27]3[CH2:28][CH2:29][CH:24]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)=[O:17])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nn(-c2ccc(Cl)c(Cl)c2)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1nn(-c2ccc(Cl)c(Cl)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 87 %

Procedure:
In analogy to the procedure described in Example 181, 1-(3,4-Dichloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 87% yield as white foam. MS: 421.2 (MH+, 2 Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:15]([OH:17])=[O:16])=[C:12]([Cl:18])[N:11]=[C:10]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[H][H].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:15]([OH:17])=[O:16])=[C:12]([Cl:18])[N:11]=[C:10]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1
Yield: 76.1 %

Procedure:
In 100 ml of ethanol was dissolved 2 g of 1-(p-nitrobenzyl)-2-phenyl-4-chloroimidazole-5-acetic acid, and following addition of 300 mg of 10% palladium-on-carbon, the solution was shaken in hydrogen streams for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure and recrystallized from ethanol-hexane. By the above procedure was obtained 1.4 g of 1-(p-aminobenzyl)-2-phenyl-4-chloroimidazole-5-acetic acid as colorless needles, m.p. 141°-145° C. (decomp.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.[C:15]([OH:20])(=O)[C:16](O)=[O:17]>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[C:16](=[O:17])[C:15](=[O:20])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Yield: 23 %

Procedure:
A suspension of 4-chloro-1-methylamino-2-nitrobenzene (1.73 g, 9.3 mmol) in 50 ml of ethanol was hydrogenated at room temperature and 2 atm. pressure in the presence of 5% palladium-on-carbon (0.5 g) until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and 50 ml of IN hydrochloric acid was added to the filtrate. The acidic filtrate was evaporated to dryness and the solid residue was refluxed with oxalic acid dihydrate (1.4 g, 11 mmol) in 100 ml of 4M hydrochloric acid for 90 min. The mixture was cooled and the precipitated product was collected by filtration and washed with water, ethanol and ether to give 0.45 g (23%) of the title compound. M.p. 341.5° C. (N,N-dimethylformamide); IR (KBr): 1700, 1660 cm-1, 1H-NMR (DMSO-d6 : 3.43 (s, 3H, CH3), 6.97-7.40 (m, 3H, ArH), 12.0 (broad s, 1H, NH); MS m/z: 212 (M+ +2, 50%), 210 (M+, 100%).
Reaction SMILES: C(O[C:4](=[O:26])[CH2:5][O:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)C[CH2:9][CH2:8]1)C.[NH3:27]>>[C:20]1([S:17]([C:13]2[CH:14]=[C:15]3[C:16](=[CH:11][CH:12]=2)[CH:7]([O:6][CH2:5][C:4]([NH2:27])=[O:26])[CH2:8][CH2:9]3)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N
Reactant: CCOC(=O)COC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Product: NC(=O)COC1CCc2cc(S(=O)(=O)c3ccccc3)ccc21

Procedure:
2-(5-Benzenesulfonyl-indan-1-yloxy)-acetamide was prepared from (6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-acetic acid ethyl ester using the procedure of step 3 of Example 1, but replacing the methylamine hydrochloride with ammonia. MS: 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]=3[O:20][CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(OC)c3OC)CC2)ccc1Cl
Yield: 14 %

Procedure:
The title compound (6 mg, 14%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2,3-dimethoxy-benzoic acid. MS: 433.5 (MH+).
Reaction SMILES: P(=O)(O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15](OCC)OCC)=[CH:9][CH:8]=1>ClC1C=CC=CC=1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:13][CH:14]=[CH:15][C:11]=2[CH:12]=1
Reactant: CCOC(CSc1ccc(Br)cc1)OCC
Agent: O=P(O)(O)O
Solvent: Clc1ccccc1
Product: Brc1ccc2sccc2c1
Temperature: 130 °C

Procedure:
5-Bromobenzo[b]thiophene (Chemical Abstracts number 4923-87-9) was prepared as described in Banfield et al.; J. Chem. Soc.; 1956; 2603-2607, and in Seed, Alexander J.; et al. J. Mater. Chem.; vol10; 2000; 2069-2080. A mixture of phosphoric acid (218 g) and chlorobenzene (2 L) was heated at 130° C. and then treated with the product from Example 165A (107.0 g) over 2 hours using a syringe pump. The mixture was heated at 130° C. for 15 hours. Dean-Stark trap was used at the beginning of the reflux to remove water from the mixture. The mixture was allowed to cool to room temperature and quenched with 400 mL of water. The bottom aqueous layer was extracted with 200 mL of methylene chloride. The combined organic layer was washed with 200 mL of 10% Na2CO3, and concentrated to brown oil (129.4 g). The crude oil was dissolved in 1 L of 10:90 EtOAC:hexane, filtered through a short pad of silica gel and concentrated to a yellow oil (85.54 g, 95.8% yield). Further purification was done by column chromatography (silica gel, 5:95 EtOAc:hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH:14]=O.CCN(CC)CC.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][NH:26][CH:23]1[CH2:25][CH2:24]1
Reactant: CC(=O)NCCc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of N-[2-(4-chloro-3-formyl-phenyl)-ethyl]-acetamide (50.1 mg, 0.222 mmol), Et3N (0.046 mL, 0.332 mmol) and cyclopropylamine (0.023 mL, 0.332 mmol) in MeOH (0.50 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (21.0 mg, 0.554 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC(CH2Cl2/MeOH 95:5) yielded the title compound (35 mg, 59%). LC-MS: tR=0.59 min; ES+: 267.17.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:24][CH2:18][C:19]2[O:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: NCc1ccco1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(NCc3ccco3)c2c1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 mL of furfurylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.05 g of the title compound is obtained, m.p.: 235° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5](N(OC)C)=[O:6].CON(C)C(=O)C1C=CN=CC=1.ClC1C(C2C=CC=CC=2)=C(Cl)C2C(=CC=C(C([C:52]3[N:56]([CH3:57])[CH:55]=[N:54][CH:53]=3)(C3C=CN=CC=3)O)C=2)N=1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:55]2[N:56]([CH3:57])[CH:52]=[CH:53][N:54]=2)=[O:6])[CH:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1ccnc(F)c1
Reactant: Cn1cncc1C(O)(c1ccncc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: CON(C)C(=O)c1ccncc1
Product: Cn1ccnc1C(=O)c1ccnc(F)c1

Procedure:
The title compound was prepared using 2-fluoro-N-methoxy-N-methylisonicotinamide (Intermediate 28: step a) in place of N-methoxy-N-methylisonicotinamide (Intermediate 25: step a) according to the procedure described in Intermediate 25: step b.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1)([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1
Reactant: CCOC(=O)c1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2nnc(-c3ccccc3N)o2)cc1
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
A mixture of ethyl 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzoate (2.00 g), 5%.palladium on carbon (0.4 g) and tetrahydrofuran (50 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1, volume ratio) to give ethyl 4-[5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.23 g, yield 62%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 174–175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[O:17]=[C:18]1[N:23]([CH2:24][CH2:25][CH2:26][CH:27]=O)[CH2:22][CH2:21][CH2:20][O:19]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:22][CH2:21][CH2:20][O:19][C:18]3=[O:17])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=CCCCN1CCCOC1=O
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCCCN1CCCOC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca. 13 mg 50 umole), was added 440 μL solution of 4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde (0.125 M in 1,2 dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 M slurry of sodium triacetoxyborohydride in 1,2 dichloroethane. The reaction was shaken at room temperature for 48 h. After quenching with 2 mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL water and ethyl acetate to workup flasks. The organic phase was washed, dried and concentrated. Purification by chromatography yielded 3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one 19, MS: 375 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>N1C=CC=CC=1.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[CH:17][N:16]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(Cc2cnc(NCCCN)[nH]c2=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCNc3ccc(C#N)cn3)[nH]c2=O)cn1

Procedure:
2-Chloro-5-cyanopyridine (0.61 g), 2-(3-aminopropylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.09) and potassium carbonate (0.61 g) were heated together under reflux in pyridine (10 ml) for 2.5 hr. The mixture was stripped, the residue taken up in water and the pH adjusted to 3 with hydrochloric acid. After extracting with chloroform the aqueous solution was filtered and the pH raised to 6.5 with sodium hydroxide. The precipitate thus obtained was chromatographed (silica gel, chloroform/methanol, graded 1:0 to 20:1) and the required component recrystallised twice from ethanol to give 2-[3-(5-cyanopyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone 0.2 H2O, (0.38 g; 25%) m.p. 175°-177° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>N1C=CC=CC=1>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Nc1nccs1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1)C(F)(F)F
Yield: 50.3 %

Procedure:
Prepared using general procedure 15, method A. A solution of 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride (3 g, 8.43 mmol) and 2-aminothiazole (0.84 g, 8.43 mmol) in pyridine (2 ml) was stirred overnight at RT. The reaction was quenched with water, extracted with DCM, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography using 0-5% methanol in DCM gave N-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide (1.78 g, 50% yield). LC/MS: (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z M+1 obs=420.3; tR=1.41 min.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])(=O)=O>>[CH3:22][C:21](=[CH:20][CH2:19][CH2:18][CH:17]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:24])[CH3:23]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(C)=CCCC(C)OS(C)(=O)=O
Product: CC(C)=CCCC(C)n1ccc2c(C=O)cccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 1.02 g of indole-4-carbaldehyde and (2-methyl-2-hepten-6-yl) methanesulfonate instead of the benzyl bromide used in Example 1 to give 1.36 g of 1-(2-methyl-2-hepten-6-yl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 76%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][CH2:28][N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CN(CCN)S(C)(=O)=O
Solvent: CN(C)C=O
Product: CN(CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O)S(C)(=O)=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(2-aminoethyl)-N-methylmethanesulfonamide employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.93 (1H, br s), 10.91 (1H, br s), 9.99 (1H, br s), 8.10 (1H, br s), 7.35-7.25 (3H, m), 7.18-7.08 (2H, m), 3.98 (2H, br s), 3.46 (2H, br s), 3.21 (2H, br s), 2.85 (3H, s), 2.81 (3H, s); HRMS calcd for C20H21FN4O5S+H+: 449.1295. Found 449.1292.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCCCCCCOc1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of phenol (0.58 g) and 1,7-dibromoheptane (4.76 g) in dimethylformamide (5 ml) was added potassium carbonate (4.3 g) and the mixture was heated at 80° C. for 6 h. The mixture was cooled and the solvent was removed under reduced pressure. Toluene (10 ml) was added and removed under reduced pressure. The residue was chromatographed on silica gel using hexane as eluent. This gave 1-bromo-7-phenoxyheptane (1.15 g). 1H-NMR (CDCl3) δ 1.3-1.7 (6H, m), 1.7-2.1 (4H, m), 3.41 (2H, t), 3.95 (2H, t), 6.8-7.0 (3H, m) and 7.2-7.4 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.CC[O-].[Na+].[I-].[Na+].[CH3:19][N:20]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+].[Cl-]>C(O)C>[CH3:19][N:20]([C:27]([CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: CN(C(=O)CCCCl)c1ccccc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCO
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)c1ccccc1

Procedure:
1.6 Grams of 6-hydroxycarbostyril, 0.7 g of sodium ethylate, 1.6 g of sodium iodide and 2.4 g of N-methyl-N-(4-chlorobutyryl)aniline are added to 30 ml of ethanol and refluxed under agitation for 6 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from chloroform-petroleum ether to obtain 1.3 g of 6-[3-(N-methylanilinocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 187°-189° C.
Reaction SMILES: [ClH:1].Cl.[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH2:8][C@@H:7]1[CH3:20])([CH3:5])[CH3:4].[C:21]([C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C(Cl)Cl.C(OCC)C>[ClH:1].[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:15][CH2:16][N:17]([C:26]3[CH:25]=[N:24][C:23]([C:21]#[N:22])=[CH:28][CH:27]=3)[CH2:18][CH2:19]2)=[O:13])[CH2:8][C@@H:7]1[CH3:20])([CH3:5])[CH3:4]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(C)N1CCN(C(=O)C2CCNCC2)C[C@@H]1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C#N)nc3)CC2)C[C@@H]1C
Yield: 12.5 %

Procedure:
(S)-1-Isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride (D29) (0.2 g), 2-cyano-5-bromopyridine (0.14 g) and potassium carbonate (0.22 g) were stirred in DMSO (4 ml) at 120° C. for 2 h. After cooling, the potassium carbonate was filtered off and the DMSO filtrate was diluted with MeOH (20 ml). The crude mixture was poured onto a 10 g isolute SCX column which was washed first with MeOH (50 ml) and then eluted with 10% ammonia in MeOH (50 ml). The product was further purified by column chromatography (silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base which was dissolved in DCM (10 ml) and treated with 1N HCl in diethyl ether to give the title compound (E78) as a light yellow solid (30 mg). LCMS electrospray (+ve) 356.(MH+). 1H NMR [DMSO-d6]δ: 1.09 (3H, d, J=6.4 Hz), 1.33-1.35 (6H, d, J=6.5 Hz), 1.54-1.74 (4H, m), 2.98-3.16 (5H, m), 3.23-3.68 (3H, m), 3.83-4.45 (5H, m), 7.37 (1H, dd, J=8.8 Hz), 7.72 (1H, d, J=8.8 Hz), 8.4(1H, d, J=2.8 Hz), 10.9 (1H, bs)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([CH2:14][CH2:15][N:16]1[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]1=[O:28])[CH2:12]2)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([CH2:14][CH2:15][N:16]1[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]1=[O:28])[CH2:12]2
Reactant: CC(C)(C)OC(=O)NC1C2CN(CCN3C(=O)COc4ccc(C#N)cc43)CC21
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: N#Cc1ccc2c(c1)N(CCN1CC3C(N)C3C1)C(=O)CO2

Procedure:
tert-Butyl{3-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamate (Intermediate 94) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][C:10](=[O:42])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:46]I>CN(C)C=O>[C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][N:9]([C:10](=[O:42])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:16]=1)[CH3:46])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 0.42 h
Yield: 7.9 %

Procedure:
A solution of (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid tert-butyl ester (0.0910 g, 0.153 mmol) in dimethylformamide (1.0 mL) at 0° C. was treated with NaH (1 small spatula tip). After 25 min., MeI (0.0240 mL, 0.385 mmol) is added and the reaction is stirred for 1 h. The reaction mixture is quenched with saturated NH4Cl (aq) (2 μL) and extracted with EtOAc (3×10 mL). Combined extracts are washed with brine (1×), dried over MgSO4, filtered, and conc. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 10% EtOAc to 60% EtOAc giving (±)-3-({4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoyl}-methyl-amino)-propionic acid tert-butyl ester (7.4 mg, 8%) as a clear syrup. MS (ES): 554.0 [M+H-(t-Bu)]+.