Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC(O)=O.[F:6][C:7]([F:35])([F:34])[C:8]([N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][O:21]C(=O)C(F)(F)F)[C:14]=2[O:13][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11]1)=[O:9].O>CO>[F:35][C:7]([F:6])([F:34])[C:8]([N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][OH:21])[C:14]=2[O:13][C:12]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:11]1)=[O:9]
Reactant: O=C(OCc1cccc2c1OC(c1ccccc1)=CN2C(=O)C(F)(F)F)C(F)(F)F
Agent: NCC(=O)O
Solvent: O
Solvent: CO
Product: O=C(N1C=C(c2ccccc2)Oc2c(CO)cccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
Glycine buffer (pH 10, 6.33 ml) was added dropwise to a solution of (±)-4-trifluoroacetyl-8-trifluoroacetoxymethyl-2-phenyl-1,4-benzoxazine (953 mg, 2.20 mmol) in methanol (19 ml) at room temperature and the mixture was stirred for 30 min. To the mixture was added water (70 ml) and the mixture was stirred at room temperature for 20 min. and then extracted with ethyl acetate. The extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure to give (±)-4-trifluoroacetyl-2-phenyl-1,4-benzoxazine-8-methanol (793 mg, quantitative yield) as a pale orange oil.
Reaction SMILES: O=C1CNCCN1.[CH2:8]([N:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][C:17](=O)[CH:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][CH3:12])[CH3:9].[OH-].[Na+].C1(C2NCCN(CCN(CC)CC)C2)C=CC=CC=1>O.CCOCC.O1CCOCC1>[CH2:8]([N:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCN(CC)CCN1CCNC(=O)C1c1ccccc1
Agent: CCN(CC)CCN1CCNC(c2ccccc2)C1
Agent: O=C1CNCCN1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN(CC)CCN1CCNCC1c1ccccc1

Procedure:
89 g. of said keto piperazine dissolved in 200 cc. of dioxane are added drop by drop to a suspension of 20 g. of lithium aluminum hydride LiAlH4 in 800 cc. of ether. After addition of the keto piperazine, the reaction mixture is boiled under reflux for 6 hours. It is then decomposed by successively adding 20 cc. of 15% sodium hydroxide, 20 cc. of water, 60 cc. of 15% sodium hydroxide solution, and finally 40 cc. of water. The filtered solution is concentrated by evaporation and the residue is distilled in a vacuum. The resulting oil which distills at a temperature between 102° C. and 115° C./0.05 mm. Hg, is dissolved in benzene and is extracted therefrom by shaking in 10 % hydrochloric acid. The base is set free from its hydrochloride solution by the addition of 10 % sodium hydroxide solution and is repeatedly distilled in a vacuum. An almost colorless oil of the boiling point 114°-117° C./0.07 mm. Hg is obtained. The yield corresponds to the theoretical yield. The compound contains a small amount of 3-phenyl-1-(diethylamino ethyl) piperazine.
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].C([N:23]([CH2:26][CH3:27])CC)C>ClCCl>[O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:23][C:26]1[CH:27]=[CH:8][C:7]([CH3:15])=[CH:6][CH:2]=1)=[O:4]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(=O)c2c(-c3ccccc3)cc3ccccn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.3 %

Procedure:
To an ice-cold solution of oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (0.5 g, 1.76 mmol) and p-toludine (0.21 g, 1.94 mmol) in dichloromethane (10 ml) was added triethylamine (0.5 ml, 3.52 mmol). The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated under vacuum. Column chromatography on silica gel afforded 2-oxo-2-(2-phenyl-indolizin-3-yl)-N-p-tolyl-acetamide (0.4 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([C:27](O)=[O:28])[NH:25][CH:26]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([C:27]([NH:14][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:28])[NH:25][CH:26]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1-n1cncn1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1-n1cncn1

Procedure:
3-Methoxy-4-(1H-1,2,4-triazol-1-yl)benzenamine, prepared as described in Bioorg. Med. Chem. Lett, 13:2059 (2003), was converted to the title compound (45 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (30 mg) following the procedure described in step C of Example 1. MS (ESI) 394 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[C:17]([O:24][CH3:25])[CH:16]=1.N1C=CC=CC=1>O1CCCC1>[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]#[N:21])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: COc1cc(O)ccc1C(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(O)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
Trifluoroacetic anhydride (1.3 ml, 9.36 mmol) was added to a solution of 4-hydroxy-2-methoxybenzamide {Liebigs Ann Chem (1982)1836-1869} (600 mg, 3.6 mmol) and pyridine (0.72 ml, 9.36 mmol), in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and treated with 2M hydrochloric acid (100-ml). It was then extracted with ethyl acetate (2×100 ml). The organic layers were combined and washed with brine (100 ml), dried over magnesium sulphate, filtered and then evaporated under reduced pressure to give an orange solid. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (70:30 to 50:50, by volume) to provide the title compound (320 mg, 60%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][O:11][C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCCc1ccc(F)c(F)c1
Product: CN1c2cc(OCCc3ccc(F)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,4-difluorophenyl)ethanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])[CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:31][CH:21]1[CH2:22][CH:17]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9]2)[CH2:18][CH2:19][N:20]1[C:23]([O:25][CH2:26][C:27]([Cl:28])([Cl:30])[Cl:29])=[O:24]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(n2cc(-c3ccc(F)cc3)c3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(n2cc(-c3ccc(F)cc3)c3ccccc32)CC1Br
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl 4-[3-(4-fluorophenyl)-1H-indol-1-yl]piperidine-1-carboxylate 10b (4.0 g), N-bromosuccinimid (1.5 g) and tetrachloromethane (60 ml) was refluxed for 2 h. The reaction mixture was cooled to room temperature and the precipitate was filtered off. Evaporation of the solvent afforded the crude 2,2,2-trichloroethyl 2-bromo-4-[3-(4-fluorophenyl)-1H-indol-1-yl]piperidine-1-carboxylate (4.4 g) as an oil which was used without further purification. A mixture of the crude 2-bromo-indole (4.4 g), zinc powder (4.4 g) and 90% acetic acid in water (150 ml) was heated at 40° C. for 30 min. The reaction mixture was filtered and the solvent evaporated in vacuo. To the remaining oil was added ethyl acetate (50 ml) and the thus obtained solution was washed successively with water, 4N aqueous NaOH and brine. Evaporation of the solvents afforded the title compound as an oil (2.9 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17].C(N(CC)C(C)C)(C)C>ClC(Cl)C>[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])[CH:7]=1
Reactant: COC(=O)Cc1cccc(CN)c1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CCCS(=O)(=O)NCc1cccc(CC(=O)OC)c1

Procedure:
Following the procedure described in Preparation 8, (3-aminomethyl-phenyl)-acetic acid methyl ester hydrochloride (603 mg, 2.80 mmol) was converted to the title sulfonamide by reaction with 1-propanesulfonyl chloride (0.375 mL) and N,N-diisopropylethylamine (2.0 mL) in dichloroethane (10 mL). 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 4H), 4.60 (bs, 1H), 4.29 (s, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 2.92 (t, 2H), 1.79 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:15][C:16]1[C:21]([C:22]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[N:6]=[CH:5][N:4]=[C:3]3[N:2]([CH3:14])[CH3:1])=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=1
Reactant: CN(C)c1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 19 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4,N4-dimethylquinazoline-4,8-diamine (Intermediate-54, 100 mg, 0.53 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 184 mg, 0.64 mmol), oxalyl chloride (203 mg, 1.6 mmol), DMF (1 drop) and DIPEA (344 mg, 2.67 mmol) in CH2Cl2 (2 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ10.43 (s, 1H), 8.70-8.68 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 8.14-8.11 (t, J=5.6 Hz, 1H), 7.95-7.93 (d, J=8.4 Hz, 1H), 7.51-7.47 (t, J=8.0 Hz, 1H), 7.41-7.39 (d, J=8.4 Hz, 1H), 7.36-7.32 (t, J=8.0 Hz, 1H), 4.31-4.29 (d, J=5.6 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 1.13 (s, 9H); MS (m/z): 458.22 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.CN1CCN(C)[C:16]1=[O:21].C[O-].[Na+]>CO>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[O:21][CH3:16]
Reactant: CN1CCN(C)C1=O
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc2c(O)cccc12
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-8-hydroxy-2-methylquinoline (9 g), 1,3-dimethyl-2-imidazolidinone (100 ml) and 28% solution of sodium methoxide in methanol (135 ml) was stirred at 150° C. for 4 hours. The reaction mixture was cooled to ambient temperature followed by partition into ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crystalline residue was washed with n-hexane to give 8-hydroxy-4-methoxy-2-methylquinoline (5.57 g).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([OH:11])[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[CH:1]1([CH2:7][C@H:8]2[CH2:9][O:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC[C@@H](O)CC1CCCCC1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C1CCC(C[C@H]2CO2)CC1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of (S)-3-cyclohexyl-1,2-propanediol in CH2Cl2 was added triethylamine (6.6 mL), 2,4,6-triisopropylbenzenesulfonyl chloride (11.5 g), and DMAP (0.386 g). After 14 h, the reaction was diluted with ether, chilled to 0° C., filtered through celite and concentrated. The residue was dissolved in ethanol (100 mL), and 1M NaOH was added (32 mL). After 30 min, the reaction was carefully concentrated, diluted with water (100 mL) and extracted into ether (3×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated to give a colorless aromatic oil which was purified first by passage through a plug of silica gel eluting with 5%EtOAc/hexane, then by bulb-to-bulb distillation under reduced pressure to give a colorless aromatic oil (3.3 g, 75%). 1H NMR (300 MHz, CDCl3) δ0.90-1.09 (m, 2H), 1.10-1.85 (m, 11H), 2.43 (dd, J=5.1, 2.7 Hz, 1H), 2.75 (dd, J=5.1, 4.5 Hz, 1H), 2.94 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1.[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C(O)CCC>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:28][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Reactant: Nc1ccccc1N
Solvent: CCCCO
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Nc3ccccc3N)nc21

Procedure:
Analogously to Example 1, 308 mg (1.0 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine [described in Stage 1.2] and 324 mg (3 mmol) of 1,2-phenylenediamine are reacted in 10 ml of n-butanol in a glass pressure reactor for 19 h at 140° C., followed by addition of 486 mg (4.5 mmol) of 1,2-phenylenediamine and further reaction at 135° C. for 17 h. After purification by means of column chromatography, 2-[2-amino-phenyl-amino]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained; FAB-MS: (M+H)+=380; HPLC: tret (grad20/2)=11.36 minutes.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH3:17]
Reactant: C=CCc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1ccccc1OCC(=O)OCC
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A mixture of 2-allyl-phenol (10 g, 74.5 mmol), ethyl 2-bromoacetate (12.4 mL, 112 mmol) and cesium carbonate (36.5 g, 112 mmol) in DMF (180 mL) was heated at 60° C. overnight. The mixture was cooled and filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel to give 14.5 g of title compound. 1H NMR (400 MHz, CDCl3) • 7.19˜7.14 (m, 2H), 6.97˜6.92 (m, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.09˜5.95 (m, 1H), 5.11˜5.02 (m, 2H), 4.54 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.46 (d, J=6.8 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([N:26]3[CH2:31][CH2:30][C@:29]([CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:28][C:27]3=[O:43])[CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>O1CCCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]([N:26]3[CH2:31][CH2:30][C@:29]([CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:28][C:27]3=[O:43])[CH3:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)COc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(OCCO)cc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: -10 °C
Reaction time: 4 h

Procedure:
1 M solution of LiAlH4 in tetrahydrofuran (0.15 mL) was added to a solution of (4′-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-biphenyl-4-yloxy)-acetic acid methyl ester (125 mg) in tetrahydrofuran (2 mL) cooled to −10° C. under argon atmosphere. The resulting mixture was stirred at −10° C. for 2 h and at room temperature for 1 h, before another portion of LiAlH4 (1 M solution in tetrahydrofuran, 0.04 mL) was added at −10° C. The cooling bath was removed and the solution was stirred at room temperature for another 4 h. Then, water was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](Br)[CH:26]([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:12][C:13](=[O:16])[N:14]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2cc(=O)n(CC(C)C)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 91.3 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and isobutyl bromide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 91.3%.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]([CH2:14][C:15]([OH:17])=[O:16])[C:11]([OH:13])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]>C(Cl)(=O)C>[CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:14][C:15](=[O:16])[O:17][C:11]2=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(CC(=O)O)C(=O)O)s1
Solvent: CC(=O)Cl
Product: CC(C)Cc1ccc(C2CC(=O)OC2=O)s1
Yield: 85 %

Procedure:
10 g of (5-isobutyl-2-thienyl)succinic acid was added to 40 cc of acetyl chloride and the mixture was refluxed for 1 hour 30 minutes. The excess acetyl chloride was evaporated under reduced pressure. Distillation of the residue provided 7.9 g (yield=85%) of (5-isobutyl-2-thienyl)succinic anhydride.
Reaction SMILES: [CH3:1][N:2]1[C:10]([NH:11][C:12]([NH:14]C(=O)C2C=CC=CC=2)=[S:13])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1>[OH-].[Na+]>[CH3:1][N:2]1[C:10]([NH:11][C:12]([NH2:14])=[S:13])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1
Reactant: Cn1nc2c(c1NC(=S)NC(=O)c1ccccc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc2c(c1NC(N)=S)CCCC2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A suspension of compound 18 (3 g, 9.5 mmol) in 30 mL of 5% NaOH aqueous solution was stirred in an oil bath of 90° C. for 8 hrs and cooled down to room temperature. Ice was added while stirring to the reaction mixture. The resulting suspension was filtered, and the cake was washed with cold water (10 mL×3) and further dried in vacuo to afford the desired product 5 as an off-white powder.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.[C:30]1([C:36]2[NH:37][C:38](=[O:47])[N:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:20])[N:44]3[CH2:43][CH2:42][CH:41]([N:39]4[CH:40]=[C:36]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:37][C:38]4=[O:47])[CH2:46][CH2:45]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Yield: 30 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.23 mmol) and 4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one (60 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 30% yield. MS m/e (M+H)+=610.3. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 10.68 (d, J=4.27, 1H), 8.30 (d, J=3.97, 2H), 8.23 (s, 1H), 7.50 (d, J=7.93, 1H), 7.45 (d, J=7.63, 1H), 7.31 (m, 2H), 7.22 (s, 1H), 7.14 (m, 4H), 5.41 (d, J=16.78, 1H), 4.66 (m, 3H), 4.55 (m, 1H), 4.13 (m, 2H), 3.99 (m, 1H), 3.33 (m, 1H), 3.18 (m, 1H), 3.05 (dd, J1=16.02, J2=8.70, 1H), 2.94 (m, 1H), 2.68 (m, 1H), 2.44 (m, 1H), 1.81 (m, 3H), 1.62 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.C1C(=O)N([Cl:28])C(=O)C1>C(#N)C>[Cl:28][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A suspension of 2-methoxy-6-(4-methoxyphenyl)naphthalene (0.51 g, 1.93 mmol) and NCS (0.28 g, 2.13 mmol) in acetonitrile (20 mL) was heated to reflux for 3 hr. The resulting solution was cooled to room temperature and the resulting solid was collected by filtration and rinsed with acetonitrile to yield 0.41 g (72%) of the title compound as a white solid: mp 158–164° C.; 1H NMR (CDCl3): δ 3.87 (3H, s), 4.05 (3H, s), 7.03 (2H, d, J=8.62 Hz), 7.32 (1H, d, J=9.02 Hz); 7.65 (2H, d, J=8.55 Hz), 7.82 (2H, d, J=9.01 Hz), 7.95 (1H, d, J=1.36 Hz), 8.27 (1H, d, J=8.81 Hz); MS (El) m/z 298 (M)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CS([Cl:42])(=O)=O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Cl:42])=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CO)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-methanol and 1.84 ml triethylamine were dissolved in 150 ml dichloromethane. To this ice cooled solution were added 0.82 ml methanesulfonylchloride. The cooling bath was removed and the reaction mixture was stirred at room temperature additional three hours. The reaction mixture was washed three times with 50 ml saturated NaHCO3 solution dried over MgSO4 and the solvent was removed in vacuo to provide 3.1 g 4-Butyl-5-(3-chloro-4-chloromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole as crude material. This material was used without further purification.