Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:27][C:23]1[CH:22]=[C:21]([CH2:20][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:26]=[CH:25][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
171 (580 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (238 mg, 1.1 equivalent) and benzylbromide (1.1 équivalent, 206 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 172 as white solid (513 mg, 71%). 1H NMR (CDCl3): δ 1.46 (s, 9H), 2.64 (s, 1H), 3.05 (m, 1H), 3.18 (m, 1H), 4.39 (m, 1H), 5.20 (s, 1H), 5.25 (s, 4H), 6.95 (d, 1H, J=7.1 Hz), 7.00 (d, 1H, J=7.9 Hz), 7.07 (s, 1H), 7.20 (m, 2H), 7.27 (d, 2H, J=7.4 Hz), 7.32 (t, 1H, J=7.9 Hz), 7.50 (m, 6H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH-:14].[Na+]>P(=O)(O)(O)O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[Br:12]
Reactant: Nc1cc(Br)c2ncc(Br)cc2c1
Reactant: [OH-]
Agent: O=P(O)(O)O
Agent: [Na+]
Product: Oc1cc(Br)c2ncc(Br)cc2c1
Temperature: 180 °C

Procedure:
6-Amino-3,8-dibromoquinoline (0.15 g) was suspended in phosphoric acid (75%, 11 ml) and heated in a sealed glass tube at 180° C. for 72 hours. The mixture was allowed to cool to ambient temperature, diluted with ice (50 ml) and taken to pH 2 with aqueous sodium hydroxide (4M). The brown suspension that formed was extracted with ethyl acetate (twice), dried over magnesium sulphate then evaporated under reduced pressure to give 3,8-dibromo-6-hydroxyquinoline (M+—H 300, 2×Br) as a dark red solid that was used in the next stage without further purification, 1H NMR (d6 DMSO) δ: 7.14(1H, d); 7.60(1H, d); 8.52(1H, d); 8.71(1H, d).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)cccc1C(=O)OC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1c(OC)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To methyl 3-hydroxy-2-prop-2-en-1-ylbenzoate (10.3 g, 53.6 mmol, M. A. Eissenstat et al., J. Med. Chem. 1995, 38, 3094-3105) and cesium carbonate (26.2 g, 80.4 mmol) in DMF (100 ml) was added methyl iodide (15.2 g, 102.2 mmol). The reaction mixture was stirred at room temperature for 18 h, then filtered and concentrated. The residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The layers were separated, the organic layer was washed with 5% lithium chloride (2×100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to provide methyl 3-(methyloxy)-2-prop-2-en-1-ylbenzoate (10.3 g, 93% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.41 (m, 1H), 7.24 (m, 1H), 7.02 (m, 1H), 6.97 (m, 1H), 4.97 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:16][C:17]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=3[NH2:19])=[N:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: Cc1ccc(N)c(CCl)c1
Reactant: CCOc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: CCOc1ccc2[nH]c(SCc3cc(C)ccc3N)nc2c1
Yield: 44 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.00 g of 2-mercapto-5-ethoxybenzimidazole instead of 2-mercaptobenzimidazole and 3.71 g of 2-(chloromethyl)-4-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate. Crystallization during concentration of the dichloromethane extract gave 2.13 g of the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][CH2:18][CH2:19]O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>ClC(Cl)Cl>[Cl:29][CH2:19][CH2:18][CH2:17][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][O:9]1
Reactant: O=S(Cl)Cl
Reactant: OCCCC1(c2ccc(F)cc2)OCc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1ccc(C2(CCCCl)OCc3ccccc32)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 24.2 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-propanol in 8 parts of pyridine and 90 parts of trichloromethane were added dropwise 12.1 parts of thionyl chloride. Upon completion, the whole was heated slowly to 50° C. and stirring at this temperature was continued for 3 hours. The reaction mixture was poured onto ice-water. The organic phase was separated, washed with a sodium hydrogen carbonate solution (10%), dried and evaporated, yielding 20 parts of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran as a residue (intermediate 12).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:12]([O:11][C:9]([C:3]1([F:2])[CH2:4][CH2:5][N:6]([C:15]2[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=2)[CH2:7][CH2:8]1)=[O:10])[CH3:13]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CCOC(=O)C1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(F)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2 g, 9.4491 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.5426 g, 9.4493 mmol) and sodium carbonate decahydrate (2.53 g, 23.6 mmol) in ethanol (15 mL) was stirred at 60° C. for 12 h. The reaction mixture was filtered through celite, the solvent was evaporated and the residue was dried under vacuum to give the title compound (2.7 g, 97%) as a pale yellow gum, which was used without further purification. LCMS (pH 10) MH+ 298, RT 1.19 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[C:23]([F:26])([F:25])[F:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([O:29]C)=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[C:23]([F:26])([F:25])[F:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([OH:29])=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
To a solution of (R)-methyl 2-(4-fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate (35 mg, crude) in methanol (15 mL) was added a solution of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with aqueous hydrochloric acid (1N). The product was collected by filtration and purified by Prep-HPLC under the following conditions: Column, silica gel 19 mm*100 mm; mobile phase, A:B=0.05% TFA:ACN B %=35%˜100% 0˜8 mins; Detector, 5 um. 18.2 mg. (R)-2-(4-Fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylic acid was obtained as a yellow solid (2 steps yield=5.3%).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:6]=1)C=C.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:7]1[CH:6]=[C:5]([NH2:4])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:33][CH2:32][C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH:13]=2)[N:8]=1
Reactant: C=CCNc1cc(NCc2ccccc2OC)nc2ccc(Cl)cc12
Reactant: NCc1cccnc1
Product: COc1ccccc1CNc1cc(N)c2cc(NCc3cccnc3)ccc2n1

Procedure:
The title compound, MS: m/e=386.4 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline-2,4-diamine and 3-picolylamine
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(#N)C>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[C:26]([CH3:34])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
In a flask containing (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (100 mg, 0.18 mmol) was added ethanol (3 mL) and concentrated hydrochloric acid (three drops) and it was stirred at 25° C. for 45 min. It was then diluted with acetonitrile and absorbed onto silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (55 mg, 69%) as a yellow foam: [α]32589=−73.6° (c=0.14, methanol); ES-HRMS m/e calcd for C21H27N3O5S (M+H)+ 434.1745, observed 434.1745; 1H NMR (400 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.77-2.28 (m, 8H, 4×CH2), 2.63 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.67 (q, J=5.5 Hz, 2H, OCH2), 3.91 (m, 1H, ArCHCO), 3.99 (t, J=5.5 Hz, 2 H, NCH2), 4.82 (t, J=5.5 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.46 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.86 (d, Jo=8.5 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:18]#[N:19].CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1.O>C(O)(=O)C>[C:18]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:2]=1[N:1]1[CH:22]=[CH:26][CH:25]=[CH:24]1)#[N:19]
Reactant: COC(=O)c1ccnc(-c2ccc(N)c(C#N)c2)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(-n3cccc3)c(C#N)c2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
131 mg of methyl 2-(4-amino-3-cyanophenyl)isonicotinate and 67 μl of 2,5-dimethoxytetrahydrofuran were dissolved in 1.3 ml of acetic acid solution, followed by heating and stirring at 100° C. for 4 hours. The solution was poured into water, followed by extraction with ethyl acetate. The solvent of the organic layer was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1 to 1:1) to obtain 100 mg of methyl 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([N+:24]([O-])=O)[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([NH2:24])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(COC)c1c[nH]c2cccc(COC(C)=O)c12)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(COC(C)=O)c12
Yield: 62.5 %

Procedure:
3-(4-acetoxymethylindol-3-yl)-2-nitro-4-methoxy-butyric acid ethyl ester (226 g) is hydrogenated in ethanol (2.3 l) with Raney nickel as catalyst under hydrogen of normal pressure without addition of heat. 3 mol of hydrogen is taken up in 31/2 hours, whereby the temperature reaches a maximum of 45° C. After filtering of the catalyst and evaporation of the residue, the raw product is chromatographed on silica gel with a mixture of dichloromethane (97.5%) and ethanol (2.5%). 130 g of the title compound as noncrystalline diastereomeric mixture is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:20]C)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>>[CH2:24]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1)[CH:23]=[CH2:22]
Reactant: COc1cc(Br)c2oc(-c3ccc(OC)c(F)c3)nc2c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route c, step b, from 7-bromo-2-(3-fluoro-4-methoxyphenyl)-5-methoxy-1,3-benzoxazole, allyltributyltin and dichlorobis(trio-tolylphosphine)palladium, followed by demethylation according to Example 20, step e. The desired product was obtained as a light pink solid, m.p. 169-171° C.; MS m/e 284 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:29](I)[CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:29][CH2:30][CH3:31])[CH:21]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: Cn1c(=O)cc(-c2cccc(O)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCOc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Yield: 100 %

Procedure:
A mixture of interm. (7-h) (9.5 g), propyl iodide (5.9 ml) and K2CO3 (10.1 g) was stirred and refluxed for 4 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 10.4 g (100%) of 6-(4-chlorobenzoyl)-1-methyl-4-(3-propoxyphenyl)-2(1H)-quinolinone (interm. 7-i).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2ccsc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1cn(CCCc2ccc(OCc3coc(-c4ccsc4)n3)cc2)cn1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-thienyl)oxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 102-103° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>O.[Cu]Cl>[NH2:6][C:3]1[CH:4]=[CH:5][N:1]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:2]=1
Reactant: Brc1cccnc1
Reactant: Nc1cc[nH]n1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn(-c2cccnc2)n1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
A 4-neck round bottomed flask (500 mL) was charged with copper(I) chloride (2.51 g, 25.3 mmol), 1H-pyrazol-3-amine (15.8 g, 190 mmol), potassium carbonate (35.0 g, 253 mmol), and N,N-dimethylformamide (100 mL). The mixture was stirred under nitrogen for 10 minutes and 3-bromopyridine (12.2 mL, 127 mmol) was added. The mixture was heated at 110° C. for 18 hours, at which point HPLC analysis indicated that ˜15.5% 3-bromopyridine remained. The reaction was allowed to cool to 20° C. and concentrated to give a brown residue. Water (200 mL) was added and the resulting suspension was stirred at 20° C. for 2 hours and filtered. The solid was rinsed with water (2×50 mL) and dried to afford a pale green solid. The solid was suspended in water (200 mL) and the resulting suspension was heated at 90° C. for 2 hours and was filtered hot through a Celite® pad. The pad was rinsed with hot water (50 mL). The combined filtrates were allowed to cool to 20° C. to afford a yellow suspension, which was stirred at 20° C. for 2 hours and filtered. The solid was rinsed with water (2×50 mL) and air dried to afford the desired product as a light yellow crystalline solid (11.6 g, 57%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(ON1[C:29](=[O:30])[CH:28]2[C:31](=C=O)[CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:37])C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(#N)C>[CH:19]1([CH2:18][O:17][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:37])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH:14]([F:16])[F:15])[CH2:21][CH2:20]1
Reactant: CCON1C(=O)C2=CC=CC(=C=O)C2C1=O
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (0.78 g, 2.9 mmol) and N-ethoxy-carbonyl-phthalimide (0.64 g, 2.9 mmol) in 30 ml of water and acetonitrile (1:1) was added sodium carbonate (0.33 g, 31 mmol). The mixture was stirred at room temperature for 5 hours. 1N HCl was added dropwise until pH=2. The mixture was extracted with ether (2×25 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a colorless oil (1.1 g, 91%). 1HNMR (CDCl3): δ0.32-0.38 (m, 2H), 0.60-0.67 (m, 2H), 1.17-1.28 (m, 1H), 3.33 (dd, J=6, 17 Hz, 1H), 3.79 (dd, J=10, 17 Hz, 1H), 3.86 (d, J=8 Hz, 2H), 4.92 (broad, 1H), 5.74 (dd, J=6, 10 Hz, 1H), 6.58 (t, JH-F=75 Hz, 1H), 7.10 (s, 2H), 7.16 (s, 1H), 7.69-7.74 (m, 2H), 7.78-7.83 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:8]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([N:25]4[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]4)[C:10]=3[C:9]=2[CH:11]=1)#[N:16]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (590 mg, 1.6 mmol) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (918 mg, 4.9 mmol) in N,N-dimethylacetamide (7.6 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (40 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 12 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as a white solid, which was used in the next step without any further purification (530 mg, 63%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[N+:19]([O-])=O)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[H][H]>CO.C1COCC1.[Pd]>[OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Yield: 97.8 %

Procedure:
A solution of 3.0 g (9.7 mmol) of (7R,9aS)-7-hydroxymethyl-2-(4-fluoro-2-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1 H-pyrido[1,2-a]pyrazine in 50 mL of methanol and 50 mL of THF was treated with 0.30 g of 10% Pd/C and treated with 30 psi of hydrogen in a Parr apparatus for 1.5 h. The catalyst was removed by filtration and the red solution concentrated to give 2.65 g (98%) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)[CH3:15]
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: CNC
Product: CN(C)c1cc2c(=O)[nH]cnc2cn1
Yield: 60 %

Procedure:
6-Chloro-3H-pyrido[3,4-d]pyrimidin-4-one was reacted with dimethylamine (2.0 molar solution in methanol) in a pressure vessel at 130° C. for 32 hours. The reaction mixture was concentrated in vacuo and the resulting solid washed with ethyl acetate. This solid was heated in 2-propanol to give a suspension, which was filtered. The filtrate was concentrated in vacuo to give the product (60%).