Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[CH:8]=1.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH2:13]([C:9]1[CH:8]=[C:7]([CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CO)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (34 ml of a 2.5M solution in hexanes) was added to a solution of 1-bromo-3-ethylbenzene (15 g) in tetrahydrofuran (320 ml) at −78° C. After 1 hour N,N-dimethylformamide (15 ml) was added. The mixture was stirred at −78° C. for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol (250 ml) and treated with sodium borohydride (1.51 g) portionwise. The mixture was stirred at room temperature for 16 hours, quenched with 2M HCl (100 ml) and stirred for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 2M HCl. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography eluting with 5-10% ethyl acetate in isohexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:18])([CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16])[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:18])([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Into a solution wherein 0.5 g (R)-2-(2,4-difluorophenyl)-3-propionyloxy-1,2-propanediol obtained in Example 37 was dissolved in 5 ml of ethyl acetate was added dropwise 0.66 g of methanesulfonyl chloride at a temperature of 0° to 5° C., and thereto was added dropwise 0.46 g of pyridine at a temperature of 0° to 5° C. After dropping, the resulting liquid was stirred at room temperature for 16 hours. To the reaction mixture was added 20 ml of 1N hydrochloric acid and an organic layer separated. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 0.53 g of oily (S)-2-(2,4-difluorophenyl)-1-propionyloxy-3-methanesulfonyloxy-2-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 24.3 minutes ((R)-form) and 26.9 minutes ((S)-form)).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:31]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>C(O)(=O)C.CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (198 mg, 0.426 mmol) was dissolved in acetic acid (2.8 mL), and iron powder (0.36 g, 6.4 mmol) was added to the solution. Reaction was stirred at room temperature for 2 h. The mixture was diluted with 30 mL of EtOAc, filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc, and neutralized with NaHCO3. The layers were separated, and the aqueous layer was extracted with further EtOAc. The combined organic layers were dried and concentrated under reduced pressure to give the sub-title compound as a white solid (176 mg, 95%), which was used in the next step without further purification. LCMS calc. for C22H35N4O5 (M+H)+ m/z=435.3. found 435.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=1)=[O:6]
Reactant: N=C(N)CCCCc1ccc(F)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(CCCCc1ccc(F)cc1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 5-(4-fluoro-phenyl)-pentanamidine hydrochloride (example 93.2) in the presence of TBTU and DIPEA to give 2,5-dichloro-N-[5-(4-fluoro-phenyl)-1-imino-pentyl]-nicotinamide as brown oil. MS: m/e=368.1 [M+H+].
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1>CC(C)=O.[Ag]=O>[CH2:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:1][CH3:3]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CC(C)I
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3.15 g of silver oxide and 2.25 ml of isopropyl iodide were added to a solution of 4.5 g of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 90 ml of acetone and the mixture was heated at 50° C. for 3 hours and was then cooled. The mixture was filtered and the filtrate was distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture. The fractions were distilled to dryness and the residue was dissoved in 200 ml of refluxing ethyl acetate. The mixture was filtered and the filtrate was concentrated to 150 ml and cooled to 20° C. Crystallization was induced and the mixture was iced overnight and vacuum filtered. The recovered product was washed with ethyl acetate and dried to obtain 3.9 g of 3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 210° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28]([O:30]CC)=O)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>CO>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH:38][C:28](=[O:30])[CH2:27][S@:19](=[O:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1)[CH3:34]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Solvent: CO
Product: CCN(CC)CCNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 30 °C
Yield: 60.3 %

Procedure:
(S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (73 mg, 0.16 mmol) in anhydrous MeOH (1.5 mL) was added N,N-diethylethylenediamine (0.12 mL, 0.84 mmol) dropwise. The reaction mixture was heated at 30° C. for 4 hours. The reaction mixture was evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed once with brine, dried (anhydrous Na2SO4), concentrated. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH to 10:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a foamy solid (50 mg, 59%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([O:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2nc(NC(=O)CO)sc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)COC(=O)c3ccccc3)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Hydroxyacetylamino)-6-methoxybenzothiazole (1.2 g) prepared in Example 3 is dissolved in pyridine (50 ml) and thereto is added dropwise benzoyl chloride (0.6 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off, washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (1.3 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C@H:48]([CH3:58])[C@H:49]([NH:56][CH3:57])[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[C:43]([O:47][C@H:48]([CH3:58])[C@H:49]([N:56]([CH3:57])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1)[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CN[C@H](CN1CCCC1)[C@@H](C)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCCC2)[C@@H](C)OC(C)(C)C)ccc1F
Yield: 17.9 %

Procedure:
4-Fluoro-3-methylbenzoic acid (101 mg, 0.66 mmol), TBTU (232 mg, 0.72 mmol) and DIPEA (0.172 mL, 0.99 mmol) was stirred in DCM (2 mL) for 1 h. (2R,3R)-3-tert-butoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M7) (150 mg, 0.66 mmol) was added and the resultant mixture was stirred at rt overnight. The reaction mixture was washed with NaHCO3 (8% aq., 2 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (43 mg, 18%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.94, 1.05-1.15, 1.55-1.72, 2.20, 2.21-2.28, 2.31-2.45, 2.60-2.66, 2.77, 2.83, 2.90, 3.27, 3.44-3.50, 3.70-3.77, 3.87-3.93, 4.51-4.58, 7.08-7.22, 7.23-7.28, 7.37.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)O)cc1C1CCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C1CCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 3-cyano-5-cyclobutyl-4-methoxybenzoic acid (190 mg), toluene (2.0 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.07 mL) were added, and the mixture was stirred at 60° C. for 3 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (204 mg) as a brown oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11]3.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:17])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]3
Reactant: CN1C(=O)Cc2cc3ccccc3cc2S1(=O)=O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(=O)C(C(=O)Nc2ccccc2)c2cc3ccccc3cc2S1(=O)=O
Reaction time: 20 h
Yield: 36.8 %

Procedure:
To a solution of 1.3 g (5 mmol) 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide and 0.7 ml (5 mmol) triethylamine dissolved in 10 ml DMSO at room temperature was added 0.6 g (5 mmol) phenylisocyanate. After stirring for 20 hr the resulting mixture was quenched with dilute HCl in an ice bath and then extracted with ether (2 times). The combined ether extracts were washed, dried and concentrated to give 1.9 g crude product. This material was recrystallized from ethanol followed by recrystallization from ethylacetate to give 0.7 g 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.O1CCCC1>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=2)[CH:13]=1
Reactant: FC(F)(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2cccc(C(F)(F)F)c2)cc1O
Yield: 27 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[3-(trifluoromethyl)phenyl]ethynyl}pyridazine (Intermediate 15) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (2:1). The crude material was purified by reverse phase chromatography, eluting with 5-80% acetonitrile/water with a 0.05% formic acid modifier in the water. The crude product was recrystallised from ethanol/heptane to give a white solid (yield=27%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:11][C:10]=2[CH3:25])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:32]=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:30]=[CH:29][C:28]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:26][C:27]1[CH:32]=[C:31]([N:33]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]4([OH:24])[CH2:19][CH2:20][S:21][CH2:22][CH2:23]4)=[CH:11][C:10]=3[CH3:25])[CH:6]=[CH:7][CH:8]=2)[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])(=[O:35])=[O:36])[CH:30]=[CH:29][C:28]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(CO)c1
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of 4-({[3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (0.90 g, 2.51 mmol), ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.05 g, 2.64 mmol) and tributylphosphine (0.86 mL, 3.26 mmol) in tetrahydrofuran (15 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.85 g, 3.26 mmol) under stirring at room temperature, and the mixture was stirred for 10 hr. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.71 g, yield 92%) as a pale-yellow amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([F:35])[CH:37]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccc(F)c2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 3-fluoro-benzylbromide (135 μL). The reaction mixture is allowed to stir at room temperature for 18 h. The resulting suspension is poured into water (10 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 425 mg (81%) of the title compound as a white solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:19](=C)[C:20](O)=O)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].C>[Pd].O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:19][CH2:20][C:1]([OH:2])=[O:4])[CH:10]=[C:9]([O:8][CH3:7])[C:14]=1[O:15][CH3:16]
Reactant: C=C(C(=O)O)c1cc(OC)c(OC)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [K+]
Solvent: O
Product: COc1cc(CCC(=O)O)cc(OC)c1OC
Reaction time: 1 h
Yield: 167.5 %

Procedure:
6.8 g of potassium carbonate is added to a solution of 21.44 g of 3,4,5-trimethoxyphenylpropenoic acid and 45 ml of water then the medium is hydrogenated for one hour under a pressure of 1200-1300 mbars in the presence of 1.8 g activated charcoal with 10% palladium, in this way 2.1 l of hydrogen is absorbed. The reaction medium is filtered, followed by washing with water and acidifying with 50 ml of hydrochloric acid (2N). After separation, the residue is washed with water and dried under reduced pressure at ambient temperature. In this way 19.8 g of the expected product is obtained (M.P.=102-103° C.)
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[NH:3]1.C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH3:1][CH:2]1[N:3]2[C:4]3[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]1)[C:16](=[O:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc2c(c1)NC(C)CC2
Product: CCOC(=O)c1cn2c3c(ccc(C)c3c1=O)CCC2C

Procedure:
Using the procedure of Example 25, 2,7-dimethyltetrahydroquinoline and diethyl ethoxymethylenemalonate are reacted to give solid ethyl 6,7-dihydro-5,10-dimethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 106°-108° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([N:17]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2].[NH3:37]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:37])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([N:17]([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 100 %

Procedure:
[Step 4] Reactions and treatments were carried out in the same manner as in Example 118, using 83.5 mg of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholin ophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 86.9 mg (100%) of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholin ophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxamide was obtained as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([O-])=O.[Na+]>CO>[CH2:1]([O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 96.5 %

Procedure:
109 g (0.374 mol) of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester, 92.5 g (0.34 mol) of stearyl alcohol and 0.2 g of sodium formate (0.003 mol) are introduced into a vessel and melted and stirred at 100° C. under nitrogen. As soon as a melt is obtained, cautiously evacuation is carried out and at the same time the melt is heated to an internal temperature of from 150 to 160° C. The methanol formed is distilled off and condensed in a cold trap. As soon as an internal pressure of <10 mbar is reached, the internal temperature is increased to from 170 to 180° C. and further evacuation to <1 mbar is carried out. As soon as IT=180° and a pressure of <1 mbar is reached, those conditions are maintained for one hour and then, in the course of from 1 to 2 hours at IT=200-210° C., the excess β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester is removed by distillation. The reaction melt then contains <0.2% starting materials and has a content of >98% β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid octadecyl ester. The reaction melt is cooled, and left to stand for crystallisation. Yield 96.5%; m.p. 51° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH2:13][O:12][C:11]1([CH3:22])[CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][O:12][C:11]1([CH3:22])[CH3:21])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CCC(=O)O)COC1(C)C
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
Sodium hydroxide (27 mL of a 4.0 M solution in H2O, 108 mmol, 3.0 equiv.) was added to a solution of (4S)-4-(2-methoxycarbonylethyl)-2.2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (prepared as described in Chida et al., J. Chem. Soc., Chem. Commun. 1992, 1064) (10.5 g, 36.5 mmol, 1 equiv.) in CH3OH (150 mL), and the resulting cloudy reaction mixture was stirred at 23° C. for 3.5 h. The mixture was concentrated under reduced pressure to ˜30 mL volume, and then was partitioned between 0.5 M HCl (150 mL) and EtOAc (2×150 mL). The combined organic layers were dried over MgSO4 and were gravity filtered. The filtrate was concentrated under reduced pressure and the residue dried under vacuum, to afford (4S)-4-(2′-carboxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (10.0 g, 100% crude yield). This material was used without further purification: 1H NMR (CDCl3, mixture of rotamers) δ 1.49 (s), 1.57 (s), 1.60 (s), 1.84-2.05 (m), 2.39-2.41 (m), 3.71-3.74 (m), 3.91-4.05 (m).