Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:6][C:5]=1[N:23]1[C:32](=[O:33])[C:31]2[C:26](=[N:27][C:28]([S:34][CH3:35])=[N:29][CH:30]=2)[NH:25][C:24]1=[O:36].I[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:6][C:5]=1[N:23]1[C:32](=[O:33])[C:31]2[C:26](=[N:27][C:28]([S:34][CH3:35])=[N:29][CH:30]=2)[N:25]([CH3:38])[C:24]1=[O:36]
Reactant: CI
Reactant: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To the suspension of NaH (60% dispersion in mineral oil, 19.7 mg, 0.49 mmol) in DMF is added N-[4-Methyl-3-(7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (218 mg, 0.45 mmol) at 0° C. When H2 evolution has ceased, iodomethane (84 μl, 1.35 mmol) is added and the reaction mixture is stirred for 3 hours at room temperature. The mixture is diluted with ethyl acetate, and washed with 5% aqueous Na2S2O3 solution to remove DMF. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is crystallized from MeOH to give N-[4-Methyl-3-(1-methyl-7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (184 mg, 82%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CO>[OH:20][C:6]1[C:5]([CH2:22][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]([OH:21])[C:3]([O:2][CH3:1])=[C:8]2[C:7]=1[C:12](=[O:13])[CH:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Reactant: C1CCNCC1
Reactant: C=O
Solvent: CO
Product: COc1c(O)c(CN2CCCCC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 55 °C
Reaction time: 4.5 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.1 ml), piperidine (8.5 g) was stirred under for 4.5 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 35.3 g of purity 99.2%. MS: (API-ES) m/z 382.5[M+H]+, 404.5[M+Na]+; 1H NMR (DMSO-d6, 400 MHz) δ 8.05˜8.06 (m, 2H, Ar-2′,6′-H), 7.60˜7.61 (m, 3H, Ar-3′,4′,5′-H), 6.89 (s, 1H, 3-H), 3.95 (s, 2H, CH2), 3.83 (s, 3H, 8-OCH3), 2.79 (s, 4H, CH2), 1.64 (m, 4H, CH2), 1.50 (m, 2H, CH2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[CH:32]=[N:33][S:34][CH:35]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:31]3[CH:32]=[N:33][S:34][CH:35]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Brc1cnsc1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnsc3)c3cc(Cl)ccc23)c1
Temperature: 145 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.250 g, 0.723 mmol) was combined with CuO (0.118 g, 1.48 mmol), potassium carbonate (0.130 g, 0.941 mmol) and 4-bromoisothiazole (0.250 g, 1.52 mmol) in pyridine (2 mL) and the reaction was heated to 145° C. overnight. After cooling the reaction was partitioned between H2O and DCM and the aqueous layer was extracted with DCM. The combined organics were dried over MgSO4 and concentrated then submitted to silica gel chromatography (0-20% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: C(O)(=O)C.Cl.[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C@@H:12]([CH2:18][CH3:19])[C:13]([O:15]CC)=[O:14])=[CH:9][C:8]=1[NH:22][C:23](=[O:38])[C@H:24]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27]>O>[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C@@H:12]([CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[NH:22][C:23](=[O:38])[C@H:24]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27]
Reactant: CCOC(=O)[C@H](CC)Cc1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](Cc1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C(=O)O
Temperature: 140 °C

Procedure:
15.2 ml of acetic acid and 7.6 ml of concentrated hydrochloric acid were added to 1.96 g (3.89 mmol) of ethyl (+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)butanoate. The reaction mixture was stirred under reflux for 5 h (bath temperature 140° C.). After cooling, water was added. The mixture was extracted repeatedly with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. Chromatography of the residue on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→2:1) gave 1.46 g (78.6% of theory) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:18][OH:19])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5].CN1CCOCC1.[CH3:27][C:28]1[N:32]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[O:35])[N:31]=[C:30]([C:45]([F:48])([F:47])[F:46])[CH:29]=1.ON1C2C=CC=CC=2N=N1.CC(N=C=NC(C)C)C>O1CCCC1>[OH:19][CH2:18][C@H:3]([NH:2][C:42]([CH:39]1[CH2:40][CH2:41][N:36]([C:34](=[O:35])[CH2:33][N:32]2[C:28]([CH3:27])=[CH:29][C:30]([C:45]([F:46])([F:48])[F:47])=[N:31]2)[CH2:37][CH2:38]1)=[O:43])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)[C@@H](N)CO)[C@@H]1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N[C@@H](CO)C(=O)N(C)[C@@H]2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
A solution of (2S)-2-amino-3-hydroxy-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]propanamide monohydrochloride (546.33 mg, 2.2 mmol) (i.e. the product of Example 17, Step B) and N-methylmorpholine (222.53 mg, 2.2 mmol) in 8 mL of tetrahydrofuran was cooled to 0° C. and 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinylcarboxylic acid (638.56 mg, 2 mmol) (i.e. the product of Example 17, Step D) was added followed by N-hydroxybenzotriazole (27 mg, 0.2 mmol) and N,N-diisopropylcarbodiimide (265 mg, 2.1 mmol). The reaction mixture was stirred for 16 h at room temperature and filtered. The precipitate was washed with tetrahydrofuran and the resulting filtrate and washings were concentrated in vacuo. The residue was dissolved in dichloromethane and the resulting solution was washed with water, 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate and brine, dried over MgSO4 and concentrated in vacuo. The resulting product was purified by medium-pressure liquid chromatography on silica gel using 0-20% methanol in ethyl acetate as eluant to give 600 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Fc1ccc(-c2noc(-c3cccnc3)n2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J=6.8 Hz, 2 H), 7.74-7.70 (m, 1 H), 8.20-8.15 (m, 2 H), 8.58-8.54 (m, 1 H), 8.91-8.89 (dd, J=1.7, 1.7 Hz, 1 H), 9.35 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:13]2[N:14]=[C:15](O)[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].P(Cl)(Cl)([Cl:26])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:26][C:15]1[N:14]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:2][CH:3]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)Oc1ccc(-c2cc3ncccc3c(Cl)n2)cc1

Procedure:
200 mg 7-(3-fluoro-4-trifluormethoxy-phenyl)[1,6]-naphthyridine-5-ol (5.1) and 10 μL N,N-diethylaniline were stirred into 4 mL phosphorus oxychloride overnight at 120° C. The reaction mixture was evaporated down, followed by co-evaporation with toluene (×3) and the residue purified via silica gel chromatography (ethyl acetate dichloromethane/methanol 4:1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([O:36]CC2C=CC([N+]([O-])=O)=CC=2)=[O:35])[CH2:25][N:24]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:22].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([OH:36])=[O:35])[CH2:25][NH:24]1)=[O:22]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C[C@@H]4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC[C@@H]4C)C3)[C@H](C)[C@H]12

Procedure:
205 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(2S)-2-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 240 μl of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 250 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as described in Example 7(b), to give 30 mg of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=2[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1c(COc2ccc(Cl)cc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
4-Chlorophenol (64.0 mg; 0.5 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile (120.0 mg; 0.5 mmol) [prepared by the method of Ashton and Hynes, J. Med. Chem. 16, 1233 (1973)] in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 140 milligrams of 2-(4-chlorophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].ClCCl>O1CCOCC1>[C:1]1([N:7]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[C:27](=[O:29])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ccnc3ccccc23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccccc1)c1ccnc2ccccc12

Procedure:
To a solution of phenyl-quinolin-4-yl-amine (13 g) and N-ethyl-N,N-diisopropylamine (1.5 eq) in dioxane (105 ml) was added acetic anhydride (28.1 ml, 5 eq). The solution was warmed to reflux of dioxane for 5 days. After cooling, dichloromethane was added and the solution was washed by water and sodium hydroxide 1N. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the mixture was purified by chromatography on silica gel (dichloromethane/ethanol (95:5)) to afford N-phenyl-N-quinolin-4-yl-acetamide (10 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][C:28](O)=[O:29].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][C:28]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:9][CH:10]1[C:14]([NH2:16])=[O:15])=[O:29]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N2CCN(c3ccccc3C)CC2C(N)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
4-(2-Methylphenyl)piperazine-2-carboxamide (39 mg, 0.18 mmol), 2,4-dimethoxyphenylacetic acid (42 mg, 0.21 mmol), EDC (42 mg, 0.22 mmol) and HBT (31 mg, 0.23 mmol) were combined in DMF (5 ml) and treated with triethylamine to adjust the pH to ca. 9 (moistened E. Merck colorpHast indicator). The mixture was stirred at ambient temperature for 64 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluted with 2% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to provide the title compound.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)O.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1F
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 350 mg (1.97 mmol) of the compound from Example 8 and 470 mg (1.97 mmol) of the compound from Example 84A in analogy to the synthesis of the compound from Example 101. 191 mg (24% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].O[N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([O:35][N:37]4[C:41](=[O:42])[CH2:40][CH2:39][C:38]4=[O:43])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)ON5C(=O)CCC5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a solution of N-(cholest-5-en-3β-oxycarbonyl)glycine (2.92 g) in a mixture of dioxane (40 ml) and chloroform (6 ml) were added successively N-hydroxysuccinimide (0.69 g) and dicyclohexylcarbodiimide (1.236 g) at 0° C. and the reaction mixture was stood for 16 hours in a refrigerator. The resulting precipitate was collected by filtration and the filtrate was concentrated in vacuo to give succinimidyl N-(cholest5-en-3β-oxycarbonyl)glycinate (3.23 g).
Reaction SMILES: C(C1[CH:46]=[CH:45][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:5]C=1)#N.[OH-:47].[K+].Cl.[CH2:50]([OH:53])[CH2:51][CH3:52]>O>[C:50]([C:51]1[CH:46]=[CH:45][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:5][CH:52]=1)([OH:47])=[O:53]
Reactant: [OH-]
Reactant: CCCO
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(C(F)(F)F)cc2)Cc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(C(F)(F)F)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution of 450 mg (0.72 mmol) of methyl 4-[(4E)-3-(4-cyanobenzyl)-5-(2-{4-[4-(trifluoromethyl)phenoxy]butoxy}phenyl)pent-4-en-1-yl]benzoate in 15 ml of 1-propanol and 2 ml of water is mixed with 1207 mg (21.5 mmol) of potassium hydroxide and stirred at 110° C. for 12 h. After cooling, the mixture is acidified with 1 M hydrochloric acid, and the crystals which have separated out are filtered off with suction, washed several times with water and dried. 447 mg (0.65 mmol, 90% of theory, purity 92%) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[N:4][CH:3]=1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Yield: 77 %

Procedure:
A mixture of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal) (1.09 g, 5.291 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (1.06 g, 5.291 mmol) in chloroform (50 ml) and MeOH (2.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (3.37 g, 15.873 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (1.591 g, 77%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:17]=[N:18][C:19]=2[CH3:20])=[N:9][CH:8]=1>O.C1COCC1.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=3)=[C:19]([CH3:20])[N:18]=[N:17]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A solution of lithium hydroxide monohydrate (143 mg, 3.39 mmol) in water (5.8 mL) was added dropwise to a suspension of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid methyl ester (581 mg, 1.7 mmol) in THF (5.8 mL) and methanol (2 mL). The reaction mixture was then stirred at room temperature for 30 min and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (538 mg, 97%) as a white solid. MS: m/e=327.2 [M−H]−.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C:9]([S:21](Cl)(=[O:23])=[O:22])=[CH:10][C:11]2[CH2:12][CH2:13][C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:20])[C:15]2([CH3:19])[CH3:18])=[CH:10][C:9]=1[S:21]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCC(=O)C2(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1S(=O)(=O)N1CCCC1)CCC(=O)C2(C)C
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 75 %

Procedure:
The THF (4 ml) solution of 3-methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonyl chloride (Compound CC1, 295 mg, 0.974 mmol) was cooled to 0° C., and the tetrafuran (1 ml) solution combining pyrrolidine (121 μl, 1.5 eq.) and triethylamine (272 μl, 2 eq.) was added dropwise thereto over 2 min. The mixture was stirred at 0° C. until Compound CC-1 disappears. The reaction solution was added with distilled water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of disodium ethylenediamine tetraacetic acid. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (246 mg, 75%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:34])[CH2:37][CH2:36]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.