Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)(=O)[CH2:2][CH3:3].B.C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)C1
Yield: 53.2 %

Procedure:
Following the same procedure as described in Example 47.2, N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (170 mg, 0.39 mmol) in THF (20 ml) was then treated with 1M BH3.THF (3.9 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (86 mg, 52%) as a pale yellow oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C@@H:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][C@H:2]([CH2:6][C@@H:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4]
Reactant: C1=COCCC1
Reactant: CCCC[C@H](C)C[C@@H](O)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
In a flask were charged 3.5 g of (2R,4S)-2-hydroxy-4-methylcaprylic amide synthesized in Step 5, 2.21 g of 3,4-dihydropyran, 50 ml of diethyl ether, and 0.1 g of p-toluenesulfonic acid at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 100 ml of a 1% sodium hydrogencarbonate aqueous solution and extracted with diethyl ether. The extract was washed with water and concentrated to obtain 6.6 g of a crude product, which was then purified by silica gel column chromatography to obtain 3.5 g (67.4%) of the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[CH:21]1[C:22]2[C:17](=[C:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cccc3cnccc23)CC1
Agent: Cl
Solvent: CO
Product: c1cc(NCC2CCNCC2)c2ccncc2c1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 33 (171 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (149 mg) as light yellow powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](=O)([O-])[O-].[Na+].[Na+]>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCNC1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (0.4 g, 1.85 mmol) in formic acid (5.4 mL) and aqueous formaldehyde (40%, 4.8 mL) was heated at 85° C. for 2.5 h. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×70 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 100:0) gave the title compound (0.131 g). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 129-131° C.; MS m/z (relative intensity, 70 eV) 229 (M+, 7), 157 (5), 129 (6), 58 (30), 57 (bp).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Br:7]/[C:8](=[CH:11]\N(C)C)/[CH:9]=O.C(O)C>C(O)(=O)C>[Br:7][C:8]1[CH:9]=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: CN(C)/C=C(\Br)C=O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1cnc2ccnn2c1

Procedure:
3-Aminopyrazole (0.75 g, 9.04 mmol) was mixed with (2Z)-2-bromo-3-(dimethylamino)acrylaldehyde obtained at the previous step (1.85 g, 10.4 mmol). Absolute ethanol (20 mL) and glacial acetic acid (2 mL) were added. The reaction mixture was stirred under reflux for 16 h and evaporated to dryness. The residue was washed on a filter with cold ethanol/hexane mixture (3:1) and dried in a vacuum oven at 30° C. to give 6-bromopyrazolo[1,5-a]pyrimidine.
Reaction SMILES: Cl.C([C:4]1[C:9]([OH:10])=[C:8]([CH2:11][OH:12])C(CO)=CN=1)=O.C(N(CC)CC)C.C([O:25][C:26](=[O:28])[CH3:27])(=O)C>O1CCCC1>[CH3:4][C:9]([CH2:8][C:11]([CH2:27][C:26]([OH:25])=[O:28])=[O:12])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ncc(CO)c(CO)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
A solution of one equivalent of 2-formyl-3-hydroxy-4,5-dihydroxymethylpyridine hydrochloride in 400 ml. anhydrous tetrahydrofuran is treated with four equivalents of triethylamine and aged for one hour at room temperture. Then three equivalents of acetic anhydride are introduced, and the reaction mixture is aged 4 hours at room temperature. The reaction mixture is concentrated under reduced pressure to a gum. This is treated with a mixture of 300 ml. of diethyl ether and 300 ml. of distilled water. After shaking well, the layers are separated and the ether layer is dried over magnesium sulfate. After evaporation to dryness, the desired triacetate is obtained as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:20][CH3:21])=[C:17]([OH:19])[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22]N(C)C=O.CI.C(OCC)(=O)C>O>[CH3:22][O:19][C:17]1[CH:18]=[C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][C:16]=1[O:20][CH3:21]
Reactant: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1O
Reactant: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
5-[1-(4-Fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol (50.0 mg, 0.176 mmol), 5 mL of N,N-dimethylformamide and methyl iodide (16.4 uL, 0.264 mmol) were combined in a vial and stirred at room temperature overnight. An additional 0.5 mL of methyl iodide was added and stirring continued for 2 days at room temperature and then 10 mL of ethyl acetate and 10 mL of water were added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 10% ethyl acetate in hexanes to 50% ethyl acetate in hexanes over 20 minutes to give 5-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole (25 mg, 48%) as a white solid. LC/MS (EI) tR 4.14, m/z 299.1 (M++1). 1H NMR (CDCl3 300 MHz) δ 3.7 (s, 3H); 3.9 (s, 3H); 6.5 (s, 1H); 6.7 (s, 1H); 7.0 (s, 2H); 7.1 (m, 2H); 7.3 (m, 2H); 7.7 (s, 1H).
Reaction SMILES: C1(S([N:10]2[C:22]3[C:21]([N:23]4[C:35]5[C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=[CH:31][C:30]=5[C:29]5[C:24]4=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>CS(C)=O.O>[C:21]1([N:23]2[C:35]3[C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc2c3ccccc3n(-c3cccc4c5ccccc5n(S(=O)(=O)c5ccccc5)c34)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c3ccccc3n(-c3cccc4c3[nH]c3ccccc34)c12
Temperature: 25 °C

Procedure:
65 g (123 mmol) of methyl 9-benzenesulfonyl-9H-[1,9′]bicarbazolyl-1′-carboxylate and 48 g (856 mmol) of potassium hydroxide in 65 ml of dimethyl sulfoxide and 21 ml of water are heated at 60° C. for 1 h. The mixture is subsequently cooled to room temperature, neutralised using 1 M HCl solution and extracted with dichloromethane. The solvent is evaporated in vacuo, and the residue is purified by chromatography (heptane/ethyl acetate 10:1). Yield: 45 g (116 mmol), 95% of theory.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][S:15][C:16]1[N:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=1>ClCCl>[CH3:14][S:15][C:16]1[N:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)=[O:11])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CSc1nccc(Oc2ccc(N)cc2)n1
Solvent: ClCCl
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)n1
Reaction time: 5 h
Yield: 79.7 %

Procedure:
A solution of 41.7 g (219 mmol) 3-trifluoromethyl-phenyl isocyanate in 50 ml dichloromethane was added within 45 min. drop by drop at 5-10° C. to a solution of 51.0 g (219 mmol) 4-(2-Methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued for 5 h at 5° C. The reaction mixture was kept in a cooling room overnight at 4° C. The formed precipitate was isolated by cold filtration and washed thrice with 40 ml ice cold dichloromethane. After an additional washing with portions of isohexane (250 ml total) the product was dried at 40° C. in vacuum to give 73.4 g (80%) 1-[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21](=[O:34])[N:12]2[C:13]=1[C:14]([O:16]C(C)(C)C)=[O:15])=[O:5])[CH3:2].C(O)=O>O>[CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21](=[O:34])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
A solution of 75 mg. of tert-butyl 3-(2'-ethoxycarbonylvinyl)-7-phenoxyacetamido-3-cephem-4-carboxylate in 10 cc. of 98-100 percent formic acid, any remainder being water, was allowed to stand at room temperature for 1.5 hours. After evaporation under reduced pressure of the formic acid, isolation of the acidic material by extraction provided 55 mg. of the desired above-named acid, which could be crystallized from ether or ethanol, m.p., 193°-196° C. The IR, NMR, and ultraviolet (UV) spectra and elemental analyses were in accord with the assigned structure.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=3)[CH2:8]2)[CH2:1]1)=[O:10]
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3cccc(C(F)(F)F)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-6-trifluoromethyl-pyridine. MS (ESI): mass calculated for C23H20F3N3OS, 443.49; m/z found 444.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.62-7.33 (m, 5H), 7.29-7.05 (m, 2H), 7.04-6.80 (m, 2H), 6.37 (s, 1H), 4.01-2.47 (m, 10H).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:34][C:35]([O:38][C:39]([N:41]1[C@H:44]([C:45]([OH:47])=[O:46])[CH2:43][CH2:42]1)=[O:40])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.O[N:58]=[C:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.O>[C:59](=[NH:58])([NH:66][O:46][C:45]([C@@H:44]1[CH2:43][CH2:42][N:41]1[C:39]([O:38][C:35]([CH3:34])([CH3:36])[CH3:37])=[O:40])=[O:47])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: NC(=NO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)ONC(=N)c1ccccc1
Reaction time: 2 h

Procedure:
PyBOP (2.53 g, 4.85 mmol) was added to a 0° C. solution of Boc-L-azetidine-2-carboxylic acid (650 mg, 3.23 mmol) and DIPEA (1.66 mL, 9.69 mmol) in DCM (14 mL) and the rxn mixture was stirred at rt for 20 min, before N′-hydroxybenzimidamide (440 mg, 3.23 mmol) was added and stirring continued at rt for 2 h. To the rxn mixture was added H2O and the mixture extracted with DCM (2×). The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield (S)-tert-butyl 2-((benzimidamidooxy)carbonyl)azetidine-1-carboxylate B-1-1 which was used further without purification.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3F)[O:8][C:4]=2[CH:3]=1.[C:22](=O)([O-])[O-:23].[K+].[K+].CO>O>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[O:23][CH3:22])[O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Temperature: 60 °C
Yield: 44.7 %

Procedure:
A mixture of 0.28 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.24 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 6-chloro-2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 91”).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH:23]=[O:24])[CH:15]=[C:16]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:17]=2)[N:12]=[C:11]([CH3:25])[C:10]=1[CH3:26])C1C=CC=CC=1.C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[OH:8][C:9]1[C:18]2[C:13](=[C:14]([CH:23]=[O:24])[CH:15]=[C:16]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:17]=2)[N:12]=[C:11]([CH3:25])[C:10]=1[CH3:26]
Reactant: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCC(C)c1cc(C=O)c2nc(C)c(C)c(O)c2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
800 Milligrams of the resultant 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline was dissolved in 2.5 ml of 20% sulfuric acid and stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was neutralized with an aqueous saturated sodium hydrogencarbonate solution to produce precipitates, which were washed with water and n-hexane and then dried under reduced pressure to obtain 490 mg of 4-hydroxy-6-s-butyl-8-formyl-2,3-dimethylquinoline. 440 Milligrams of 4-hydroxy-6-s-butyl-8-formyl-2,3-dimethylquinoline was suspended in a mixture of 3 ml of acetic anhydride and 0.5 ml of pyridine and the mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, neutralized with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The resultant organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (10:1) to obtain 220 mg of 4-acetoxy-6-s-butyl-8-formyl-2,3-dimethylquinoline (yield 13%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:22][CH:23]([F:27])[C:24](Cl)=[O:25]>>[F:22][CH:23]([F:27])[C:24]([C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)=[O:25]
Reactant: O=C(Cl)C(F)F
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)cc2)CC1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)C(F)F)cc3)cc2)CC1

Procedure:
The preparation is carried out analogously to Example 4 from 0.5 mol of 4-(trans-4-propylcyclohexyl)biphenyl and 0.5 mol of difluoroacetyl chloride.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48](B4OC(C)(C)C(C)(C)O4)[CH:49]=3)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)[CH3:30].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48]([C:7]4[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:11]([N:12]5[CH2:23][CH2:22][N:21]6[C:14](=[CH:15][C:16]7[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=76)[C:13]5=[O:26])[CH:10]=[C:9]([F:27])[CH:8]=4)[CH:49]=3)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 189a (381.9 mg, 0.850 mmol), 3-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (201a) (560 mg, 1.275 mmol), Pd(PPh3)4 (49.1 mg, 0.043 mmol), Na2CO3 aqueous solution (1.0 N, 2.81 mL, 2.81 mmol), 1,2-dimethoxy-ethane (4 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 238a.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][C:6]=1[F:34])=[O:4].Cl.[OH-].[Na+]>O1CCOCC1.O1CCCC1.CO>[Cl:33][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:34])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:32])[C:18]([OH:31])([C:23]1[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=1)[C:19]([F:22])([F:21])[F:20]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 175, step 6, 3′-chloro-3-fluoro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester (Example 176) was treated first with aqueous HCl in dioxane, followed by aqueous NaOH in tetrahydrofuran/methanol to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=468.1 [M−H+].
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH:7]([C:9]([O-:11])=[O:10])[CH2:6][NH:5][CH2:4]2)[CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:2]1[C:3]2([CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][NH:5][CH2:4]2)[CH2:1]1
Reactant: O=C([O-])C1CNCC2(CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CNCC2(CC2)C1

Procedure:
The above product of tert-butyl(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylate was stirred in 8 mL of 50% TFA in methylene chloride solution (v/v) for 4 hours. After removal of solvent, the residue was dried under high vacuum overnight to give (6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylic acid. LC-MS: m/z 344.1 (M+H)+.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[CH:17]1(NC2CCCCC2)[CH2:22]CCC[CH2:18]1.C(O)C.C(I)CC.[C:37](=[S:39])=[S:38]>>[CH:11]1([NH:12][CH:13]2[CH2:5][CH2:4][CH2:3][CH2:14][CH2:1]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:18]([S:39][C:37]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:38])[CH2:17][CH3:22]
Reactant: S=C=S
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCCI
Solvent: CCO
Product: CCCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), dicyclohexylamine (7.3 g) and 50% ethanol (55 ml) is added dropwise carbon disulfide (1.2 ml). The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise n-propyl iodide (3.4 g). The mixture is further stirred at room temperature for 10 minutes. The reaction mixture is distilled to remove the solvent. The resulting precipitates are collected by filtration and washed with ether to give dicyclohexylamine salt of the title compound. This product is treated with 10% HCl to give the title compound (4.6 g, 69%) as colorless needles, m.p. 180° C. (decomp.) (recrystallized from ethanol).
Reaction SMILES: [C:1]([NH:5][Si:6](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]([CH:23]=[C:24]([CH3:26])[CH3:25])=[CH-:22].[K+]>C1COCC1>[C:1]([NH:5][Si:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:25][C:24]([CH3:26])=[CH:23][C:21]([CH3:22])=[CH2:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: [CH-]=C(C)C=C(C)C
Reactant: CC(C)(C)N[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C=C(C)C[Si](NC(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.3238 g (1.12 mmol) of (N-t-butylamino)(chloro)diphenylsilane in 50 mL of THF was added 1.500 g (1.12 mmol) of potassium 2,4-dimethylpentadienide. The reaction mixture was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed in vacuo to give the product as a pale yellow oil. The yield was 0.3633 g 93.0%. 1H NMR (C6D6) δ 7.79 (m, 4H), 7.22 (m, 6H), 5.65 (s, 1H), 5.08 (s, 1H), 4.98 (s, 1H), 2.44 (s, 2H), 1.84 (s, 3H), 1.57 (s, 3H), 1.30 (s, 1H), 1.09(s, 9H), (s, 6H). 13C NMR(C6D6)δ 142.7, 138.5, 136.0, 135.8, 129.6, 128.0, 126.5, 113.7, 50.2, 33.9, 27.9, 25.1, 24.5