Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])(C)(C)C.Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]([NH2:36])CC(O)=O)=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]2[NH:36][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]2=[O:7])=[CH:22]1
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1[C@H](Cc2c[nH]c3ccccc23)NCCN1CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.10 g, 19.16 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (4.90 g, 19.23 mmol) in methanol (50 mL) and stir for 10 minutes. Add sodium cyanoborohydride in solution (19.0 mL, 1M in THF, 19.0 mmol) and stir under an inert atmosphere for 18 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[O-2].[Mn+4].[O-2].ClCCl>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[O:17])=[CH:18][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(CCOc1ccc(CO)cc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN(CCOc1ccc(C=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[2-(N-methyl-N-phenylamino)ethoxy]benzyl alcohol (3.36 g), manganese (IV) oxide (11.3 g) and dichloromethane (150 ml) were stirred at room temperature overnight. The mixture was filtered through a Soxhlet thimble and the residue extracted with refluxing dichloromethane for 2.5 hours. The solvent was evaporated to afford the title compound, an oil, which was used without further purification.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[CH3:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 75.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methylthiophenylboronic acid (153 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (170 mg, 80.0%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH3:15].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:15]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(N)cc1C
Yield: 77.2 %

Procedure:
A mixture of 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester (1.47 g, 6.64 mmol) and 5% Pd/C (0.29 g) in MeOH (100 mL) is exposed to a hydrogen atmosphere (60 psi) for 12 h. The mixture is filtered through Celite and purified by flash chromatography to yield the title compound (0.99 g, 77%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]2[N:8]=[C:9]([C:31]#[N:32])[N:10]=[C:11]([C:12]3[CH:13]=[N:14][C:15]([O:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=3)[C:6]=2[CH:5]=[CH:4]1.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:34].[Na+].C(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C.CCOC(C)=O.C(O)(=O)C.C(N(CC)CC)C>[ClH:1].[CH2:33]([N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][O:22][C:15]2[N:14]=[CH:13][C:12]([C:11]3[C:6]4[CH:5]=[CH:4][N:3]([CH3:2])[C:7]=4[N:8]=[C:9]([C:31]#[N:32])[N:10]=3)=[CH:17][C:16]=2[C:18]([F:20])([F:21])[F:19])[CH2:26]1)[CH3:34]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1ccc2c(-c3cnc(OCCC4CCCNC4)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: CC=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1CCCC(CCOc2ncc(-c3nc(C#N)nc4c3ccn4C)cc2C(F)(F)F)C1
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
Triethylamine (90 μL) was added to a solution of 7-methyl-4-{6-[2-(piperidin-3-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (100 mg) in dichloroethane (2 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. After mixture was ice-cooled, acetic acid (61 μL), sodium triacetoxyborohydride (91 mg), and acetaldehyde (36 μL) were added thereto, and the mixture was stirred for 1 hour under ice-cooling. After a saturated aqueous NaHCO3 solution was added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:EtOAc=80:20 to 40:60). The obtained product was dissolved in EtOAc (1 mL), then a 4 M solution of hydrogen chloride in EtOAc (0.3 mL) was added thereto at room temperature, and the mixture was stirred at the same temperature for 10 minutes. The precipitate was collected by filtration, whereby 4-{6-[2-(1-ethylpiperidin-3-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (92 mg) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:15]([NH:12][NH:11][C:9](=[O:10])[C:8]1[CH:13]=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)NNC(=O)C=Cc2ccccc2)cc1
Reaction time: 6 h
Yield: 71.8 %

Procedure:
In a flask were placed 5 g of p-methoxycarbonylbenzoylhydrazine, 4.3 g of cinnamoyl chloride and 30 ml of N-dimethylacetamide, and the reaction was carried out with stirring at 30° - 40° C for 6 hours. After completion of the reaction, the produced precipitate was collected by filtration and washed with water. The so obtained precipitate was then recrystallized twice from acetic acid and dried under reduced pressure to yield 6 g of N-cinnamoyl-N'-(p-methoxycarbonylbenzoyl)hydrazine as white crystals, m.p. 207° C. Analysis: Calculated for C18H16N2O4 : C, 66.67%; H, 4.94%; N, 8.64%, Found: C, 66.51%; H, 4.98%; N, 8.71%.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:21][OH:22])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:16][C:15]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[CH:11][C:12]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (R)-2-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 94, 0.14 g, 0.36 mmol) and zinc dust (0.12 g, 1.78 mmol) in MeOH-THF (1:1, 16 ml) was slowly added saturated ammonium chloride (2.0 ml). The reaction mixture was stirred at 25° C. for 1 hour, to which was then added saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 minutes. The Zn dust was removed by filtration and washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), dried over sodium sulfate, and concentrated. The crude product was used directly for the next step without further purification. MS: Calcd.: 368; Found: [M+H]+ 369.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[Na].[OH2:21]>C(O)CCC>[CH2:11]([O:21][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
7-Fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5 g) was added to a solution of sodium (0.9 g) in butanol (50 ml) and the mixture was heated at 100° for 19 hours. The mixture was poured into water (200 ml). The resulting precipitate was collected and recrystallised twice from industrial methylated spirit to give the novel compound 7-butoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 187°-190°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:29]O.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[F:20]
Reactant: COc1cccc(CO)c1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CBr)c1F

Procedure:
Triphenylphosphine (11.1 g) was added to a solution of the subtitle product of step ii) (5.0 g) in DCM (200 ml) followed by the portionwise addition of carbon tetrabromide (14.0 g). The reaction was stirred for 4 h before the addition of further triphenylphosphine (2.0 g) and carbon tetrabromide (2.0 g) and stirring maintained for 1 h. The mixture was concentrated to 30 ml volume and diluted in Et2O (300 ml). The solid precipitate was filtered and washed with Et2O (3×) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (10% Et2O/iso-hexane) to afford the subtitle compound as a clear oil. Yield: 5.2 g.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)#[N:13]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:17]1[CH:18]=[C:14]([C:12]#[N:13])[NH:15][CH:16]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Trichloracetyl chloride (44.4 g, 27.3 mL, 244 mmol) in dichloromethane (75 mL) was added over 20 min to a mechanically stirred suspension of aluminum trichloride (54.3 g, 407 mmol) in dichloromethane (150 mL). The resulting mixture was stirred for 30 min, and then 2-cyanopyrrole (15.0 g, 163 mmol) in dichloromethane (75 mL) was added over 30 min. The reaction was heated at reflux for 5 h and then allowed to cool. The reaction was diluted with ethyl acetate (600 mL) and then quenched slowly with water (300 mL). The layers were separated and then the organic layer was washed with water and brine, dried (magensium sulfate) and evaporated under reduced pressure to afford a quantitative yield of desired product (39.0 g, 100%) containing trace impurities. This material was used in the next step without further purification. 1H NMR (DMSO-d6) δ 8.14 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[C:41]([CH3:49])[CH:40]=4)[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O.Cl>CCOC(C)=O.O1CCOCC1>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[C:41]([CH3:49])[CH:40]=4)[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)c(-c2ccc(C(=O)O)c(C)c2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6′-fluoro-4′-methoxy-3-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (55 mg, 0.074 mmol), lithium hydroxide monohydrate (31 mg, 0.74 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature overnight. LCMS trace of reaction aliquot indicated completion of reaction. Crude mixture was acidified by HCl (1N aq.). Volatiles were removed under reduced pressure. Pot residue was dissolved in a water/MeCN mixture and purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford a light yellow glass. This residue was dissolved in EtOAc and washed w/water (10 mL×2), separated, dried/Na2SO4, filtered and concentrated to afford the title compound. LCMS (ESI) calc.=729.16; found=730.15 (+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 8.10 (t, J=7.8 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.70 (s, 1.5H), 7.66 (d, J=8 Hz, 1H), 7.62 (s, 1.5H), 7.47-7.38 (m, 3H), 7.30-7.25 (m, 1H), 6.85 (dd, J=12.5, 3 Hz, 1H), 5.61 (d, J=8 Hz, 0.5H), 5.31 (d, J=8 Hz, 0.5H), 4.94 (d, J=4.5 Hz, 0.5H), 4.91 (d, J=4 Hz, 0.5H), 4.15 (d, J=16.5 Hz, 0.5H), 3.93 (d, J=16 Hz, 0.5H), 3.86 (s, 3H), 3.86-3.76 (m, 1H), 2.68 (s, 3H), 0.57 (d, J=6.5 Hz, 1.5H), 0.46 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH:16]=1.O1CCCC1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])O.[Na+]>O.ClCCl>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]([F:15])([F:13])[F:14])=[CH:7][C:6]=2[CH:16]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2oc(CCC(F)(F)F)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc2oc(CCC(F)(F)F)cc2c1
Yield: 95.4 %

Procedure:
A solution of 2.0 g (8.7 mmol) of 5-amino-2-(3,3,3-trifluoropropyl)benzofuran in 30 ml of a 9/1 mixture of tetrahydrofuran and water is reacted for 30 minutes with 0.92 ml (9.6 mmol) of ethyl chloroformate in the presence of 1.1 g (13 mmol) of sodium hydrogen-carbonate. The reaction medium is then diluted with water and dichloromethane, then the organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. 2.5 g of product are obtained.
Reaction SMILES: [Mg].[CH3:2][S:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][Mg]Cl)=[CH:6][CH:5]=1.CSC1C=CC(CCl)=CC=1.C(Cl)C1C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=O)[CH:36]([CH3:42])[CH2:35]2>CCOCC.C1(C)C=CC=CC=1>[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH:37]([CH2:8][C:7]1[CH:11]=[CH:12][C:4]([S:3][CH3:2])=[CH:5][CH:6]=1)[C:36]([CH3:42])=[CH:35]2
Reactant: CC1Cc2cc(F)ccc2C1=O
Reactant: CSc1ccc(C[Mg]Cl)cc1
Agent: CSc1ccc(CCl)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCc1ccccc1
Solvent: Cc1ccccc1
Product: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Temperature: 30 °C
Reaction time: 0.07 h

Procedure:
Twenty-five grams (1.04 moles) of magnesium turnings were placed in a dried flask under N2 with 400 ml. of ether. Ten ml. of 0.05 molar p-methylthiobenzyl magnesium chloride in ether is added and the mixture is warmed to 30°C. About 2-3% of 39.7 g. (0.23 moles) of p-methylthiobenzyl chloride in 75 ml. of toluene is added. After 3-5 minutes of stirring an exotherm to 32°-33°C occurs signifying initiation of the reaction. After aging for 5 minutes, the rest of the benzyl chloride is added dropwise over 90 minutes. The reaction is aged for 30 minutes with stirring. 5-Fluoro-2-methyl-1-indanone (32.6 g., 0.199 mole) is added dropwise over 45 minutes. After aging for 30 minutes, the milky supernatant mixture is decanted from the magnesium. The flask and residual magnesium are rinsed with toluene. The reaction is then quenched by the addition of 120 ml. of 3N sulfuric acid. The lower layer is discarded. To the organic layer is added 80 ml. of 1:10 concentrated sulfuric acid, acetic acid and the two-phase mixture, stirred vigorously for one hour and water (100 ml.) is added. The bottom layer is discarded and the organic layer is washed with 100 ml. of water and 200 ml. of 2N sodium hydroxide. After a final water wash the organic layer is concentrated to give 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene. Similarly, when p-methylsulfinylbenzyl chloride is used in place of p-methylthiobenzyl chloride in the above example, the corresponding p-methylsulfinylbenzyl indene is obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11](O)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:27]=[CH:26]1>>[CH2:1]([O:8][C@H:9]([C@H:11]([N:25]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:27]=[CH:26]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]cn1
Reactant: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Product: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)OCc2ccccc2)cn1

Procedure:
Methyl 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]-imidazole-4-carboxylate was prepared from (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (obtained in Preparation 26) and methyl imidazole-4-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[C:15]2[N:16]=[C:17]([N:19]3[CH2:22][CH:21]([NH:23]C(=O)OC(C)(C)C)[CH2:20]3)[O:18][C:14]=2[C:13]([N:31]2[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32]2)=[C:12]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]=1[CH3:45])#[N:9].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:8]([C:10]1[C:15]2[N:16]=[C:17]([N:19]3[CH2:22][CH:21]([NH:23][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:20]3)[O:18][C:14]=2[C:13]([N:31]2[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32]2)=[C:12]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]=1[CH3:45])#[N:9]
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(NS(C)(=O)=O)C3)nc2c1C#N
Yield: 20.2 %

Procedure:
With cooling with ice, trifluoroacetic acid (1 ml) was added to a dichloromethane (2 ml) solution of tert-butyl (1-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}azetidin-3-yl)carbamate (I-195) (77.6 mg, 0.15 mmol), followed by stirring with cooling with ice for 1 hour. The reaction liquid was concentrated under reduced pressure, dissolved in dichloromethane (2 ml), and with cooling with ice, triethylamine (210 ml, 1.52 mmol) and methanesulfonyl chloride (25.6 μl, 0.33 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), and washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1) to obtain the entitled compound (15.0 mg, 19.7%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5](C2C=CC(CCCC(O)=O)=CC=2)[O:4][CH2:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])=[C:36]([C:45]#[N:46])[CH:35]=2)=[O:32])=[C:24]([CH3:47])[CH:23]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1>>[C:45]([C:36]1[CH:35]=[C:34]([NH:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([B:5]3[O:6][CH2:7][C:2]([CH3:20])([CH3:1])[CH2:3][O:4]3)=[CH:23][C:24]=2[CH3:47])[CH:39]=[CH:38][C:37]=1[S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])#[N:46]
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2C)cc1C#N
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B3OCC(C)(C)CO3)cc2C)cc1C#N
Yield: 88 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 8B (448 mg, 1.00 mmol) was reacted with 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to afford 8C (425 mg, 88%) as an off-white solid. MS (ESI) m/z 413.1 (M−H)− for free boronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[N+:9]([O-])([O-:11])=[O:10].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Fc1ccc(Br)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
1-Bromo-4-fluorobenzene (50.0 g) was added to concentrated sulfuric acid (200 mL) slowly at 0° C., followed by slow addition of KNO3 (43.3 g). The resulting mixture was stirred at 0° C. for 1 hour. TLC indicated the reaction was complete. The reaction mixture was poured onto ice slowly, and extracted with EtOAc (3×200 mL). The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated to afford 1-bromo-4-fluoro-2-nitrobenzene (D39) (52.0 g) as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[NH2:27][C:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1>>[OH:32][CH2:31][C:28]1([NH:27][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:25])[CH2:30][CH2:29]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: NC1(CO)CC1
Product: N#Cc1ccc2c(c1)cc(C(=O)NC1(CO)CC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and (1-amino-cyclopropyl)methanol in a manner similar to that described in Example 11.