Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:20][OH:21])[CH:15]2[C:6]([CH3:18])([C:7]3[C:12]([CH2:13][CH2:14]2)=[C:11]([O:16]C)[CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:4][C:3]1=[O:19].B(Br)(Br)Br.C(=O)([O-])[OH:27].[Na+]>ClCCl.CCCCCC>[OH:21][CH2:20][C:2]1([CH3:1])[CH:15]2[C:6]([CH3:18])([C:7]3[C:8](=[O:27])[CH:9]=[CH:10][C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]1=[O:19]
Reactant: COc1cccc2c1CCC1C(C)(CO)C(=O)CCC21C
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(CO)C(=O)CCC2(C)C3=C(CCC12)C(=O)C=CC3=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In 4 ml of dichloromethane was dissolved 150 mg of the compound obtained in Example 8, and under ice-cooling, 1.2 ml of a solution (1.0M) of boron tribromide in n-hexane was added. The mixture was stirred at 0° C. for 1.5 hours, and then it was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. In 10 ml of ethanol was dissolved 34 mg of the resulting crude crystals, and after addition of an aqueous solution (6.8 ml) containing 83 mg of potassium dinitrosulfonate and 34 mg of dipotassium hydrogen phosphate, the mixture was stirred at room temperature for 13 hours. The reaction mixture was then diluted with water and extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent=ethyl acetate:n-hexane=1:9) to provide 1 mg of the object compound.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.[NH2:14][N:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:33][C:34]([CH3:36])=O>C(O)C>[CH2:39]([O:38][C:32]([C:33]1[C:34]([CH3:36])=[N:14][N:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][C:25]=12)=[O:37])[CH3:40]
Reactant: CCOC(=O)C1=CCN(N)C=C1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccn2nc(C)c(C(=O)OCC)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl N-aminoisonicotinate 2,4-dinitrophenol salt (10.2 g) was suspended in ethanol (147 ml), and potassium carbonate (3.77 g) was added, which was followed by stirring at room temperature for 30 min. To the mixture was added ethyl acetoacetate (3.69 ml), and the mixture was stirred at 60° C. for 5 hr with heating. The insoluble matter was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/1) to give the objective compound (2.70 g) as an amber-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5](F)=[O:6].[NH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([NH2:16])=[O:6]
Reactant: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: N
Product: NC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
242.5 g (1 mol) of 3-chloro-4-trifluoromethoxybenzoyl fluoride were allowed to drop into 500 ml of 25% strength by weight aqueous ammonia solution with ice cooling, then the mixture was stirred for 30 minutes and the precipitate which deposited was filtered off with suction. 227 g of product having a melting point of 98° C. were obtained. This corresponds to a crude yield of 95% of theory.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:3].F[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)[CH3:3]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 90 °C

Procedure:
To a solution of piperidin-4-yl-acetic acid ethyl ester hydrochloride (24 mmol) in anhydrous DMSO (20 mL) is added 1-(4-fluoro-phenyl)-ethanone (24 mmol) and potassium carbonate (24 mmol). The resulting mixture is heated at 90° C. for 36 hr. The reaction mixture is allowed to cool to rt, poured into cold water (100 mL), and extracted with EtOAc (40 mL×3). The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel flash chromatography (hexane/ethyl acetate 2:1) to give the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.86 (2H, d), 6.85 (2H, d), 4.15 (2H, q), 3.89 (2H, br, d), 2.90 (2H, dt), 2.51 (3H, s), 2.27 (2H, d), 2.04 (1H, m), 1.83 (2H, br, d), 1.38 (2H, dt), 1.27 (3H, t); LC-MS (M+1): 290.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.720 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added tert-butyl (2S)-2-[(aminooxy)methyl]pyrrolidine-1-carboxylate 93 (0.234 g, 1.085 mmol, US 2007/118830 A1), 1-hydroxybenzotriazole (0.147 g, 1.085 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.208 g, 1.085 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 94 (0.30 g, 88%) as a white foam.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=1.C([Mg]Cl)(C)C>C1COCC1>[O:18]=[CH:4][C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][C:25]1[CH:26]=[CH:21][CH:22]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C[C@H](Cc1cccc(OC(F)(F)F)c1)NC(=O)OCc1ccccc1
Temperature: -20 °C

Procedure:
To a solution of the commercially available benzyl {(2S)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (5.52 g, 20.75 mmol) and 1-bromo-3-(trifluoromethoxy)benzene (5 g, 20.75 mmol) in THF (100 ml) cooled in an ice/methanol/dry ice cooling bath was added isopropylmagnesium chloride (20.75 ml, 41.5 mmol) dropwise under nitrogen while internal temperature was maintained between −35 and −15° C. (monitored w/ an immersed temperature probe). After addition, the reaction was stirred cold and allowed to warm to ambient overnight. The reaction crude was then cooled to −20° C. and slowly quenched into a stirred mixture of crushed ice and HCl (1N, ice bath cool). The resulting mixture was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure. The pot residue was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and concentrated in vacuo to afford a colorless oil of 3.9824 g as the titled compound. LCMS calc.=367.1. found=390.00 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[C:23]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)[S:24][C:17]=23)=[C:11]([F:31])[CH:10]=1)[CH2:4][C:5]([OH:7])=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:33][C:2]([F:32])([F:1])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[C:23]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)[S:24][C:17]=23)=[C:11]([F:31])[CH:10]=1)[CH2:4][C:5]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:7]
Reactant: Nc1ccccc1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(CC(=O)O)C(F)(F)F)cc4F)c3s2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(CC(=O)Nc5ccccc5)C(F)(F)F)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To a stirred solution of 320 (150 mg, 0.31 mmol), aniline (43 μL, 0.47 mmol) and N, N-diisopropylethylamine (0.19 mL, 1.09 mmol) in dry N,N-dimethylformamide (4 mL) at room temperature was added HATU reagent (356 mg, 0.94 mmol). The mixture was stirred at room temperature for 16 h. A saturated aqueous solution of sodium bicarbonate was added and the aqueous solution was extracted twice with EtOAc, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 3:97 to 8:92) to afford the title compound 317 (111 mg, 0.20 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.11 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.66 (s, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.30 (t, J=8.0 Hz, 2H), 7.21 (t, J=8.8 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.86 (dd, J=13.6, 2.4 Hz, 1H), 6.67 (dd, J=8.8, 2.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 6.44 (d, J=5.6 Hz, 1H), 4.86-4.53 (m, 1H), 3.72 (s, 3H), 2.92 (dd, J=15.6, 3.2 Hz, 1H), 2.76 (dd, J=15.6, 9.6 Hz, 1H). LRMS (M+1) 556.0 (100%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.80 min, m/z=473.1-474.1 [M+H]+, m/z=472.2-471.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.61 (m, 1H) 1.78-1.88 (m, 1H) 2.17-2.25 (m, 1H) 2.53 (s, 3H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.11-3.19 (m, 2H) 3.22-3.30 (m, 2H) 3.33-3.37 (m, 1H) 4.60 (t, J=4.89 Hz, 1H) 7.34 (dd, J=8.31, 3.42 Hz, 3H) 7.69 (dd, J=7.95, 2.32 Hz, 1H) 7.83-7.88 (m, 2H) 7.98 (d, J=2.45 Hz, 1H) 8.49 (d, J=2.20 Hz, 1H) 8.74 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-2-but-3-enyloxy-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as light yellow solid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)[CH2:18][CH3:19].Cl>C1COCC1.O>[CH2:17]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:18][CH3:19]
Reactant: CCCOc1cccc(C=O)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1cccc(C=CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To ethyl diethylphosphonoacetate (24.7 g) was added THF (200 ml), and sodium hydride (60%, 4.4 g) was added at 0° C. to the resulting mixture, to which was then added dropwise a solution of 3-propoxybenzaldehyde (16.1 g) in THF (100 ml). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water, was neutralized with hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain ethyl 3-propoxycinnamate (24.0 g) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[I-].C(O[C:9]1[C:10]([C:14]2[CH:15]=[N+:16](C)[CH:17]=[CH:18][CH:19]=2)=[N:11]S[N:13]=1)CCC>C(O)C>[NH2:11][CH:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:9]#[N:13]
Reactant: CCCCOc1nsnc1-c1ccc[n+](C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(N)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (240 mg, 6.4 mmol) was added to a solution of 3-(4-butoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.60 g, 1.6 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° C. for 1 h. After evaporation the residue was dissolved in water and extracted with ethyl acetate. The dried organic phases were evaporated and the residue purified by column chromatography (SiO2, eluent: ethyl acetate/methanol (4:1)). The title compound was crystallized as the oxalate salt from acetone to yield 280 mg (M.p 158° C.; M+ : 253; Compound 4).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl>C1COCC1.ClCCl.CO.O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH:3]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydroxide (100 g, 2.50 mol) in 1.8 L of a 10:8 mixture of water and methanol was added 4-hydroxyacetophenone (136 g, 1.00 mol). After stirring at room temperature for 30 minutes, 4-Methoxybenzaldehyde (136 g, 1.00 mol) was added to this mixture. The reaction mixture was stirred at 50° C. oil bath for 16 hours. A clear yellow solution resulted which was allowed to stir at room temperature for 30 minutes. 1N HCl aq (500 mL) and 600 mL of a 1:1 mixture of dichloromethane and THF were added to result two layers. The organic layer was washed by saturated NaHCO3 aq. (300 mL×2) and water (300 mL×3) and evaporated to yield orange solid. This solid was washed by 300 mL of EtOAc two times. The resulted yellow solid was dried in vacuo. Yield 133 g (52%). 1H NMR (CDCl3): δ3.85 (s, 3H), 6.93 (m, 4H), 7.47 (d, 1H), 7.50 (d, 2H), 7.75 (d, 1H), 7.96 (d, 2H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.[C:7]([NH:10][C:11]#[N:12])(=[O:9])[CH3:8].[Na]>CC(N(C)C)=O>[C:7]([N:10]([CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:10]([C:11]#[N:12])[C:7](=[O:9])[CH3:8])[C:11]#[N:12])(=[O:9])[CH3:8]
Reactant: CC(=O)NC#N
Reactant: ClC/C=C\CCl
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: CC(=O)N(C#N)C/C=C\CN(C#N)C(C)=O

Procedure:
25.0 g (0.2 mol) of cis-1,4-dichlorobut-2-ene and 46.7 g (0.4 mol+10% excess) of sodium acetylcyanamide are reacted in 80 ml of dimethylacetamide at 70°-88° C. for 4 hours. The reaction mixture is then filtered with suction, the filtrate is introduced into 400 g of ice and the resulting suspension is filtered. The residue is dried over phosphorus pentoxide at room temperature under 0.13 mbar to give 29.4 g (66.7% of theory) of the desired compound, which has a melting point of 73.8°-75.2° C.
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:30]1([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:32][CH2:31]1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:30]1([N:33]2[CH:37]=[C:36]([C:2]3[C:3]([O:16][C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]4)[CH:35]=[N:34]2)[CH2:32][CH2:31]1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ncccc3C)c2CC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ncccc3C)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100-mL, round-bottom flask was charged with (S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.129 g, 0.34 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.025 g, 0.03 mmol), potassium carbonate (0.142 g, 1.03 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.243 g, 1.04 mmol), 1.4-dioxane (10 mL) and water (2 mL). The resulting mixture stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was passed through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate-petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (54% to 80% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.0285 g, 21%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.00-1.03 (m, 4H), 1.16 (d, J=6.60 Hz, 3H), 1.32-1.42 (m, 1H), 2.20-2.28 (m, 5H), 2.48 (s, 3H), 2.54-2.59 (m, 1H), 3.57-3.64 (m, 1H), 4.75-4.80 (m, 1H), 6.95-7.00 (m, 1H), 7.22-7.27 (m, 1H), 7.54 (d, J=8.40 Hz, 1H), 7.63 (s, 1H), 7.72-7.77 (m, 2H), 7.80 (s, 1H). MS (ESI, pos. ion) m/z 403 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[NH:21][CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=5[Cl:32])[N:24]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=1[CH3:43]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[N:21]([C:34]5[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=5[CH3:43])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=5[Cl:32])[N:24]=4)=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)n2)c(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1-n1cc(-c2ccc(Cl)cc2Cl)nc1Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1

Procedure:
2-(4′-Cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (250 mg, 0.54 mmol) was treated according to general procedure B using 2-fluoro-5-nitrotoluene to provide 2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(2-methyl-4-nitro-phenyl)-1H-imidazole, which was collected without purification. Treatment of the nitro compound as described in general procedure C provided 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-3-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[C:18]([F:35])=[C:19]([CH:32]=[CH:33][CH:34]=1)/[CH:20]=[C:21]1\[C:22](=[O:31])[NH:23][C:24]2[C:29]\1=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH:20]1[C:19]1[CH:32]=[CH:33][CH:34]=[C:17]([Br:16])[C:18]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Br)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (5.9 g, 28 mmol) prepared in Example 1 and E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one (5.3 g, 15 mmol) prepared in Example 95 in dichloromethane (200 mL) were added triethylamine (14 mL, 101 mmol) and AgF (2.5 g, 20 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (30 g, 120 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (10-40% EtOAc in hexanes) to give as rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a light yellow solid (1.2 g, 14%)