Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:9][C:6]1[C:7]([F:8])=[C:2]([F:1])[CH:3]=[C:4]2[C:5]=1[C:18]([OH:20])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[N:10]2
Reactant: CCOC(=O)C(=CNc1cc(F)c(F)c(F)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(F)c(F)c(F)c2c1O
Temperature: 250 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of 3,4,5-trifluoroaniline (5.00 g, 34.0 mmol) and diethyl ethoxymethylenemalnate (5.00 mL, 34.0 mmol) was stirred at 120° C. for 1 h. After cooling, diisopropyl ether was added to the reaction mixture and the resulting precipitates were collected by filtration to give diethyl [[(3,4,5-trifluorophenyl)amino]methylene]malonate (8.02 g, 74%) as a white powder. A mixture of diethyl [[(3,4,5-trifluorophenyl)amino]methylene]malonate (7.83 g, 23.1 mmol) and diphenyl ether (20 mL) was stirred at 250° C. for 1 h. After cooling, the resulting precipitates were collected by filtration. The filtered precipitates were suspended in hexane, and then filtered to give ethyl 5,6,7-trifluoro-4-hydroxy-3-quinolinecarboxylate (6.27 g, 94%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH:13]2[CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11]O)[NH:5][C:4](=[O:16])[N:3]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH:13]3[CH2:15][CH2:14]3)[CH2:9][CH2:10][CH2:11][N:5]2[C:4](=[O:16])[N:3]=1
Reactant: O=c1nc(Cl)cc(N(CCCO)C2CC2)[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1nc(Cl)cc2n1CCCN2C1CC1
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-6-(cyclopropyl(3-hydroxypropyl)amino) pyrimidin-2(1H)-one (2 g, 8.21 mmol) in tretrahydrofuran (20 mL) were added DIAD (2.394 mL, 12.31 mmol) and triphenylphosphine (3.23 g, 12.31 mmol) at r.t., stirred for 3 h, and concentrated. Purification via C-18 column, and afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:41][CH:42]=2)O1.N#N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[N:41][CH:42]=4)=[C:3]([C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of compound 18b (0.50 g, 1.2 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (0.44 g, 1.4 mmol) in dioxane/water (4:1 v/v, 5 mL) was purged with N2. Dichloro(diphenylphosphinoferrocene)palladium (42 mg, 0.06 mmol) was then added, followed by solid Cs2CO3 (0.94 g, 2.9 mmol). The reaction mixture was stirred at 85° C. for 1 h under N2, and allowed to cool to rt. EtOAc (100 mL) was then added. The organic layer was washed with water (2×50 mL), and brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash column chromatography on silica gel (0-40% EtOAc/heptanes) to give compound 38a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H29N7O3: 548.2 (M+H). found: 548.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:37][Si](C)(C)C)[C:35]#[CH:36].[SiH3]O[SiH3]>N1CCCCC1.[Cu]I.CCOCC>[CH3:12][C:9]1([CH3:13])[CH2:10][CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[C:5]([C:36]#[C:35][CH2:34][OH:37])[CH:6]=[CH:7][C:8]1=2
Reactant: C#CCO[Si](C)(C)C
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Cu]I
Agent: [SiH3]O[SiH3]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CC1(C)CCC(C)(C)c2cc(C#CCO)ccc21

Procedure:
114 g of crude 2-bromo-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (GC-purity: 76.5%) was dissolved in 250 ml of piperidine and successively treated with 4.80 g of ((Ph)3P)4Pd, 0.95 g of CuI, and 1.35 g of (Ph)3P. The internal temperature was then raised to 90°-95° C. and 150 ml of propargyloxy-trimethylsilane were added via dropping funnel within 4 hours. After 1 additional hour the reaction mixture was poured onto crashed ice/HCl conc. and vigorously stirred until TLC indicated that all silylether had been cleaved. EtOEt was added, the layers were separated and the organic phase washed with H2O and brine. Drying over Na2SO4, evaporation of the solvent and purification by flash chromatography (silica gel, hexane/AcOEt=85:15) afforded 60.6 g of 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-prop-2-yn-1-ol as ochre yellow crystals of m.p. 84°-85° C. (GC-purity >96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl.N[CH:13]1[CH2:18][CH2:17][CH2:16]C[CH:14]1[OH:19].C[Si](C)(C)N[Si](C)(C)C.[Na].BrCC1CCCO1>CC(O)C.[Ni](I)I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:16][CH:17]2[CH2:18][CH2:13][CH2:14][O:19]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: I[Ni]I
Agent: BrCC1CCCO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(C)O
Product: Clc1ccc(CC2CCCO2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of (4-chlorophenyl)dihydroxyborane (524.0 mg, 3.351 mmol), 2-aminocyclohexanol hydrochloride (42 mg, 0.28 mmol) and nickel iodide (87.3 mg, 0.279 mmol) in i-PrOH (10.00 mL) was added sodium hexamethyldisilazane (1.075 g, 5.864 mmol) at 0° C. Then the mixture was stirred at rt for 5 min before 2-bromomethyl-tetrahydro-furan (460.00 mg, 2.80 mmol) was added by syringe. The resulting mixture was then stirred at 60° C. for 5 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(5% AcOEt in hexane).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[O:13][CH3:14].CO>CCOCC>[Br:12][C:8]1[C:7]([O:13][CH3:14])=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: COc1c(Br)cccc1CO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
2.4 g of lithium borohydride (LiBH4) was added to a solution of 5.3 g of 3-bromo-2-methoxy-benzoic acid methyl ester 5 in 200 mL of ether (Et2O) at 0° C. After stirring for 5 minutes, 5 mL of methanol was added. The reaction mixture was warmed to room temperature and kept there for 2.5 hours. Thereafter, 2.4 g more of lithium borohydride was added. The reaction mixture was quenched with aluminum chloride. After standard aqueous work up, and silica gel column purification (hexane/ethyl acetate 2:1), 4.0 g of 3-bromo-2-methoxy-phenyl-methanol 6 was obtained.
Reaction SMILES: [C:1]([O:9]CCCC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:15](O)(=O)C>>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:15]
Reactant: CC(=O)O
Reactant: CCCCOC(=O)c1cccnc1
Solvent: O
Product: CC(=O)c1cccnc1
Yield: 61 %

Procedure:
A tubular reactor with an i. d. of 23.5 mm was filled with 270 ml (≈227 g) of catalyst from example 1. A mixture of butyl nicotinate (30 g/h), water (54 g/h) and acetic acid (210 g/h) was fed over an evaporator using a metering pump to the tubular reactor heated by a salt bath. A small flow of nitrogen (1 l/h) guaranteed the transport of the vapours. The temperature of the bath was 410° C. The reaction vapours were condensed in an aqueous circulation system. After a total running time of 35 h, the reaction solution was collected. A portion of this solution corresponding to a total of 710 g of butyl nicotinate was worked up to isolate the product. 81% of butyl nicotinate was converted to give 293 g of 3-acetyl-pyridine, corresponding to a selectivity of 75% and a yield of 61%. The selectivity of pyridine formation was 4%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cccc(OC)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-methoxy-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 8): tR=1.30 min; Mass spectrum (ESI+): m/z=535 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[F:11][C:4]1[CH:3]=[C:2]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[O:12])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Oc1ccccn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-n2ccccc2=O)cc1F
Temperature: 150 °C
Yield: 49.4 %

Procedure:
To a solution of 10.96 g of 4-bromo-2-fluoro-benzoic acid in 40 ml of DMSO was added subsequently 6.67 g of 2-hydroxypyridine, 1.10 g of 8-hydroxyquinoline, 1.43 g of Cu(I)I and 7.61 g of K2CO3 and the mixture was heated to 150° C. for 18 h. The suspension was diluted with water, filtered, the residue was washed with AcOEt, triturated with MeOH, filtered and dried to give 5.77 g of the title compound 35e. MS: 234.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(-c2ccc(OC3CCNCC3)nc2)cc1
Reaction time: 24 h
Yield: 80.8 %

Procedure:
4-[5-(4-Fluorophenyl)pyridin-2-yloxy]piperidine-1-carboxylic acid tert-butyl ester (0.88 g) was dissolved in methanol (20 ml) and treated dropwise with a 1.0 M solution of HCl in diethyl ether (24 ml). After stirring for 24 h, the resultant mixture was evaporated. The residue was dissolved in 2% citric acid (30 nml) and washed with diethyl ether (2×15 ml). The aqueous phase was then basified with sodium hydroxide to pH 13 and extracted with ethyl acetate (3×30 ml). The combined ethyl acetate extracts were then washed with water (3×10 ml), saturated brine (10 ml), dried (Na2SO4) and evaporated to furnish the title compound as a white solid (0.52 g, 81%)
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21]I>CN(C=O)C>[C:3]1([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.1 g, 29.0 mmol) is added to 2-phenyl-5-nitro-1H-indole (Example 5b, 6.5 g, 26.0 mmol) in 100 mL of DMF. The mixture is stirred at room temperature for 1 hour. MeI (1.62 mL, 26.0 mmol) is added dropwise and the mixture is stirred at room temperature for 1 hour. The resulting mixture is poured into H2O/ice and the product is filtered off and washed with H2O. The solid is recrystallized from hexane and filtered off. Yield: 6.5 g (99.7%); Rf (2/1 hexane/ethyl acetate): 0.60; IR (KBr): 3434, 2923, 1515, 1462 cm−1; 1H-NMR (d6-DMSO) 8.50 (d, J=1.5 Hz, 1H); 7.90 (dd, J=8.6 Hz, 1.5 Hz, 1H); 7.80-7.30 (m, 6H); 6.75 (s, 1H); 3.75 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N12CCCN=C1CCCCC2.[NH2:17][C:18]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)=[O:21]>CS(C)=O>[NH2:17][C:18]1[N:41]=[C:40]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH:39]=[CH:38][C:19]=1[C:20](=[O:21])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: NCC(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: Nc1nc(NCC(=O)O)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
Glycine (935 mg, 12.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.86 mL, 12.5 mmol) were added to 2-amino-N-(4-benzyloxy-benzyl)-6-chloro-nicotinamide described in Preparation Example A+-18 (454 mg, 1.25 mmol) under nitrogen atmosphere, and the solution was stirred for 6 hours at 130° C. Dimethylsulfoxide (35 mL) was added to the reaction mixture, which was then filtered with polytetrafluoroethylene membrane filter (Whatman Inc), the filtrate was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (287 mg, 0.551 mmol, 44%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]=[C:5]([O:33]C(OCC)=O)[CH2:6][CH:7](OC(OCC)=O)[C:8]1[N:9]([CH:24]([CH3:26])[CH3:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Cl-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][C:5](=[O:33])/[CH:6]=[CH:7]/[C:8]1[N:9]([CH:24]([CH3:25])[CH3:26])[C:10]2[C:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)OC(=CC(=O)OC)CC(OC(=O)OCC)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 4 h

Procedure:
In a 100 ml three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen delivery line, 2.17 g of crude 3,5-bis-ethoxycarbonyloxy-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-pent-2-enoic acid methyl ester are dissolved in 50 ml of DMF, 1.0 g of pyridinium p-toluenesulfonate is added and stirring is carried out for 4 hours at 80° C. The reaction mixture is then cooled, poured into 150 ml of saturated sodium chloride solution and extracted four times with 50 ml of ethyl acetate. The combined organic phases are washed six times with 50 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product (brownish-orange resin) is purified by means of flash chromatography (hexane/ethyl acetate=10:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:17])([F:16])[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[CH:6]=1.[CH3:18]I.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:18][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:4]([F:3])([F:16])[F:17])=[CH:6][C:7]1=[O:15]
Reactant: O=c1cc(C(F)(F)F)c2ccccc2[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(C(F)(F)F)c2ccccc21
Reaction time: 1 h
Yield: 93.7 %

Procedure:
KOH (10.54 g, 188.0 mmol) was added to a solution of 4-trifluoromethyl-1H-quinolin-2-one (4.00 g, 18.8 mmol) in DMF (160 mL). After 1 hour, the mixture was treated with MeI (11.7 mL, 188.0 mmol), then stirring was continued overnight. EtOAc (200 mL) was added, followed by saturated aqueous NH4Cl to adjust the aqueous pH to 6.5. After separation of the layers, the aqueous phase was extracted further with EtOAc (2×200 mL). The combined organic extracts were washed with H2O (200 mL) and brine (200 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (PE-EtOAc, 4:1 to 7:3) yielded 1-methyl-4-trifluoromethyl-1H-quinolin-2-one (4.00 g, 94%): δH ((CD3)2SO)=3.65 (s, 3H), 7.10 (s, 1H), 7.40 (t, 1H), 7.65–7.80 (m, 3H). This compound (8.70 g, 38.3 mmol) was added portionwise with stirring over 20 min to fuming H2SO4 (30% oleum, 17.5 mL) at 84° C. The bath temperature was raised to 120° C. for 1 hour, before being cooled back down to 20° C. Thereupon, the mixture was added slowly to saturated aqueous NaCl (60 mL) and stirred for 30 min. The solid produced was collected & dried under vacuum at 50° C. to give sodium 1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonate: δH((CD3)2SO)=3.65 (s, 3H), 7.10 (s, 1H), 7.65 (d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H). This compound was suspended in MeCN-sulfolane (1:1, 52 mL), before being treated with POCl3 (18.8 mL, 201.7 mmol). The mixture was heated to 88° C. for 1.5 hours, before being cooled to 20° C. over 0.5 hour. On cooling to <5° C., ice cold H2O (128 mL) was added, the temperature being maintained below 7° C. The mixture was stirred at 0° C. for 20 minutes, then the solid formed was collected and washed with H2O to afford, after drying, the title compound (9.62 g, 73%): δH (CDCl3)=3.80 (s, 3H), 7.25 (s, 1H), 7.65 (d, 1H), 8.25 (dd, 1H), 8.50 (d, 1H). Preparation 2: 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonyl chloride
Reaction SMILES: C1(C2NC(CO)=CN=2)C=CC=CC=1.[C:14]1([C:20]2[N:21]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:22]([CH2:25]O)=[CH:23][N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(C1N(CC2C=CC=CC=2Cl)C(/C=C(\CC2C=CC3OCOC=3C=2)/C(OC)=O)=CN=1)CCC.C1(C2N(CC3C=CC=CC=3Cl)C(C=O)=CN=2)C=CC=CC=1.[CH3:89][O:90][C:91]1[CH:92]=[C:93]([CH2:99][CH2:100][C:101]([O:103]C)=[O:102])[CH:94]=[CH:95][C:96]=1[O:97][CH3:98]>[O-2].[O-2].[Mn+4]>[C:14]1([C:20]2[N:21]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:22]([CH:25]=[C:100]([CH2:99][C:93]3[CH:94]=[CH:95][C:96]([O:97][CH3:98])=[C:91]([O:90][CH3:89])[CH:92]=3)[C:101]([OH:103])=[O:102])=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCc1cnc(-c2ccccc2)n1Cc1ccccc1Cl
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Agent: [Mn+4]
Agent: CCCCc1ncc(/C=C(\Cc2ccc3c(c2)OCO3)C(=O)OC)n1Cc1ccccc1Cl
Agent: O=Cc1cnc(-c2ccccc2)n1Cc1ccccc1Cl
Product: COc1ccc(CC(=Cc2cnc(-c3ccccc3)n2Cc2ccccc2Cl)C(=O)O)cc1OC

Procedure:
By the procedure of Example 1(ii) Method B, using benzamidine methyl ether in place of valeramidine methyl ether, 2-phenyl-5-hydroxymethylimidazole is prepared and converted to 2-phenyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole. The 5-hydroxymethyl group is oxidized using manganese dioxide by the procedure of Example 1 (iii). The resulting 2-phenyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde is used in the procedure of Example 27 with methyl 3-(3,4-dimethoxyphenyl)propanoate to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:25]([OH:27])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.[C@H:42]1([NH2:52])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44][CH2:43]1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:24][O:23][C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@H:9]([C:25](=[O:27])[NH:52][C@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH2:10]2)=[CH:20][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: N[C@@H]1CCCc2ccccc21
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)N[C@@H]3CCCc4ccccc43)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-((4-(methoxycarbonyl)benzyl)oxy)pyrrolidine-2-carboxylic acid (1.2 g, 3.2 mmol) in DMF (10 mL) was added EDC (0.91 g, 4.7 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.43 g, 3.2 mmol). The reaction mixture was stirred at rt for 5 min and treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (0.54 g, 3.6 mmol) in DMF (5 mL) and 4-methylmorpholine (0.70 mL, 6.3 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated and washed successively with aq. NaHCO3 solution, brine, and 1N HCl solution. The organics were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.3 g, 81%). 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 2H), 7.33 (d, J=6.8 Hz, 2H), 7.13-6.94 (m, 3H), 6.85-6.80 (m, 1H), 5.21-5.01 (m, 1H), 4.49-4.33 (m, 2H), 4.11 (d, J=3.1 Hz, 1H), 3.93 (s, 3H), 3.70-3.41 (m, 2H), 2.74 (d, J=3.3 Hz, 2H), 2.05 (s, 2H), 1.90-1.68 (m, 3H), 1.58 (s, 1H), 1.45 (s, 10H); MS(ESI+) m/z 509.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:21])[CH:8]=[CH:7]2)([O-])=O.C(C1C=CC2C(=CC=C(N)C=2)N=1)#N>>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9](=[O:21])[CH:8]=[CH:7]2
Reactant: O=c1ccc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: N#Cc1ccc2cc(N)ccc2n1
Product: Nc1ccc2c(ccc(=O)n2Cc2ccccc2)c1

Procedure:
The title compound (34 mg) was prepared from compound 46C in a manner similar to that described in Experiment 45C. LC/MS m/z 251 [M+H]+.