Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14].C(N(C(C)C)CC)(C)C.C1COCC1>ClCCl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1ccc2ccccc2c1
Temperature: -70 °C
Reaction time: 76 h
Yield: 82.6 %

Procedure:
A solution of N,N′-bis[2-(2,4,6-trimethylbenzoyl)-3-oxobutylidene]-(1S,2S)-bis(3,5-dimethylphenyl)ethylene-1,2-diaminato cobalt (II) complexes (7.53 mg, 0.01 mmol, 2 mol %; formula (c-4)) in dichloromethane (2.0 ml) was added into a reaction vessel at room temperature under a nitrogen atmosphere, and was cooled to −70° C. Thereafter, to the reaction vessel were added a solution of 2-naphthaldehyde (78.1 mg, 0.5 mmol) in dichloromethane (1.0 ml), a mixture of nitromethane (1.0 ml, 18.5 mmol) and dichloromethane (1.0 ml), and diisopropylethylamine (64.7 mg, 0.5 mmol) in this order. The reaction mixture was stirred for 76 hours, and THF containing water was then added into the reaction mixture to stop the reaction. After a usual aftertreatment was performed, the resultant crude product was separated and purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give 1-(2-naphthyl)-2-nitroethanol (89.7 mg, yield 83%). The optical purity of the product was analyzed by high performance liquid chromatography (optical activation column: Chiralpak AD-H manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.; EtOH 10% in hexane, flow rate 1.0 ml/min, 254 nm; retention time (−)-isomer 25.1 min, (+)-isomer 30.2 min). As a result, the optical purity was 81% ee. The specific rotation [α]D29 was −30.4° (c 0.90, CH2Cl2).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([O:20][CH3:21])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:22]([Mg]Cl)[CH2:23]CCCC.C([Mg]Cl)CCCCCCC>>[CH3:21][O:20][C:9]1[CH:8]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:22][CH3:23])[CH:12]=[CH:11][C:10]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCc1ccc(Oc2ccccc2)c(OC)c1
Reactant: CCCCCC[Mg]Cl
Agent: CCCCCCCC[Mg]Cl
Product: CCCCCCCCc1ccc(Oc2ccccc2)c(OC)c1

Procedure:
The procedure as described above for synthesis of (4a) was used, except that hexyl magnesium chloride was replaced with octyl magnesium chloride. 1H NMR (300 MHz) (CDCl3): δ 7.36-6.90 (m, 8H), 3.90 (s, 3H), 2.69-2.65 (t, 2H), 1.72-1.68 (m, 2H), 1.42-1.36 (m, 10H), 1.00-0.94 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.C1N=[CH:16][N:15](C(N2C=NC=C2)=O)[CH:14]=1.CNC>C1COCC1>[CH3:14][N:15]([CH3:16])[C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 1-methyl-4-nitropyrazole-3-carboxylic acid (2.0 g) in THF (30 ml) was charged carbonyl-1,1′-diimidazole (1.9 g) over 1 hour at room temperature. The reaction was stirred overnight before cooling to 0° C. A solution of dimethylamine in THF (12 ml of a 2M solution) was added and the reaction stirred for 1 hour. The THF layer was separated and concentrated in vacuo. The crude product was purified by column chromatography on silica (30 g), eluting with 100% EtOAc (300 ml) to give N,N,1-trimethyl-4-nitropyrazole-3-carboxamide, 1235 mg.
Reaction SMILES: C(N1C=CC(O)=CC1=O)CCC.[Br:13][C:14]1[CH:19]=[CH:18][N:17]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:16](=[O:24])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][N:17]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16](=[O:24])[CH:15]=1
Reactant: O=c1cc(Br)ccn1CC1CC1
Agent: CCCCn1ccc(O)cc1=O
Product: CCCCn1ccc(Br)cc1=O

Procedure:
Intermediate D7 was prepared from intermediate D5 following the same procedure implemented for the synthesis of D3.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=O)=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.P(Cl)(Cl)(Cl)=O>>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:20])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: NC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
One gram of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and 5 ml. of phosphorus oxychloride is refluxed for 3 hours. The reaction mixture is evaporated to dryness and the residue is dissolved in methylene chloride, washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate. After passing through a short pad of hydrous magnesium silicate with eluent methylene chloride. Concentration of the eluent with addition of n-hexane gives the product, m.p. 141°-143° C.
Reaction SMILES: [C:1]1(O)C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([C:23]([OH:31])([C:26]2SC=CN=2)[CH2:24][CH3:25])[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1>>[F:8][C:9]1[CH:10]=[C:11]([C:23]([OH:31])([CH2:24][CH3:25])[CH2:26][CH3:1])[CH:12]=[C:13]([OH:15])[CH:14]=1
Reactant: Oc1ccccc1
Reactant: CCC(O)(c1cc(F)cc(OCc2ccccc2)c1)c1nccs1
Product: CCC(O)(CC)c1cc(O)cc(F)c1

Procedure:
Following the procedure described for Phenol 1, Step 3, but substituting 5-fluoro-3-(3-hydroxypent-3-yl)[O-(3,4-dimethoxybenzyl)]phenol from Step 2 for 5-fluoro-3-[1-hydroxy-1-(thiazol-2-yl)propyl](O-benzyl)phenol the title compound was obtained as a solid.
Reaction SMILES: [OH:1][C@:2]([CH3:12])([CH2:7][C:8]([O:10]C)=[O:9])[C:3]([O:5]C)=O.ClC(Cl)(Cl)[C:15]([N:17]=C=O)=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:12][C@:2]1([CH2:7][C:8]([OH:10])=[O:9])[O:1][C:15](=[O:16])[NH:17][C:3]1=[O:5]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COC(=O)C[C@@](C)(O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@]1(CC(=O)O)OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of (R)-dimethyl 2-hydroxy-2-methylsuccinate (530 mg, 3.0 mmol) in DCM (10 mL) at 0° C. was added dropwise trichloroacetyl isocyanate (530 mL, 4.5 mmol). The ice bath was removed and the reaction mixture stirred for 2 h then quenched by the addition of MeOH (2 mL) and evaporated under reduced pressure to dryness. To the residue was added 1 M K2CO3 (15 mL, 15 mmol) and the reaction mixture heated at reflux for 0.5 h. The reaction mixture was allowed to cool to rt, extracted with Et2O (2×), then acidified to pH 2 by the addition of 1 N HCl and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was triturated with Et2O, and the triturate evaporated under reduced pressure. The residue was chromatographed by silica gel chromatography eluting with 1 to 10% MeOH/DCM (bromocresol green stain) to give Compound 42a (130 mg, 24% yield) as a clear colorless oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.95 (br. s., 1H), 3.14 (d, J=17.3 Hz, 1H), 2.97 (d, J=17.3 Hz, 1H), 1.62 (s, 3H). The structure was confirmed by single crystal X-ray diffraction analysis with material crystallized from Et2O/hexanes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].CN(C=O)C.C1COCC1.C(N(C(C)C)C(C)C)C.[C:53](Cl)(=[O:58])[O:54][CH:55]([CH3:57])[CH3:56].[Li+].[OH-]>>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:28][CH2:29][N:30]([C:53]([O:54][CH:55]([CH3:57])[CH3:56])=[O:58])[CH2:31][CH2:32]2)[CH3:26])[C:17]=1[CH3:33])=[O:15]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)C)CC2)c2ccccc12
Temperature: 0 °C
Yield: 55.2 %

Procedure:
A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S)—N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (0.467 g, 0.987 mmol) (Compound 326), DMF (2.468 ml, 0.987 mmol), THF (2.468 ml, 0.987 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.638 g, 4.94 mmol). The reaction was cooled to 0° C. and isopropyl carbonochloridate (0.160 ml, 1.086 mmol) was added drop wise via syringe. The reaction was allowed to stir for 2 h to rt and was then treated with 5 N LiOH for 1H to remove any acylated pyridone. This material was extracted with ethyl acetate, washed with brine, dried with MgSO4 and filtered and conc. in vacuo. The resulting material was purified via silica gel chromatography (50 g) using ethyl acetate/MeOH (5:1) as eluent to afford pure title compound as a pale yellow solid (0.300 g, 0.545 mmol, 55.2% yield). LCMS 523 (M+1)+; 1H NMR (DMSO-d6, 400) MHz) δ 11.59 (br. s., 1H), 7.74 (d, J=7.8 Hz, 1H), 7.69 (t, J=4.9 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.13-7.01 (m, 2H), 6.15 (s, 1H), 4.78-4.67 (m, 1H), 4.32 (d, J=4.9 Hz, 2H), 4.23-4.12 (m, 1H), 4.12-4.02 (m, 1H), 3.84 (s, 3H), 3.82-3.74 (m, 1H), 2.79-2.66 (m, 1H), 2.58 (s, 3H), 2.46-2.34 (m, 2H), 2.20 (s, 3H), 1.96-1.88 (m, 1H), 1.58-1.46 (m, 4H), 1.15 (d, J=6.0 Hz, 6H), 0.95-0.89 (m, 1H), 0.74-0.65 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:14].[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39].C(N(CC)CC)C.C(#N)C>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:38](=[O:39])[C:37]([Cl:42])([Cl:41])[Cl:36])=[CH:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:14]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(NC(=O)C(Cl)(Cl)Cl)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
14.3 g of 1-hydroxy-4-amino-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide obtained in Step (b) of Synthesis I, 6 g of trichloroacetyl chloride and 3.3 g of triethylamine were added to 300 ml of acetonitrile, and the mixture was refluxed for 4 hours. After conclusion of the reaction, the reaction solution was condensed to 100 ml and water was added thereto. The solution was then extracted with ethyl acetate. After removal of the ethyl acetate by distillation, n-hexane was added to the residue. The solid precipitate was separated by filtration and recrystallized from ethanol to obtain the object compound. Yield: 10 g. Melting point: 190° - 192° C.
Reaction SMILES: C([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[I:18])[C:11]([O:13]C)=O)C1C=CC=CC=1.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[CH2:11]([O:13][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[I:18])[CH2:11][OH:13])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(I)c(Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(I)c(OCc2ccccc2)c1
Yield: 196.5 %

Procedure:
A solution of 139 g (374 mmol) of methyl 3-benzyl-4-iodobenzoate in 550 ml of tetrahydrofuran is added dropwise to a solution of 12.9 g (563 mmol) of lithium borohydride in 150 ml of tetrahydrofuran and the reaction medium is then refluxed for 3 hours. After cooling, 300 ml of saturated aqueous ammonium chloride solution are added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. 125 g (97%) of 3-benzyloxy-4-iodobenzyl alcohol are obtained in the form of white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:28]2[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:27]2=[N:26][CH:25]=1)CCC>CO.ClCCl>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]([F:34])([F:35])[F:36])=[N:32][C:27]4=[N:26][CH:25]=3)[CH:3]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Brc1cccc(-c2ccccc2-n2cncn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccc4-n4cncn4)c3)cnc2n1

Procedure:
1-(3′-Bromobiphenyl-2-yl)-1H-[1,2,4]triazole (91 mg, 0.30 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.25 mmol) by the method of Example 32. The product was obtained by preparative thin-layer chromatography on silica gel with 3% methanol in dichloromethane as eluent followed by high performance liquid chromatography to give 3-[2′-([1,2,4]triazol-1-yl)biphenyl-3-yl]-7-trifluoromethylimidazo[1,2-a]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 8.57 (1H, d, J 7), 7.95-8.11 (3H, m), 7.48-7.66 (7H, m), 7.35 (1H, J 8), 7.27 (1H, m); m/z (ES+) 407 (M++H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C(N(CC)CC)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (15 mg, 81.1 μmol) and p-bromobenzenesulfonyl chloride (21 mg, 81.1 μmol) were combined in CH2Cl2 and treated with triethylamine (2 drops). The mixture was stirred at ambient temperature for 15 min, then poured onto a silica gel column and eluted with 1:1 CH2Cl2 : hexane. The product fractions were combined and evaporated to dryness in vacuo to provide the title compound as a solid which was dried in vacuo overnight at ambient temperature: (m.p. 177°-178°).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Zn]>[OH:21][C:19]([CH3:20])([CH:18]=[CH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:22][CH3:23])[CH:11]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: COc1cc(CCC=CC(C)=O)ccc1OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
Using 1.19 g of 6-(p-benzyloxy-m-methoxyphenyl)-3-hexen-2-one, 0.64 ml of ethyl bromoacetate and 0.33 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 25 (a) affording 1.28 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-4-heptenoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:20][CH:19]=2)=[O:17])=[C:13]([F:30])[CH:12]=1)(=[NH:10])[NH2:9]>S(Cl)(Cl)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([N:9]([CH2:8][CH:11]=[CH2:12])[CH2:2][C:3]([OH:5])=[O:4])=[O:27])=[CH:20][CH:19]=2)=[O:17])=[C:13]([F:30])[CH:12]=1)(=[NH:10])[NH2:9]
Reactant: N=C(N)c1ccc(OC(=O)c2ccc(CCC(=O)O)s2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: C=CCN(CC(=O)O)C(=O)CCc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 167.9 %

Procedure:
3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoic acid trifluoroacetic acid salt (38 mg, 0.084 mmol) was dissolved in thionyl chloride (500 μL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, M-21 (18.8 mg, 0.11 mmol), dichloromethane (200 μL) and pyridine (300 μL) were added to the obtained residue, and the mixture was stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (500 μL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (acetonitrile-water, each containing 0.1% trifluoroacetic acid, 5-35%) to give the title compound (25.5 mg, 0.047 mmol, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][CH2:15]Cl)[CH3:13])(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:28][C:24]=2[CH:23]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][CH2:15][N:32]2[CH2:31][CH2:30][CH:29]([C:27]3[NH:26][C:25]4[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=4[N:28]=3)[CH2:34][CH2:33]2)[CH3:13])(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: CN(CCCl)S(=O)(=O)c1cc(Cl)c(Cl)cc1C(F)(F)F
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Product: CN(CCN1CCC(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared using the procedure described in Example 1 using 4,5-dichloro-N-(2-chloroethyl)-N-methyl-2-trifluoromethyl-benzenesulfonamide (D12) and 4-(5-fluoro 1H benzimidazol-2-yl)piperidine (D17). MH+ 581/583/585.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:17]>O>[Cl:17][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 25.4 g of 2-amino-4-methyl-6-methoxypyrimidine in 150 ml concentrated hydrochloric acid was cooled to ca. 0° C. and treated with a solution of 25.3 g of sodium nitrite in 50 ml water, added over a period of 30-40 minutes. The thick orange reaction mixture was stirred at room temperature for 4-5 hours and then adjusted to pH 10 by addition of 12.5N sodium hydroxide solution. The precipitate was filtered and extracted thoroughly with approximately 600 ml of hot ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 7.2 g of 2-chloro-4-methyl-6-methoxypyrimidine as a white, crystalline solid, m.p. 36°-38° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=3)[N:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1cccc(NC(=O)c2ccc(F)cc2)n1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,6-Diaminopyridine (10.9 grams, 0.1 mole) was dissolved in 500 milliliters dichloromethane and trietbylamine (28.0 milliliters, 20.2 grams, 0.2 mole) was added. The solution was chilled to 0° C. before 4-fluorobenzoyl chloride (24.0 milliliters, 31.7 grams, 0.2 mole) was added drop-wise over the course of 30 minutes. After stirring for 2 hours at 0° C., the solution was allowed to warm to room temperature (25° C.) and stirred for 18 hours. The resulting precipitate was isolated by filtration and suction dried. The precipitate was recrystallized from 300 milliliters of refluxing ethanol, isolated by filtration, rinsed with ethanol, suction dried, and vacuum dried in an oven overnight. The yield was 34.0 grams of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:53]1[CH2:57][C:56](=[O:58])[NH:55][CH2:54]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:53]4[CH2:57][C:56](=[O:58])[NH:55][CH2:54]4)=[O:23])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (452 mg, 1.00 mmol, 1.00 equiv), dichloromethane (50 mL), EDCI (384 mg, 2.00 mmol, 2.00 equiv), HOBt (270 mg, 2.00 mmol, 2.00 equiv), TEA (303 mg, 2.99 mmol, 3.00 equiv), imidazolidin-4-one hydrochloride (135 mg, 1.10 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 200 mg (38%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Cc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(Cl)c(Cl)c1
Temperature: 135 °C
Yield: 98.7 %

Procedure:
To a solution of (3,4-dichlorophenyl){2-[3-(phenylmethoxy)phenyl]ethyl}amine (4.32 g, 0.011 mol) in chlorobenzene (40 ml) was added 4-hydroxy phenyl acetic acid (2.43 g, 0.014 mol), followed by phosphorus trichloride (5 ml, 0.005 mol). The reaction was allowed to reflux at 135° C. overnight. Solvent was removed and the reaction was basified with 10% sodium hydroxide solution. The reaction was diluted with ethyl acetate and water. The organic was washed with brine, dried with MgSO4, filtered, and concentrated to provide the title compound (5.5 g, 99% yield): ES-MS (m/z) 506 [M+H]+.