Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.CCCCCC.[CH:39](=O)[C:40]1[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:42].[Na].Cl>O>[CH:39]([C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[OH:42])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCCCCC=Cc1ccccc1O
Temperature: 5 °C

Procedure:
A suspension of n-heptyltriphenylphosphonium bromide (25.00 g, 0.057 mole), in dry, deaerated tetrahydrofuran (150 ml) was vigorously stirred at 5° C. under nitrogen and n-butyl lithium, 1.55 molar in hexane (46.6 ml, 0.073 mole, 1.3 equivalents), added dropwise. The reaction was stirred for 20 mins at 5° C., then treated dropwise with a suspension of sodium salicylaldehyde [prepared from salicylaldehyde (6.33 g, 0.052 moles) and one molar equivalent of sodium hydride in dry, deaerated THF (150 ml) under nitrogen] at 10° C. After stirring at 10° C. for 1 h, the reaction was poured into water (500 ml), acidified with dilute hydrochloric acid and extracted twice with diethyl ether. The combined organic extracts were washed with water (twice) and dried, (MgSO4). Evaporation of the solvent in vacuo yielded a pale yellow oil, which was purified by column chromatography using silica gel, eluting with dichloromethane/hexane [1:1] to give 6.14 g (58 %) of the single E isomer as a pale yellow oil.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[OH-].[Na+].[CH3:14][CH:15]=[O:16]>O>[F:11][CH:2]([F:1])[C:3]1[O:4][C:5]([CH:15]([OH:16])[CH3:14])=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1
Reactant: O=c1cc(C(F)F)occ1O
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1oc(C(F)F)cc(=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice bath cooled suspension of 2-difluoromethyl-5-hydroxy-pyran-4-one (1.00 g, 6.17 mmol), obtained as described in Example 4, in deionized water was added a 6.0M NaOH solution (1.23 mL, 7.40 mmol). A clear dark brown red solution was obtained, and CH3CHO (6.0 mL, 107 mmol) was added dropwise. After 2 hrs, the reaction mixture was cooled in ice and another 3 mL of CH3CHO (54 mmol) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The progress of the reaction was monitored by HPLC Method 1 as described above. Thus, after 24 hrs, the composition (% as peak percent area) of the reaction mixture was as follows: desired product (72%), starting material (7%), side products (15%, 2 major less polar components). The reaction mixture was cooled in ice and the pH was adjusted to 6 with the addition of a 6.0M HCl solution (1 mL). The mixture was concentrated in vacuo, and the residue was taken up in EtOAc. The organic layer was washed with brine (2×15 mL). The combined brine layers were back-extracted with EtOAc (2×). The organic fractions were combined, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of CH2Cl2 and MeOH (25/1, v/v) as eluant. Fractions rich in product were combined together, and concentrated to give 6-difluoromethyl-3-hydroxy-2-(1-hydroxy-ethyl)-pyran-4-one as an oil. HPLC purity (peak area percent) of this material is 88.0% at λ=280 nm using HPLC Method 1 as described above.
Reaction SMILES: CC([CH:5]1[CH2:11][N:10](C([O-])=O)[CH2:9][C:8]2[CH:15]=[C:16]([C:19]3[CH:20]=[C:21]4[NH:27][C:26]([NH:28][C:29]([O:31]CC5C=CC=CC=5)=[O:30])=[N:25][C:22]4=[N:23][CH:24]=3)[CH:17]=[CH:18][C:7]=2[O:6]1)(C)C.[ClH:39]>CO.O1CCOCC1>[ClH:39].[C:8]1([CH2:9][N:28]([C:26]2[NH:27][C:21]3[C:22]([N:25]=2)=[N:23][CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:7]4[O:6][CH2:5][CH2:11][NH:10][CH2:9][C:8]=4[CH:15]=2)[CH:20]=3)[C:29](=[O:30])[OH:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:7]=1
Reactant: CC(C)(C)C1CN(C(=O)[O-])Cc2cc(-c3cnc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)ccc2O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)N(Cc1ccccc1)c1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Temperature: 55 °C
Yield: 76 %

Procedure:
To the solution of 1,1-dimethylethyl-7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-imidazo[4,5-b]pyridine-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (4.5 g, 8.73 mmol) in methanol (20 ml) was added 4 N HCl in dioxane at room temperature. Then the reaction mixture was heated to 55° C. for 3 hours. After cooling to room temperature, the precipitate collected by filtration, washed with a minimum of methanol and dried to give phenylmethyl[6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (3.0 g, 76% yield). 1HNMR (400 MHz, CD3OD): 8.59 (m, 1H), 8.51 (s, 1H), 7.85 (m, 1H), 7.79-7.75 (m, 1H), 5.37 (s, 2H), 4.53 (s, 2H), 4.37-4.32 (m, 2H), 3.67-3.64 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33].O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNS(=O)(=O)C(C)C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
A solution of the compound of Example 53, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL CH2Cl2 was treated with triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated dropwise with isopropylsulfonyl chloride (0.351 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mL CH2Cl2 and 25 mL water and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from CH2Cl2/hexanes gave 308 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)propane-2-sulfonamide as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>CN(C=O)C>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:19][CH3:20])[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1Cl
Temperature: 70 °C
Yield: 97.7 %

Procedure:
Methyl-4-hydroxy-3-chlorobenzoate (10 g, 53.6 mmol) and potassium carbonate (14.8 g, 107.2 mmol) were suspended in DMF (110 ml) and then ethyl iodide (8.56 ml, 107.2 mmol) was added. The reaction mixture was heated to 70° C. overnight. The reaction mixture was filtered and the residue washed with ether. The organic solutions were evaporated in vacuo and then dissolved in EtOAc and washed with aq. NaOH and water, dried and evaporated to dryness in vacuo to afford the title compound (11.24 g) as a yellow oil. MS (ES): C10H1135ClO3 requires 214; found (MH+) 215.
Reaction SMILES: COC(=O)C[NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41](=[O:52])[CH2:42][CH2:43][CH:44](N)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48]>CCCCCCC.C(OCC)(=O)C>[CH3:50][O:49][C:47](=[O:48])[CH2:46][CH2:45][CH:44]([NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH2:43][CH2:42][C:41]([O:40][CH3:39])=[O:52]
Reactant: COC(=O)CCC(N)CCC(=O)OC
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CCC(CCC(=O)OC)NC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-heptanedioic acid dimethyl ester (J. Am. Chem. Soc. 2005, 127 (50), 17877-17887) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (69%). MS (ESI): m/z=669.19 [M+H]+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:35]=1)[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:16]=1)[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cc(Cl)cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cc(Cl)cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](Cl)=[O:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(Cl)c(Cl)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-dichlorobenzoyl chloride, there is obtained ethyl N-(3,4-dichlorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 138° C.;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[CH3:18][O:17][N:16]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
4-(Trifluoromethyl)benzoyl chloride (5.0 g, 23.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.3 mmol, 1.1 eq.) were combined in CH2Cl2 (200 mL) at 0° C. and treated with pyridine (4.3 mL, 52.6 mmol). After stirring for 2 hours, the mixture was allowed to attain ambient temperature, diluted with diethyl ether and washed with water, aqueous HCl, and water the organic phase was separated and concentrated to provide the title compound which was used directly in the next step. 1H NMR (300 MHz, d6-DMSO) 7.90 (m, 4H), 3.52 (s, 3H), 3.28 (s, 3H); MS (DCI/NH3) m/e 234 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[N:20]=[CH:21][N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=4)[C:11]3=[O:43])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[N:20]=[CH:21][NH:22][CH:23]=4)[C:11]3=[O:43])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1N(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C1N(c2c[nH]cn2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of racemic (1S,2R) and (1R,2S)-2-(4-chlorophenyl)-1′-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (115 mg, 0.2 mmol) in DCM (2 mL) and water (0.5 mL) was added TFA (0.1 mL) dropwise at 0° C. The mixture was stirred for 14 hours at room temperature. The mixture was poured into the sat. aqueous NaHCO3 solution, extracted with DCM (3×10 mL), dried and concentrated to give the title product. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as white powder (60 mg, 89%). LC/MS m/e calcd. for C19H14ClN3O: 335, observed (M+H)+: 336.1 1H NMR (400 MHz, DMSO-d6) δppm 2.13 (dd, J=9.09, 5.05 Hz, 1 H) 2.42 (dd, J=8.08, 4.80 Hz, 1 H) 3.23 (t, J=8.72 Hz, 1 H) 6.20 (d, J=7.58 Hz, 1 H) 6.81 (t, J=7.20 Hz, 1 H) 7.16 (t, J=7.83 Hz, 1 H) 7.30-7.45 (m, 5 H) 7.66 (s, 1 H) 8.27 (s, 1 H). MS calcd. for C19H14ClN3O 335, obsd. (ESI+) [(M+H)+] 336.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1(OC)[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:6]([C:7](O)=O)[CH:5]1[OH:16])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=O)[O:27]CC>C1COCC1>[CH2:1]([O:3][C:4]1[C:12]([O:27][CH3:26])=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:6]([CH3:7])[C:5]=1[OH:16])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC1=CC(OC)(OCC)C(O)C(C(=O)O)=C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc(C)c(O)c(OCC)c1OC

Procedure:
53 g of 3,5-diethoxy-2-hydroxy-3-methoxybenzoic acid prepared in Referential Example 5 and 45.5 g of triethylamine were dissolved in 400 ml of THF, and 48.4 g of ethyl chlorocarbonate in 100 ml of THF was dropwise added thereto with ice cooling while stirring. After the completion of the dropwise addition, the formed crystals were separated by filtration and washed with 100 ml of THF. The mother liquor was combined with the wash liquid, and a 10% aqueous solution of 30.3 g of sodium borohydride was added to the resultant solution and cooled by ice while stirring. After the completion of the dropwise addition, the mixture was stirred at room temperature for one hr, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane :ethyl acetate=95.5) to prepare 40 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([C:16]2(O)[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[O:19][CH2:18][CH2:17]2)[CH2:15][CH2:14]1.FC1C=C(F)C=C2C=1C(C1C3C(=C(CSC)C=CC=3)NC=1)(C)CCO2>>[CH:13]1([C:16]2([C:9]3[C:8]4[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=4)[NH:11][CH:10]=3)[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[O:19][CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: OC1(C2CC2)CCOc2cc(F)cc(F)c21
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Product: CSCc1cccc2c(C3(C4CC4)CCOc4cc(F)cc(F)c43)c[nH]c12

Procedure:
The title compound was prepared starting from 450 mg (2.54 mmol) of the compound from Example 8A and 574 mg (2.54 mmol) of the compound from Example 172A in analogy to the synthesis of the compound from Example 193. 80 mg (8% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CNCC1c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of 4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (7.5 g, Reference Example 4) in methylene chloride (100 ml), at 23° C., was treated dropwise with triethylamine (5.8 ml). After stirring for 15 minutes the mixture was treated dropwise with a solution of benzoyl chloride [prepared in a separate vessel by treating a stirred solution of benzoic acid (5 g) in methylene chloride (15 ml), at 23° C., with oxalyl chloride (5 ml) and after stirring for 2 hours evaporating the reaction mixture] in methylene chloride (3.5 ml). The resulting dark brown mixture was stirred for 1.5 hours at 23° C. then filtered. The filtrate was successively washed with water (100 ml), then twice with hydrochloric acid (100 ml, 1N), then with brine (100 ml), then water (100 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa) affording the title compound (10 g) as a viscous oil. 1H-NMR [400 MHz, (CD3)2SO at 383° K.] δ 1.13 (t, J=7 Hz, 3H); 3.49 (m, 1H); 3.65 (m, 1H); 3.75 to 3.90 (m, 2H); 3.90 to 4.20 (m, 2H); 4.09 (m, 2H);7.40 to 7.65 (m, 5H); 7.66 (d, J=8.5 Hz, 2H); 8.19 (d, J=8.5 Hz, 2H). MS [DCI (reactant gas, ammonia)]: 369[M+H]+, 386[M+NH4]+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[S:32]1[CH:36]=[C:35]([CH2:37][CH2:38][NH2:39])[N:34]=[CH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][CH2:37][C:35]1[N:34]=[CH:33][S:32][CH:36]=1)=[O:5]
Reactant: NCCc1cscn1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCc1cscn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), 2-(thiazol-4-yl)ethanamine (8.92 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(thiazol-4-yl)ethyl)acetamide (10.1 mg, 0.019 mmol, 40.2% yield): LCMS=542.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.82 (1 H, d, J=2.01 Hz), 8.13 (2 H, d, J=8.28 Hz), 7.49-7.72 (8 H, m), 7.08 (1 H, d, J=2.01 Hz), 5.08 (1 H, s), 3.53-3.69 (2 H, m), 3.03 (2 H, t, J=6.78 Hz); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)O.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH:37]1([Mg]Br)[CH2:39][CH2:38]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:37]1[CH2:39][CH2:38]1)[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(Br)cc2)N1CC(F)(F)F
Reactant: Br[Mg]C1CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccc(Br)cc2)(C2CC2)N1CC(F)(F)F
Reaction time: 0.08 h

Procedure:
To a −18° C. solution of 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (2 g, 4.6 mmol) in anhydrous THF (20 mL) was added triethylamine (2.6 mL, 18 mmol). The reaction was stirred for 5 min and then thionyl chloride (0.0.37 mL, 5 mmol) was added dropwise. After 10 min, 0.5M cyclopropylmagnesium bromide in THF (36 mL, 18 mmol) was added. The reaction mixture was warmed from −18° C. to 0° C. and allowed to stir for 6 hours and then quenched with 25 mL 1N aqueous HCl and extracted with 150 mL ethyl acetate. The organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (120 g silica gel cartridge, linear gradient 10-70% EtOAc/hexanes) followed by crystallization from hexanes gave 6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a green solid. 1H NMR (CDCl3, 400 MHz) δ 7.56 (s, NH); 7.46 (br d, 2H, J=8.61 Hz); 7.21 (dd, 1H, J=8.42 and 2.20 Hz); 7.12 (br d, 2H, J=7.14 Hz); 6.85 (br m, 1H); 6.68 (d, 1H, J=8.24 Hz); 4.27 (m, 2H); 1.6 (obs, 1H); 0.77 (m, 2H); 0.19 (m, 1H); 0.09 (m, 1H); MS (Electrospray): m/z 459.0 (M+H, Br=79).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
1-Bromo-4-pentylbenzene (T-1; 50.0 g), 3-fluorophenylboronic acid (31.4 g), potassium carbonate (91.2 g), Pd(Ph3P)2Cl2 (4.63 g), toluene (150 ml), Solmix A-11 (150 ml), and water (150 ml) were added to a reaction vessel under a nitrogen atmosphere, and heated under reflux for 3 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from Solmix A-11 and dried, whereby 45.2 g of 3-fluoro-4′-pentylbiphenyl (T-2) was obtained. The yield based on the compound (T-1) was 85%.