Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:11]/[OH:12]
Reactant: O=Cc1ccccc1O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O/N=C/c1ccccc1O
Temperature: 95 °C
Reaction time: 5 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 2-hydroxybenzaldehyde (20 g, 163.93 mmol) in ethanol (200 mL). To this was added (H2NOH HCl) hydroxylamine hydrochloride (14 g, 197.18 mmol). To the mixture was added triethylamine (19.2 g, 190.10 mmol) slowly. The resulting solution was allowed to react, with stirring, for 5 hours while the temperature was maintained at 95° C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The mixture was concentrated by evaporation. The resulting solution was extracted two times with 150 mL of ethyl acetate and water. The resulting mixture was washed 3 times with 150 mL of water. The mixture was dried over MgSO4 and concentrated by evaporator. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 10 g (43%) of (E)-2-hydroxybenzaldehyde oxime as a white solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]1=[O:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:24]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:8]([N:5]1[CH2:6][CH2:7][N:2]([N:1]=[C:32]3[CH2:31][CH2:30][N:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH2:34][CH2:33]3)[C:3](=[O:22])[CH2:4]1)(=[O:9])=[O:10])[CH:20]=[CH:19]2
Reactant: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Reactant: O=C1CCN(c2cccnc2)CC1
Solvent: Cc1ccccc1
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2cccnc2)CC1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Similarly to Example 3, a solution of 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (510 mg) and 1-(3-pyridyl)-4-piperidone (260 mg) in toluene (20 ml) was refluxed for 7 hours. The reaction mixture was cooled to room temperature, and the resultant crystal was collected by filtration to obtain the title compound (480 mg) as colorless crystals.
Reaction SMILES: [N:1]1([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=4)=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O-:26].[Na+]>C1(C)C=CC=CC=1>[N:1]1([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:26][CH3:25])[N:19]=4)=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cccc(-c2nnc3ccc(N4CCCCCCC4)nn23)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nnc3ccc(N4CCCCCCC4)nn23)n1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A mixture of 6-azocan-1-yl-3-(6-chloropyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (360 mg), sodium methoxide (570 mg) and toluene (20 ml) was stirred with heating under reflux for 3 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant crude crystal was washed with diethyl ether to obtain 6-azocan-1-yl-3-(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (290 mg) as pale yellow crystals.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.[CH:37]([NH:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][C:49]([CH:54]=[CH2:55])=[CH:48][C:47]=3[N:46]=[C:45]([NH2:56])[C:44]=2[N:43]=[C:42]1[CH2:57][CH2:58][CH3:59])([CH3:39])[CH3:38]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:37]([NH:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][C:49]([CH:54]=[CH:55][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[CH:48][C:47]=3[N:46]=[C:45]([NH2:56])[C:44]=2[N:43]=[C:42]1[CH2:57][CH2:58][CH3:59])([CH3:39])[CH3:38]
Reactant: C=Cc1ccc2c(c1)nc(N)c1nc(CCC)n(NC(C)C)c12
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1nc2c(N)nc3cc(C=Cc4cccnc4)ccc3c2n1NC(C)C
Temperature: 120 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A suspension of palladium (II) acetate (0.067 g, 0.30 mmol) and tri-o-tolylphosphine (0.271 g, 0.891 mmol) in 10 mL of MeCN was placed in a 50 mL heavy wall glass pressure flask and placed under an atmosphere of nitrogen. The mixture was stirred until homogeneous. The mixture was treated with triethylamine (1.58 mL, 11.9 mmol), 3-bromopyridine (0.430 mL, 4.46 mmol) and N-isopropyl-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.92 g, 3.0 mmol). Nitrogen was bubbled through the mixture for 1 min and then the flask was sealed. The reaction was heated to 120° C. After 15 h, the homogenous orange solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between 75 mL of CHCl3 and 25 mL of 10% Na2CO3 solution. The phases were separated and the organic portion was washed with H2O (25 mL). The combined aqueous portions were back-extracted with CHCl3 (25 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange solid. The solid was purified by chromatography (SiO2, 20–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield N1-isopropyl-2-propyl-7-(2-pyridin-3-yl-vinyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.97 g) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[Cl:18][C:19]1[C:20]([O:42][CH3:43])=[CH:21][C:22]([O:40][CH3:41])=[C:23]([CH2:25][CH2:26][C:27]2([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])[CH2:28]2)[CH:24]=1>>[Cl:18][C:19]1[C:20]([O:42][CH3:43])=[CH:21][C:22]([O:40][CH3:41])=[C:23]([CH2:25][CH2:26][C:27]2([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[O:32][C:31](=[O:33])[C:30]([CH2:2][C:3]3[NH:12][C:11](=[O:13])[C:10]4[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=4)[N:4]=3)=[C:29]([OH:34])[CH2:28]2)[CH:24]=1
Reactant: COc1cc2nc(CCl)[nH]c(=O)c2cc1OC
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4cc(OC)c(OC)cc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 20 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example B(57), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 20%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10](=O)CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)[C:3]=1[OH:28].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:28]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2O)cc(C(C)(C)C)c1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2ocnc2c1
Yield: 368 %

Procedure:
A solution of 2-bromo-4-chloro-6-(3,5-di-t-butyl-4-hydroxy-phenylacetyl-amino)-phenol (35.67 g, 76.1 mmol) and phosphorus oxychloride (41.8 ml, 457 mmol) in toluene was heated under reflux for 1 hour. Volatiles were removed in-vacuo and residual amounts of phosphorus oxychloride removed by azeotropic distillation with toluene (2×50 ml). The residue was taken up in acetone (50 ml) and ether (100 ml), and treated with water (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic solvents were removed in-vacuo and the precipitate collected to give 33.36 g (93.6%) of crude benzoxazole. The crude benzoxazole was dissolved in dichloromethane (100 ml), filtered, and the filtrate diluted with methanol (100 ml). The dichloromethane was removed by distillation and the resulting crystals collected, washed, and dried in-vacuo to give 28.86 g (80.9%) of the title compound (mp 133-6° C.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12]>O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CBr
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
To a mixture of sodium hydride (1.648 g, 68.66 mmol) in tetrahydrofuran (220 mL) at 0° C. was added 2,2,2-trifluoroethanol (5.0 mL, 68.66 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and methyl 2-bromoacetate (6.2 mL, 65.39 mmol) was added. After stirring for 72 hours, the mixture was filtered through diatomaceous earth with ether washes. The filtrate was concentrated and distilled to afford the title compound as a colorless oil (8.26 g, 73%), bp 155°-60° C., MS(CI): 173(M+H); H-NMR (300 MHz, DMSO-d6): 3.68(s, 3H), 4.16(q, J=9.2 Hz, 2H), 4.33(s, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([NH2:35])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1)[C:3]([NH:35][C:28]1([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]1)=[O:4]
Reactant: NC1(c2ccc(F)cc2)CCC(=O)CC1
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(C(=O)NC1(c2ccc(F)cc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 1-(4-fluorophenyl)-4-oxocyclohexylamine hydrochloride (Description 182) according to the method of Example 1. 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, s), 7.71 (2H, s), 7.29–7.25 (2H, m), 7.01–6.96 (2H, m), 5.73 (1H, s), 3.69 (1H, q, J 7.0 Hz), 2.80–2.77 (1H, m), 2.62–2.57 (1H, m), 2.44–2.28 (6H, m), and 1.51 (3H, d, J 7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NC1CCCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CCCC3)cc2)cn1
Yield: 11 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using cyclopentylamine instead of cyclopropylmethylamine, to the title compound (14 mg, 11%) which was obtained as an off-white solid. MS: m/e=413.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([CH2:10][CH3:11])[CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Cl)ccc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(Cl)ccc1O
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a solution of 4-chloro-2-ethyl-1-methoxybenzene (Preparation 5, 7.0 g, 41.0 mmol) in dichloromethane (20 mL) at 0° C. was added a 1M solution of boron tribromide in dichloromethane (20.5 mL, 20.5 mmol). After 2 hours, further boron tribromide solution (20 mL, 20.0 mmol) was added. After a further 2 hours, methanol was added and the reaction mixture concentrated in vacuo. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate in heptane) to afford the title compound (3.7 g, 58%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH:16]=[O:17])[O:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[O:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(Br)co1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2ccccc2)co1
Temperature: 110 °C
Yield: 78.8 %

Procedure:
Phenylboronic acid (1.46 g) was added to a stirred mixture of 4-bromofuran-2-carbaldehyde (2.00 g) and tetrakis(triphenylphosphine)palladium(0) (0.396 g) in N,N-dimethylformamide (57 mL) and a solution of sodium carbonate (3.03 g) in water (7 mL). The reaction was heated at 110° C. overnight. The resulting mixture was filtered and the filtrate was partitioned between water and diethyl ether. The layers were separated and the aqueous phase was extracted with diethyl ether. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:hexane=9:1) to obtain the title compound (1.55 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[Na]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Yield: 65 %

Procedure:
To a solution of tert-butyl-4-oxopiperidine-1-carboxylate (1.0 g, 0.005 mmol) in tetrahydrofuran (16 mL) in a microwave reaction vessel were added 4-chloroaniline (640 mg, 0.005 mmol) and sodium triacetoxyboryhidride (3.2 g, 0.015 mmol), followed by irradiating the solution with microwaves at 80° C. for 10 min. The reaction was terminated by the addition of distilled water. The resulting reaction mixture was diluted in ethyl acetate (100 mL) and washed with distilled water (200 mL) to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and evaporated at reduced pressure. Isolation and purification of the residue through silica gel chromatography produced tert-butyl-4-(4-chlorophenylamino)piperidine-1-carboxylate (yield: 65%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>C1COCC1>[N:29]([CH2:13][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=1)=[N+:30]=[N-:31]
Reactant: OCc1cccc(N2CCOCC2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 141 %

Procedure:
A solution of (3-morpholin-4-ylphenyl)methanol (0.10 g, 0.52 mmol), in THF (1.0 mL) was cooled to 0° C. and DPPA (0.13 mL, 0.62 mmol) was added, followed by DBU (0.093 mL, 0.62 mmol). The solution was allowed to warm to r.t. and stirred for 12 h. The solution was poured into EtOAc (100 mL) and this was washed with H2O (50 mL) and 5% HCl(aq) (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 0.16 g (>100% yield) of 4-[3-(azidomethyl)phenyl]morpholine, (TLC: UV active spot, Rf of 0.7 in 1:1 hexanes/EtOAc), which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(=O)(O)[O-].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][CH:32](C([O-])=O)[C:33]([O:35]CC)=[O:34]>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:32](\[CH2:31][C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)/[C:33]([OH:35])=[O:34])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)[O-]
Agent: O=S([O-])O
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
Alternately, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid and (2-thienylmethyl)propanedioic acid, mono-ethyl ester are reacted to give (E)-α-[[2-butyl-1-[(4carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophene propanoic acid by heating the two substrates in toluene at reflux under reduced pressure and in the presence of piperidine as catalyst followed by hydrolysis of the intermediate ester ethyl (ethyl (E)-α-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoate). In this preparation, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid, (2-thienylmethyl)propanedioic acid, mono-ethyl ester, and toluene are charged to a glass lined steel vessel and are initially heated to 55-60° C. to afford a homogenous solution. The catalyst (66 mol % piperidine) is added and the reaction is heated to reflux (70-75° C.) under reduced pressure. Reflux conditions are maintained for 20-35 hours and additional (2-thienylmethyl)-propanedioic acid, mono-ethyl ester is added. Once the reaction is complete, water and aqueous sodium hydroxide are added to the vessel and the reaction mixture heated at reflux under atmospheric conditions for 1-3 hours. The reaction is deemed complete when the level of ethyl (E)-α-[[2-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene]-2-thiophene propanoate is less than 2.0%. The reaction is cooled to 45-50° C. and the aqueous and organic phases separated. The toluene phase is discarded. Ethanol is added to the aqueous phase and the solution is acidified with aqueous hydrochloric acid until a pH of 5.0 to 5.4 is achieved, maintaining the temperature at 50-55° C. The product slurry is cooled and allowed to stir at 10-15° C. for 2 hours. The product is isolated by centrifugation, washed and stored. Thereafter, pharmaceutically acceptable salts may be prepared as described above.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH3:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:19]([C:21]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=2)=[CH:25][CH:24]=[CH:23][N:22]=1)#[N:20].[NH4+].[Cl-]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([C:5]1[N:14]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]3[C:21]([C:19]#[N:20])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:32][CH:31]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ncccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(=O)c2cc(C)ccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2cccnc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-butyl-6-methylquinazolin-4(1H)-one (1.0 eq.) from Example 1 Step B in DMF at rt is added NaH (1.5 eq. of an 80% dispersion in oil). After 20 min, 2-cyano-3-(4-bromomethylphenyl)pyridine (1.2 eq.) is added and the mixture is stirred at rt for 3 h. Brine (100 mL) and aqueous NH4Cl (40 mL) are added and the product is extracted with EtOAc. Purification by flash chromatography gives the above titled compound.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[C:42]([CH3:45])[CH:43]=[CH:44][C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1cc(C)ccc1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cc(C)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 2.5 mL, 5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of 2-chloro-N-methoxy-5,N-dimethyl-benzamide (852 mg, 4.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The obtained residue was purified via column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (543 mg) in 48% yield. ESMS m/z (relative intensity): 534.9 [(M−32+H)]+ (35), 588.9 (M+Na)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:16][C:17]([OH:19])=O)[C:7]1=[O:20])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:45][C:46]1[C:47]([O:55][CH3:56])=[CH:48][C:49]([O:53][CH3:54])=[C:50]([NH2:52])[CH:51]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:16][C:17](=[O:19])[NH:52][C:50]2[CH:51]=[C:46]([Cl:45])[C:47]([O:55][CH3:56])=[CH:48][C:49]=2[O:53][CH3:54])[C:7]1=[O:20]
Reactant: COC(=O)CN1Cc2ccccc2N(CC(=O)O)C1=O
Reactant: COc1cc(OC)c(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1Cc2ccccc2N(CC(=O)Nc2cc(Cl)c(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (3-methoxycarbonylmethyl-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-acetic acid (Intermediate J) (395 mg, 1.078 mmol), HATU (594 mg, 1.186 mmol) and 5-chloro-2,4-dimethoxy-phenylamine (293 mg, 1.186 mmol) in DCM (5 ml) is treated with DIPEA (2.5 eq, 618 μL). The reaction solution is stirred at RT and after 24 hours the reaction mixture is diluted with 1 M HCl (5 ml) and extracted with DCM (2×15 ml). The combined separated organic layers are washed with aqueous saturated NaHCO3. The organic phase is dried over MgSO4, filtered and is concentrated in vacuo to afford the title compound as off-white solid; [M+H]+ 448.