Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@:8]1([C:13](=[O:22])[NH:14][S:15]([C:18]2([CH3:21])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH2:10][C@H:9]1[CH:11]=[CH2:12])(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[NH2:7][C@:8]1([C:13]([NH:14][S:15]([C:18]2([CH3:21])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[O:22])[CH2:10][C@H:9]1[CH:11]=[CH2:12]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Yield: 95 %

Procedure:
A solution of tert-butyl((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate (40 g, 116 mmol) in 4 N HCl in dioxane (400 mL) was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether to get crude compound (31 g, 95%). The crude compound was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97-9.29 (m, 2H), 5.47-5.66 (m, 1H), 5.32-5.44 (m, 1H), 5.22 (dd, J=10.04, 1.51 Hz, 1H), 2.38 (s, 1H), 2.03 (s, 1H), 1.71 (d, J=3.51 Hz, 1H), 1.46-1.52 (m, 4H), 1.25-1.35 (m, 1H), 0.88-1.01 (m, 2H). MS: MS m/z 245.14 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-])=O.O.O.[Sn](Cl)Cl>C(O)(=O)C>[NH2:20][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c(N)c1
Temperature: 75 °C
Reaction time: 7 h
Yield: 36.7 %

Procedure:
Methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (0.74 g, 2.47 mmol) was dissolved in acetic acid (9 mL) at 45° C. and tin (II) chloride dihydrate (2.22 g, 9.84 mmol) was added. The mixture was stirred at 75° C. for 7 h and then was concentrated in vacuo. The residue was transferred to an Erlenmeyer flask using a little ethyl acetate and diluted with ether (20 mL). The mixture was stirred while cooling in an ice-water bath and sodium hydroxide (50% solution in water) (6 mL) was added dropwise. The solid which formed was removed by filtration and was washed with hot ethyl acetate. The combined filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford methyl 2-[(3,4-diaminophenyl)carbonyl]benzoate as a yellow solid (0.245 g, 0.907 mmol, 37% yield). 1H NMR (400 MHz, d6-DMSO): 7.87 (dd, 1H), 7.65 (td, 1H), 7.57 (td, 1H), 7.32 (dd, 1H), 6.93 (d, 1H), 6.66 (dd, 1H), 6.44 (d, 1H), 5.49 (s, 2H), 4.69 (s, 2H), 3.57 (s, 3H); MS (EI) for C15H14N2O3: 293 (MNa+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7]2>O.C(O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:8]([C:21]([OH:23])=[O:22])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
An aqueous sodium hydroxide solution prepared from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 ml of water is added to a solution of 7.6 g (24.10 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in 241 ml of ethanol. The mixture is heated for two hours and then concentrated under reduced pressure. The resulting solid is taken up in 200 ml of water. The solution is washed with two times 100 ml of ethyl ether, acidified by successive additions of small amounts of concentrated hydrochloric acid and then extracted with 200 ml of ethyl acetate. The organic phase is finally washed with twice 100 ml of water, once with 50 ml of saturated sodium chloride solution, and dried over magnesium sulfate and concentrated under reduced pressure. This gives, after drying at 50° C. under reduced pressure, 6.4 g of the expected product, in the form of a solid which will be used as it is in the remainder of the synthesis.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A160) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH:1][C:27](=[O:28])[C@@H:26]([NH:25][C:23](=[O:24])[CH2:22][N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH3:30])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)[C@@H](N)Cc1ccnc(OC)c1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)[C@H](C)NC(=O)CN1CCOCC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
The crude (S)-methyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate (TFA salt, 7.7 mmol) was dissolved in DMF (10 mL). (S)-2-(2-morpholinoacetamido)propanoic acid (1.7 g, 7.7 mmol), HATU (4.40 g, 11.6 mmol) and DIPEA (1 mL) were added at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (30 mL×3) and the combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH=20:1) to afford (S)-methyl 3-(2-methoxypyridin-4-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate (1.5 g, 48% yield). (S)-methyl 3-(2-methoxypyridin-4-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate (800 mg, 2.00 mmol) was treated with a solution of lithium hydroxide-H2O (329 mg, 7.80 mmol) in water/THF (10 mL/10 mL) for 30 min. THF was removed and the aqueous phase was acidified to pH=3-4 with 1N aqueous HCl. The resulting mixture was concentrated to dryness to afford the corresponding acid, which was used directly without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][C@H:16]([CH3:23])[C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1>C(#N)C>[CH3:23][C@@H:16]1[C:17]2[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]3=[CH:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:14]5[CH2:15][CH2:16][CH2:17][CH2:13]5)=[CH:4][CH:5]=4)[N:14]([C:13]=23)[CH2:15]1
Reactant: C[C@H]1CN2C(c3ccc(CCl)cc3)=NC=C3C=CC(=O)NC1=C32
Solvent: CC#N
Product: C[C@H]1CN2C(c3ccc(CN4CCCC4)cc3)=NC=C3C=CC(=O)NC1=C32

Procedure:
This compound was prepared from intermediate 221b and the appropriate amine using the procedure described in Example 171, with the exception of using acetonitrile as solvent. Received 50 mg (11%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH2:14]O)=[CH:12][CH:11]=[C:10]([CH3:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:18].[Br-].[Li+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:18][CH2:14][C:13]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]([CH3:16])=[CH:11][CH:12]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(CO)c(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CBr)c(-c2cccc(Cl)c2)n1
Reaction time: 3 h

Procedure:
A solution of Example 36C (230 mg, 1.0 mmol) in DMF (1.5 mL) at 0° C. was treated with PBr3 (114 mL, 1.2 mmol) and lithium bromide (104 mg, 1.2 mmol), stirred for 3 hours, treated with water, adjusted to pH>7 with K2CO3, and extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N+:3]=1[CH2:9][C:10]([O:12]CC)=O.[Br-].C[O-].[Na+]>CO.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH2:9][C:10](=[O:12])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C[n+]1cc(Br)ccc1N
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CN2C=C(Br)C=CC2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide (2.86 g, 8.4 mmol) in methanol (30 mL) was added sodium methoxide (25 wt %, 2.5 mL, 10.1 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan solid. The crude material was purified by column chromatography eluting with 3, 5, and 10% methanol/dichloromethane. The product was obtained as a brown solid (56 mg, 3%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.67 (dd, J=1.6, 9.5 Hz, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.52 (s, 2H); MS (m/e): 215 (MH+); HRMS: calc'd MH+ for C7H5BrN2O 212.9672. Found 212.9664.
Reaction SMILES: C([O-])=O.[NH4+:4].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH2:4])=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: O=C[O-]
Product: NC(c1ccccc1)c1ccc(Br)cc1
Temperature: 150 °C
Yield: 72.5 %

Procedure:
Ammonium formate (20.1 g, 0.318 mol) was placed in a 3-neck flask equipped with temperature controller, mechanical stirrer and a condenser and heated at 150° C. 4-bromobenzophenone (7.2 g, 0.0276 mol) was added at once, the temperature was raised to 165° C. and the mixture was stirred at reflux for twnety-four hours. The reaction mixture was cooled to ambient temperature, triturated in ethyl acetate (350 mL), treated with charcoal and filtered through a Celite pad. The filtrate was concentrated, suspended in concentrated hydrochloric acid (120 mL) and heated at reflux for 8 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected by filtration. It was triturated in water (120 mL), basified with saturated solution of sodium bicarbonate in water and extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield (4-bromophenyl)(phenyl)methanamine (5.25 g, 0.02 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.C[O-].[Na+].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[NH:31])[NH2:30])[N:24]=1>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([OH:9])=[N:30][C:29]([C:25]2[N:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[N:31][C:11]=1[OH:13]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: N=C(N)c1cccnn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(-c2cccnn2)nc1O
Reaction time: 0.17 h

Procedure:
Dimethyl 2-(2-methoxyphenoxy)malonate (3.05 g, 12.6 mmol) (Ref. Canadian Patent Application No. CA2071193A, 1992) in methanol (15 ml) was added over 5 minutes to a stirred, 25% w/v solution of sodium methoxide in methanol (8.58 ml, 37.8 mmol of sodium methoxide) at room temperature. The resulting mixture was stirred for 10 minutes and then a solution of 3-pyridazinecarboximidamide hydrochloride (2.0 g, 12.6 mmol) in methanol (15 ml) was added dropwise over 5 minutes and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and then diluted with water (100 ml). The aqueous solution was acidified to pH 4 with sulfuric acid (20%), resulting in the formation of the title compound as a purple solid, which was isolated by filtration (1.4 g).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C(O)(=O)C>O>[C:18]([O:21][CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4])(=[O:20])[CH3:19]
Reactant: CC(Br)C(=O)c1ccc2c(c1)CN(C)C(=O)N2
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C)C(=O)c1ccc2c(c1)CN(C)C(=O)N2

Procedure:
A mixture of 6-(2-bromopropionyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone (2 g) prepared in Step 1, potassium acetate (2.64 g) and glacial acetic acid (20 ml) is refluxed for three hours. The reaction mixture is diluted with water and extracted with methylene chloride (3×50 ml) and the combined organic layers are washed with saturated aqueous sodium bicarbonate, dried, filtered and concentrated to obtain 6-(2-acetoxypropionyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone which is used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:5]3[C:4]=2[CH:3]=1.ClC1C=CC2NC(=O)N3N=C(C4CC4)N=C3C=2C=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=2)[CH:3]=1
Reactant: COCc1nc2c3cc(Br)ccc3[nH]c(=O)n2n1
Agent: O=c1[nH]c2ccc(Cl)cc2c2nc(C3CC3)nn12
Product: COCc1n[nH]c(-c2cc(Br)ccc2N)n1
Yield: 99.8 %

Procedure:
As described for example 1b) 9-bromo-2-methoxymethyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (20.9 g, 67.6 mmol), instead of 9-chloro-2-cyclopropyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one, was converted to the title compound (19.1 g, 99%) which was obtained as an off-white solid. MS: m/e=282.7/284.7 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[N:3]1.COC(C1C=CN=CN=1)=O.[H-].[Na+].CNN.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([CH3:38])[CH:31]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[C:5]2[C:6](=[NH:7])[N:2]([CH3:1])[N:3]=[C:4]2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[C:32]([CH3:38])[CH:31]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: Cn1nc(-c2ccncn2)cc1N
Agent: CNN
Agent: COC(=O)c1ccncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: Cc1cc(Br)ccc1C=C1C(=N)N(C)N=C1c1ccncn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To the suspension of 1-methyl-3-(pyrimidin-4-yl)-1H-pyrazol-5-amine (0.42 g, 2.4 mmol, prepared using A with methylpyrimidine-4-carboxylate (Ark Pharm) with NaH followed by B with methyl hydrazine) and 4-bromo-2-methylbenzaldehyde (0.48 g, 2.40 mmol, Ark Pharm) in acetonitrile (15 mL) was added p-TSA (0.09 g, 0.5 mmol) and heated to about 50° C. for about 5 h. The reaction mixture was cooled to ambient temperature and continued to stir for about 16 h. The precipitate was collected by filtration and dried under reduced pressure to afford 4-(4-bromo-2-methylbenzylidene)-1-methyl-3-(pyrimidin-4-yl)-1H-pyrazol-5(4H)-imine (0.43 g, 51%) as a light brown solid. LC-MS MS (Table 1, Method g) Rt=2.48 min, m/z 356, 358 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: Oc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 4.05 g of 2-benzyloxyphenol and 9.5 ml of N,N-dimethylformamide was added dropwise to a mixture of 0.80 g of sodium hydride and 20 ml of N,N-dimethylformamide under ice cooling and the mixture was stirred for 30 minutes. A mixture of 7.1 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 17 ml of N,N-dimethylformamide was added dropwise at the same temperature and the mixture was stirred for 1 hour. The reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed successively once with 1N—HCl and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica-gel column chromatography to give 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][S:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:29])=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][S:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:29])=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(SCc2ccccc2OCc2ccccc2)cc1

Procedure:
4-[2-benzyloxybenzylthio]benzoic acid (6.3 g) and oxalyl chloride (2.26 g) were stirred in dichloromethane (100 ml) for 18 hours. The solvent was evaporated to give 4-[2-benzyloxybenzylthio]benzoylchloride which was dissolved in dichloromethane.
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39](O)[CH:40]([OH:46])[CH2:41][CH2:42][CH2:43][CH2:44][OH:45].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:46][CH:40]([CH2:41][CH2:42][CH2:43][CH2:44][OH:45])[CH2:39][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCCC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCCCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 1.05 g, 2.0 mmol), 1,2,6-hexanetriol (0.54 g, 4 mmol) and pyridinium p-toluenesulfonate (100 mg, 0.4 mmol) in 150 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×60 mL), brine (60 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual (1.5 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-0.5% methanol in dichloromethane as eluent. This afforded 1.4 g of pure II as colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1ccccn1
Product: OC(c1ccc(Br)cc1)c1ccccn1

Procedure:
Using the same protocol as described in example 22, step 1, 2-bromopyridine (477 μL, 5.0 mmol) was added to 4-bromobenzaldehyde (1.018 g, 5.5 mmol). The crude residue obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[C:10]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CCc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH 1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=1.5 Hz, 2H), 8.05 (d, J=2.0 Hz, 2H), 7.69 (d, J=2.0 Hz, 2H), 7.67-7.36 (m, 3H), 7.28-7.15 (m, 5H), 6.77-6.73 (m, 2H), 6.62 (dd, J=8.8, 2.9 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.86 (s, 4H, 2.41 (s, 3H), 1.55 (s, 6H), MS (ES) m/e 562 M+1).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc(Oc2ccccc2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccccc2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (3.30 g), 2-chloro-4-phenoxybenzonitrile (2.30 g), anhydrous iron (III) chloride (1.60 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.15 g of desired compound (melting point: 135.0°-140.0° C.).