Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)#[N:2].C(N)CC.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1.Cl[C:41]1[N:46]2[N:47]=[CH:48][CH:49]=[C:45]2[N:44]=[C:43]([CH3:50])[CH:42]=1>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([C:41]2[N:46]3[N:47]=[CH:48][CH:49]=[C:45]3[N:44]=[C:43]([CH3:50])[CH:42]=2)[CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=1)#[N:2]
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCCN
Solvent: CCO
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)c1cc(C)nc2ccnn12

Procedure:
2.5 g (10.0 mmol) of N-(2'-cyanobiphenyl-4-yl)methyl-N-propyl amine (prepared from n-propylamine and 4-bromomethyl-2'-cyanobiphenyl by the method described in EP 490 820) and 1.8 g (10.7 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620) were heated with reflux in 20 ml dry ethanol for 4 h. The mixture was concentrated to halve of the volume in vacuo and cooled with ice, while the remaining starting amine crystallized. It was filtered with suction, and the rest of the solvent was removed. The title compound was obtained from the residue after column chromatography (silica gel, acetone/hexane 1:9 and 2:3) as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]#[C:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C.C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1C#CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCNC(=O)OC(C)(C)C
Yield: 51.9 %

Procedure:
10% Palladium on carbon (0.05 g) was added to a solution of methyl 6-(benzenesulphonylmethyl)-2-(3-t-butyoxycarbonylamino-prop-1-yn-1-yl)-3-(furan-3-yl)benzoate (Intermediate 132, 0.22 g) in ethanol (10 ml) and THF (10 ml) and the mixture was stirred at room temperature in an atmosphere of hydrogen (balloon) for 60 hours. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 25-60% to give methyl 6-(benzenesulphonylmethyl)-2-(3-t-butoxycarbonylaminopropyl)-3-(furan-3-yl)benzoate (0.115 g) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-][Mn](=O)(=O)=O.[K+].[CH2:16]1COCC1>>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C=O
Reactant: C1CCOC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(O)c1cccnc1N
Temperature: 25 °C

Procedure:
To a dry flask (dried with a heat gun under argon purge) was added dry THF (400 mL) and MeLi—LiBr (137 mL of a 1.5 M solution in Et2O, 204.9 mmol) via cannula. This solution was cooled to −78° C. when a solution of 2-aminopyridine-3-carboxaldehyde (10.0 g, 82.0 mmol) in THF (150 mL) was added dropwise via a pressure equalizing addition funnel over ˜45 min with vigorous stirring (exotherm observed, orange color persisted). Upon complete addition, the solution was allowed to stir for 1 hour at −78° C., at which time TLC (KMnO4 stain with heat) indicated that most of the starting material had been converted to product. The reaction was quenched very carefully with water (200 mL; dropwise initially), diluted with EtOAc (200 mL) and allowed to warm to rt. The layers were separated and the aqueous layer was extracted with 3% MeOH in EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Analogix; 0 to 5% MeOH in EtOAc) to give 7.78 g (68%) of the desired racemic product as a yellow oil that solidified under high vac over several days. This material was separated into its respective enantiomers (>98% ee) by SFC with a chiralcel OD-H (20×250 mm) column (10% EtOH/0.1% isopropylamine in heptane/0.1% isopropylamine).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(3-chloro-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C22H25ClN2O5 [M+H]+: 433.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])([O-:12])=[O:11]>C1COCC1.CCOC(C)=O.[Zn]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N+:10]([O-:12])=[O:11])[OH:16])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a slurry of activated zinc (6.25 g, 99.2 mmol) in 75 mL anhydrous THF, was added ethyl bromodifluoroacetate (11.0 mL, 85.8 mmol) and the mixture was heated to reflux. After a visible reaction had occurred, 2-nitrobenzaldehyde (5.0 g, 33.1 mmol) in 30 mL anhydrous THF, was added dropwise to maintain reflux. After 3 h, the solution was cooled to 23° C., diluted with EtOAc (50 mL), washed with 1M KHSO4 (2×50 mL) and brine (1×50 mL), and dried (Na2SO4). Concentration in vacuo yielded a residue which was purified by flash chromatography (chloroform:EtOH, 99:1) to afford 2-(3-ethoxy-3-oxo-2,2-difluoro-1-hydroxypropyl)nitrobenzene (8.28 g, 91%) as an orange oil, which was taken on to the next step without further characterization.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:24]1(/[CH:23]=[CH:22]/[CH2:21][C@H:15]([C@H:14]([OH:13])[CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)C[C@@H](C)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)[C@H](C/C=C/c1ccccc1)[C@@H](C)O
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of diisopropylamine (47.1 g, 466.1 mmol) in THF (500 mL) cooled to −50.degree. C. is added n-butyllithium (466.1 mmol, 2.5M in hexanes) and the resulting solution is stirred at −50.degree. C. for 0.5 h. The reaction mixture is cooled to −78.degree. C. followed by slow addition of methyl (3R)-3-hydroxybutanoate (25 g, 211.9 mmol). After 0.5 h a solution of cinnamyl bromide (45.9 g, 233.0 mmol) in HMPA (10 mL) is added and the reaction mixture is allowed to warm to 0.degree. C. and stirred for 16 h. The reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution, is poured into 400 mL of 1 M hydrochloric acid, and is extracted with two 500 mL portions of ethyl acetate. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% ethyl acetate-hexanes) to afford methyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxybutanoate as a yellow oil (42 g, 85% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:17])[CH2:15][Br:16])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C1C=CC=CC=1>[Br-:16].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:17])[CH2:15][N+:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:19]=1)([O-:9])=[O:8]
Reactant: c1ccncc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: O=C(C[n+]1ccccc1)c1ccc([N+](=O)[O-])cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suitable reaction vessel equipped with an agitator and thermometer is charged approximately 33 parts by weight of pyridine, approximately 100 parts by weight of 4-nitrophenacyl bromide, and about 600 parts by weight of benzene. The so charged mass is agitated for about 16 hours at room temperature, and thereafter the precipitate filtered off and dried. The product is N-(4-nitrophenacyl) pyridinium bromide, a white solid melting at 255-257° C., and which is soluble in water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CO.O>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Solvent: O
Solvent: CO
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CCOCC1
Yield: 70 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (60 mg, 70%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=429.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O-])([O-])=O.[K+].[K+].COS([O:23][CH3:24])(=O)=O>CC(C)=O.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(I)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
5-iodo-2-hydroxybenzoic acid (2.81 g, 10.6 mmol) was suspended in acetone (50 ml) and K2CO3 (6.77 g, 49.0 mmol) was added. The reaction was cooled in an ice water bath, and dimethylsulfate (2.4 ml, 25 mmol) was added via syringe. The reaction was warmed to room temperature, then heated to reflux, and stirred overnight. After 14.75 hours, the reaction was cooled to room temperature, diluted with water (150 ml), and stirred for 30 minutes. It was then extracted with EtOAc (3×50 ml), and the organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel (Biotage instrument, 5% EtOAc/hexanes->100% EtOAc) to give methyl 5-iodo-2-methoxybenzoate (3.08 g, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C(N(CC)CC)C.O.[NH2:18][NH2:19].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C(O)C>[F:8][C:7]1[C:2]([NH:18]/[N:19]=[CH:26]/[C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[N:3][C:4](=[O:9])[NH:5][CH:6]=1
Reactant: NN
Reactant: COc1ccc(C=O)cc1
Reactant: O=c1nc(Cl)c(F)c[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(/C=N/Nc2nc(=O)[nH]cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
A 25 mL vial was charged with 4-chloro-5-fluoropyrimidin-2(1H)-one (149 mg, 1.00 mmol),* ethanol (4 mL), triethylamine (148 μL, 1.06 mmol), and hydrazine monohydrate (52 μL, 1.07 mmol). The resulting yellow solution was agitated on an orbital shaker at room temperature for 3 h. 4-Methoxybenzaldehyde (123 μL, 1.01 mmol) was added, and the reaction mixture was heated at 50° C. for 16 h. After cooling to room temperature, the crude material was concentrated under reduced pressure and purified by reverse phase flash column chromatography to afford the title compound (49.3 mg, 19%) as a yellow solid: mp 202-208° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.60 (bs, 1H), 10.14 (s, 1H), 8.35 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.38 (t, J=5.9 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 3.80 (s, 3H); MS (ESI) ink 263 (M+H)+, 261 (M−H)−. *Driscoll, J. S.; Marquez, V. E.; Plowman, J.; Liu, P. S.; Kelley, J. A.; Barchi, J. J. J. Med. Chem. 1991, 34, 3280-3284. Yamashita, J.; Yamawaki, I; Ueda, S.; Yasumoto, M.; Unemi, N.; Hashimoto, S. Chem. Pharm. Bull. 1982, 30, 4258-4267.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CO[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C[CH2:26][O:27]C(C)=O>C1(C)C=CC=CC=1.CCO.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:26][O:27][C:13]1[CH:2]=[CH:3][C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH:12]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C=Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1cc(OC)ccc1-c1ccccc1

Procedure:
200 mg (0.83 mmol) of methyl 4-bromocinnamate were dissolved in dry toluene, added with 29 mg (0.025 mmol) of Pd(PPh3)4, a solution of 152 mg (0.91 mmol) of 4-methoxybenzeneboronic acid in 0.5 ml of EtOH, 1.66 ml of 2M Na2CO3 in water, and refluxed 2 h. Addition of EtOAc, washing with water, then with brine, filtration and flash chromatography (Merck silicagel) with Hexane/EtOAc mixtures from 95/5 to 8/2 gave 112 mg of methyl 3-(4-methoxybiphenylyl)acrylate, mp. 175-177° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1>>[ClH:1].[ClH:1].[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[CH2:28][CH2:27]2)[CH2:21][CH2:20]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Product: CN1CCC(CN2CCN(c3ccc(-c4ccc(C(F)(F)F)cc4)nn3)CC2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1-methylpiperidin-4-ylmethyl)piperazine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[C:18]1[CH:23]=[N:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][N:19]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[N:22]=[CH:23][C:18]([N:10]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:13][O:12][C:11]3=[O:14])=[N:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(Oc2cnc(Br)cn2)cc1
Reactant: O=C1NC(c2cccc(C(F)(F)F)c2)CO1
Product: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1

Procedure:
(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one is prepared from 4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and 2-bromo-5-(4-chloro-phenoxy)-pyrazine using the same conditions as example 4. 1H NMR (CDCl3, 400 MHz) δ 8.98 (d, 1H), 7.95 (d, 1H), 7.47˜7.62 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H), 5.82 (dd, 1H), 4.88 (t, 1H), 4.35 (dd, 1H); HPLC-MS calculated for C20H13ClF3N3O3 (M+H+) 436.1, found 436.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](Cl)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[F:30][C:31]([F:38])([F:37])[C:32]([CH3:36])([OH:35])[CH2:33][CH3:34]>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:35][C:32]([C:31]([F:38])([F:37])[F:30])([CH3:36])[CH2:33][CH3:34])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reactant: CCC(C)(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
900 mg of (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-chloro-3-oxo-1-propenyl]-cyclopropane carboxylate were dissolved in 3 ml of methylene chloride and 1 ml of 1-trifluoromethyl-1-methyl propanol was added thereto. The mixture was stirred for 16 hours at room temperature under inert atmosphere and away from humidity. After 3 days at room temperature, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, then with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 8-2 mixture of hexane-ethyl ether to obtain 570 mg of (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(1-trifluoromethyl-1-methyl-propyloxy) -1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[O:14]1CCCO[CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1.[N-]=C=S>C1(C)C=CC=CC=1.C(O)C.C(O)C.C1(C)C=CC=CC=1.C(O)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([NH:40][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:41]=[CH:42][C:36]=1[O:35][C:32]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:27]=[C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH:15]=[O:14])=[CH:25][N:24]=3)[S:34][C:33]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: [N-]=C=S
Solvent: CCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 2 (5.27 g, 27.0 mmol) in toluene (50.0 mL) and ethanol (50.0 mL) was added a suspension of intermediate 31 (9.52 g, 22.5 mmol) in toluene (20 mL) and ethanol (20 mL) over 30 min. After few minutes, more of isothiocyanate (1 g) in ethanol/toluene (5 mL/5 mL) mixture was added over 1 min. The reaction mixture was stirred at r.t. for an additional 30 min and concentrated under reduced pressure. The residue was triturated with toluene (70 mL), filtered and washed with toluene (20 mL) to afford a beige solid material that was suspended in 80% acetic acid (204 mL) and heated at 90° C. overnight. The reaction mixture was cooled down to r.t., and the precipitate was collected by filtration, washed with 80% AcOH (2×30 mL) to afford compound 33 (8.24 g, 72% yield) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)ccc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)OCn1cnc2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
Sodium metal (4.4 g, 19 mmol) was added to benzyl alcohol (100 ml) at ambient temperature and the mixture stirred for 30 minutes then heated at 80° C. for 1 hour. The mixture was then cooled to 40° C. and 7-fluoro-3,4-dihydroquinazolin-4-one (7.8 g, 47 mmol) was added. The reaction mixture was stirred at 130° C. for 4 hours and allowed to cool to ambient temperature and stirred for 18 hours. The solution was quenched with water (800 ml) and acidified to pH3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ether and dried for 4 hours at 60° C. under high vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (7.02 g, 63%). 7-Benzyloxy-3,4-dihydroquinazolin-4-one (7.0 g, 27 mmol) was suspended in dry DMF (50 ml) and sodium hydride was added (1.22 g of a 60% suspension in mineral oil, 30 mmol). The reaction mixture was allowed to return to ambient temperarture, chloromethyl pivalate (4.75 g, 31.5 mmol) was added over 10 minutes and the mixture was stirred for 1 hour. The reaction mixture was quenched into water (250 ml), the aqueous phase adjusted to pH5 with 2M hydrochloric acid and extracted with ether (3×300 ml). The combined ether phases were washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The solid residue was triturated with isohexane, collected by filtration and dried under vacuum to give 7-benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (9.1 g, 90%). 7-Benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.0 g, 22 mmol) was dissolved in TFA (40 ml) and the mixture was heated at reflux for 3 hours then allowed to cool to ambient temperature and stirred for 18 hours. The TFA was removed by evaporation and the residue resuspended in a mixture of ether and aqueous sodium hydrogen carbonate solution. The solid was collected by filtration, washed with water and ether and dried at 40° C. for 3 hours under high vacuum to give 7-hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (5.42 g, 90%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36](Cl)[CH:35]=4)[CH2:29][CH2:28]3)=[O:26])[CH3:23])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.Cl.[H][H]>[Pd].CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:31][CH2:32]3)=[O:26])[CH3:23])[O:15][CH2:16][CH2:17][O:18]2)=[CH:10][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2cccc(Cl)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccccc2)CC1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A suspension of 1.0 g (1.72 mmol) of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-(3-chlorophenoxy)piperidine oxalate, 0.3 g of 5% palladium on carbon, 40 ml methanol and 0.02 ml of saturated methanolic hydrogen chloride was heated at 50° under 50 psi hydrogen for 4 hours and allowed to cool to room temperature. The mixture was filtered and the methanol evaporated. The residue was dissolved in ether, washed with saturated sodium carbonate and saturated sodium chloride, and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The oxalate was recrystallized from ethanol to provide 0.42 g (45%) of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-phenoxypiperidine oxalate.