Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([C:10]2[CH:15]=[C:14]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=2[O:28][CH3:29])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.CCOC(C)=O>[C:24]([C:12]1[C:11]([O:28][CH3:29])=[C:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:30]=[CH:31][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:3][CH:4]=2)[CH:15]=[C:14]([C:16]2[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
step 3—To a solution of 140 (0.15 g, 0.36 mmol) in pyridine (3 mL) cooled to 0° C. was added methanesulfonyl chloride (0.053 g, 0.46 mmol) and the resulting solution stirred at 0° C. for 2 h, followed by 2 h at RT. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient to afford 0.17 g (97%) of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-methanesulfonylamino-N-methylbenzamide (142) as a white foam (0.17 g, 94%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33])=[O:9]
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc(N(CC)C2CCN(C)CC2)c1C
Temperature: 23 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, 1.80 g, 3.26 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt (916 mg, 4.24 mmol) in DMSO (10 mL) was added PyBOP (3.10 g, 5.87 mmol) and hunig base (1.20 g, 9.78 mmol). The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 Ethylacetate/MeOH=10/1) to give the titled compound as a white solid (264 mg, 17% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.20 (t, J=5.9 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 5.96 (s, 1H), 4.54 (d, J=5.9 Hz, 2H), 3.02 (q, J=7.0 Hz, 2H), 2.81 (m, 2H), 2.64-2.71 (m, 3H), 2.21-2.27 (s×3, 9H), 1.84-1.94 (m, 2H), 1.55-1.65 (m, 6H), 1.00 (t, J=7.4 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 473.1, [M+Na] 495.3; HPLC 94.7% purity.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22]([O-:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-methylthiazole-5-carboxylate in a mixture of tetrahydrofuran and water (2/1) is added lithium hydroxide monohydrate (6.9 equivalents) at ambient temperature. The reaction mixture is stirred at ambient temperature for 17 h and concentrated in vacuo. The residue is acidified by the addition of 4 M hydrochloric acid solution to pH ˜3. The solid is collected by filtration, washed with water and hexane, and dried in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 86.5 %

Procedure:
(+)-1-[(3-Chlorophenyl)phenylmethyl]piperazine (2.27 g, 7.90 mmol) prepared in the same manner as in Preparation Example 18 and N-cyclopropyl-6-chlorohexanesulfonamide (2.08 g, 8.69 mmol) were refluxed in N-ethyldiisopropylamine (10 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1)], to give (+)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (3.35 g) as a pale yellow oil (yield based on (+)-1-[(3-chlorophenyl)phenylmethyl]piperazine: 86.4%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42](Cl)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH:12]([C:42]([O:41][CH2:40][CH:38]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:39]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:43])[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1[CH:16]=[CH:17][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C

Procedure:
6.52 g (27.5 mmoles) of finely ground O-t-butyl-tyrosine (Chemical Dynamics Corp.) was placed in a 500 mL round bottom flask (oven dried) which was fitted with a condenser (oven dried). A nitrogen gas line was attached at the top of the condenser. The solid was suspended in 100 mL of dry dioxane and stirred vigorously. Diisopropylethylamine (9.04 mL, 80 mmoles) was added. Tms-Cl (6.98 mL, 55 mmoles) was added and let stir for 1 hour. Methylene chloride (200 mL) was added and the entire mixture was chilled in an ice bath. 9-Fluorenyl-methyloxycarbonyl chloride (6.47 g, 25 mmole) was added in one portion. The solution was stirred in ice for 20 minutes and warmed to room temperature for 1-1.5 hrs. The mixture was concentrated on a rotary evaporator and then distributed between 200 mL diethyl ether and 250 mL 2.5% sodium bicarbonate. The phases were separated and the aqueous layer was extracted with 2×50 mL diethyl ether. The ether layers were backwashed with 2×25 mL H2O. The combined aqueous layers were acidified to pH with 10% citric acid and extracted with 600 mL methylene chloride. The organic layers were dried over sodium sulfate, concentrated to an oil and dried by azeotroping with 2×30 mL acetonitrile. The oil solidified by pumping under high vacuum. Appropriate solvents were used to recrystallize the product. The product was found to be homogeneous (Table II).
Reaction SMILES: N#N.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[CH2:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]=[CH2:4])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: C=COC(=O)Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=COC(=O)Oc1ccc(C=C)cc1
Temperature: 5 °C

Procedure:
A 500 ml round bottom flask equipped with a reflux condenser, a mechanical stirrer , a thermometer, a dropping funnel and an efficient N2 blanket, is charged with 30.0 g (0.25 mole) of 4-vinylphenol, 21.8 g of pyridine and 300 ml of chloroform. The contents are then cooled down to 5 degrees C., and 25,3 g of vinyl chloroformate is added dropwise via the dropping funnel with constant stirring and the temperature maintained at 5 degrees or below. The temperature is then allowed to rise to ambient temperature and the mixture stirred overnight. The reaction mixture is then passed through a silica gel column and dried over magnesium sulfate and filtered. After the solvent is removed under pressure, the named product is recovered.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:32][C:33]3[CH:39]=[C:38]([C:40]#[N:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:27][CH2:26]1>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:26][CH2:27][CH:28]([C:31]5[NH:32][C:33]6[CH:39]=[C:38]([C:40]#[N:41])[CH:37]=[CH:36][C:34]=6[N:35]=5)[CH2:29][CH2:30]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Agent: Cl
Product: N#Cc1ccc2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Yield: 78.1 %

Procedure:
150 mg (0.5 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde described in example 1 and 136 mg (0.6 mmol) 2-piperidine-4-yl-3H-benzimidazole-5-carbonitrile hydrochloride salt were reacted and purified as described in example 6.0. 199 mg of the desired compound were obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH:23]=2)[CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (655.5 mg, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A44. A solution of 4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (254.1 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B44. Solution B44 was added to Solution A44 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (97.8 mg, 30%) as a white solid: MS (ESI) M+1=441.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][O:17][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCCN1S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of [1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (50.0 g, 0.16 mol) and 1H-imidazole (21.3 g, 0.31 mol) in CH2Cl2 (500 mL) was added tert-butylchlorodimethylsilane (35.5 g, 0.24 mol) in portions. After addition, the mixture was stirred for 1 hour at room temperature. The reaction was quenched with water (200 mL) and the separated aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum to give 1-(4-bromo-benzenesulfonyl)-2-(tert-butyldimethylsilanyloxymethyl)pyrrolidine (68.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.63-7.71 (m, 4H), 3.77-3.81 (m, 1H), 3.51-3.63 (m, 2H), 3.37-3.43 (m, 1H), 3.02-3.07 (m, 1H), 1.77-1.91 (m, 2H), 1.49-1.57 (m, 2H), 0.87 (s, 9H), 0.06 (d, J=1.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([CH:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CC1C=CC=CC=1C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:14]([CH3:15])[C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([OH:19])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1O
Yield: 98.8 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-pyrazol-5-amine (23 g, 119 mmol), dimethyl 2-acetylsuccinate (22.35 g, 119 mmol) in o-Xylene (200 mL) was added p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 2 h. The solid was filtered and washed with hexanes to afford (39 g, 99%) of the title compound. 1H NMR (500 MHz, METHANOL-d4) δ 8.14-7.95 (m, 1H), 7.93-7.79 (m, 1H), 7.51-7.27 (m, 2H), 6.62-6.35 (m, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH:34]2[CH3:40].C([O-])(O)=O.[Na+]>>[CH3:40][CH:34]1[C:33]2[C:37](=[C:29]([NH:28][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=4)[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[C:36](=[O:38])[N:35]1[CH3:39]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CC1c2cccc(N)c2C(=O)N1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4C)n2)cc1)OCC
Yield: 66.5 %

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (179.0 mg, 0.4224 mmol) and 7-amino-2,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 157A, 83.7 mg, 0.475 mmol). The reaction mixture was poured into a separatory funnel containing saturated NaHCO3 and was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified using a Teledyne/ISCO Combiflash system, eluting first with 40-100% EtOAc:Heptane and then 0-15% MeOH:CH2Cl2. The product was purified again by MDP (under basic conditions; ammonium bicarbonate buffer (pH 9)) to afford the title product as an off-white solid (158.3 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br s, 1H), 9.93 (s, 1H), 8.71 (br s, 1H), 8.48 (s, 1H), 7.38-7.80 (m, 3H), 7.15-7.33 (m, 3H), 4.59 (q, J=6.6 Hz, 1H), 3.90-4.02 (m, 4H), 3.22 (d, J=21.5 Hz, 2H), 3.01 (s, 3H), 1.43 (d, J=6.6 Hz, 3H), 1.18 (t, J=6.9 Hz, 6H). MS (ES+): m/z 564.17 (100) [MH+]. HPLC: tR=1.56 min (TOF, polar—3 min).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[CH:15]1([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[CH2:17][CH2:16]1.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>CCCCCC.O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]([CH:15]2[CH2:16][CH2:17]2)([OH:19])[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
13.8 ml (22.14 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 4.7 ml (22.14 mmol) of hexamethyldisilazane in 17 ml of tetrahydrofuran at −20° C., and the mixture was stirred at 0° C. for 30 min and then cooled again to −78° C. 2.17 ml (22.14 mmol) of ethyl acetate were added, and the mixture was stirred for 30 min and, after addition of 2.00 g (11.07 mmol) of 4-chlorophenyl cyclopropyl ketone, dissolved in 17 ml of tetrahydrofuran, stirred at −78° C. for a further hour. The reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The organic phase was washed successively with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) the acetonitrile was removed in a rotary evaporator, and the aqueous phase was extracted several times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 2.54 g (99% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.019 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (s, 9 H), 1.41 (t, J=11.77 Hz, 1 H), 1.58 (m, 1 H), 2.10 (s, 6 H), 2.77 (m, 4 H), 3.57 (s, 3 H), 3.65 (m, 1 H), 3.81 (d, J=9.56 Hz, 1 H), 4.07 (m, 4 H), 5.02 (d, J=5.52 Hz, 1 H), 6.92 (m, 4 H), 7.25 (m, 8 H), 7.56 (d, J=9.56 Hz, 1 H), 7.85 (m, 3 H), 7.96 (d, J=8.46 Hz, 2 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cc1cc(N)no1
Solvent: Brc1ccccc1
Product: Cc1cc(NC(=O)c2c(O)cc(C)n(C)c2=O)no1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 66.5 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 79 mg of 3-amino-5-methylisooxazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 141 mg of 1,6-dimethyl-4-hydroxy-N-(5-methylisooxazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 27) represented by the formula:
Reaction SMILES: [F:1][C:2](I)([F:13])[C:3](F)([F:11])[C:4]([F:10])(F)[C:5]([F:8])([F:7])[F:6].[F:15]C(F)=C(F)F>>[C:3](/[F:11])(\[C:2]([F:1])([F:13])[F:15])=[C:4](\[F:10])/[C:5]([F:6])([F:7])[F:8]
Reactant: FC(F)=C(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Product: F/C(=C(/F)C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A 240 mL Hastelloy shaker tube was flushed with nitrogen, then loaded with 5 g of aluminum chlorofluoride catalyst, cooled to -78° C., evacuated and loaded with 20 g (0.06 mole) of perfluorobutyl iodide and 50 g (0.5 mole) of tetrafluoroethylene. The reaction vessel was allowed to warm and kept on a shaker at 25-30° C. at autogenous pressure. Significant pressure drop (approximately 150 psi) was observed in the first 2 hours. After 18 hours, the pressure tube was unloaded. The product, 40 g, was collected in a -78° C. cold trap. According to 19F NMR, it was a mixture of 90% of perfluorobutene-2, mixture of cis and trans isomers in a 3:2 ratio and 10% of perfluoroethyl iodide. The calculated yield of perfluorobutene-2 based on converted perfluorobutyl iodide was 72%. According to 19F NMR, the main component (about 70%) of the residue (15 g) was a mixture of perfluorohexene-2, (minor) and perfluorohexene-3.