Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][SH:31].[F-].[Cs+].O>CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][S:31][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22]
Reactant: Fc1ccccc1CS
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2SCc2ccccc2F)nc1
Reaction time: 48 h
Yield: 82.5 %

Procedure:
5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (0.512 g, 1.46 mmol) and (2-fluoro-phenyl)-methanethiol (0.415 g, 2.92 mmol) were dissolved in dry DMSO (5 ml) and cesium fluoride (0.154 g, 2.92 mmol) was added to the clear solution. The resulting mixture was stirred at 20° for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product (0.55 g, 83%) was isolated by chromatography on silica gel eluting with a gradient (from 20-40%) of ethyl acetate in hexane. MS: 457, r.t.: 27, 1H-NMR (CDCl3, 400 MHZ) δ 9.05 (d, 1H, H—Ar), 8.44-8.41 (q, 1H, H—Ar), 8.05 (d, 1H, H—Ar), 7.34-7.27 (m, 2H, H—Ar), 7.13-7.02 (m, 2H, H—Ar), 4.61 (s, 2H, CH2 of the benzyl group), 3.16 (s, 3H, CH3 of the CH3SO2 group) ppm.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>C1COCC1.C(O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCC(=O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
200 mg of ethyl 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-4-oxobutanoate was dissolved in 2.0 ml of THF and 2.0 ml of ethanol, and 1.3 ml of aqueous 1M sodium hydroxide solution was added, followed by stirring at room temperature for 4 hours. After adding 1 M hydrochloric acid and water thereto, the insoluble materials were collected by filtration to obtain 180 mg of 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-4-oxobutanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH3:13])[C:9](=O)[O:10]C)=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[CH:19]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:16]=2)[N:3]=1.[H-].[Na+]>CN(C=O)C.O.CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[CH:19]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:16]=2)[N:5]=[C:6]2[C:7]=1[N:8]([CH3:13])[C:9](=[O:10])[NH:14]2
Reactant: COC(=O)N(C)c1c(N)nc(-c2cc(-c3ncco3)n(Cc3ccccc3F)n2)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2nc(-c3cc(-c4ncco4)n(Cc4ccccc4F)n3)nc(N)c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
To a solution of methyl 4,6-diamino-2-(1-(2-fluorobenzyl)-5-(oxazol-2-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl(methyl)carbamate (82 mg, 0.19 mmol) in DMF (3.7 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 15 mg, 0.37 mmol). The solution was immediately warmed to ambient temperature and stirred for 45 min. Water (3 mL) was added, and after stirring for 5 minutes, the crude reaction mixture was diluted with ethyl acetete (100 mL) and water (75 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were combined, washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, and filtered. The solvent was removed in vacuo to give the crude product as an orange solid. The crude material was brought up in ether (10 mL) and the orange solid was filtered off. The procedure was repeated to give 6-amino-2-(1-(2-fluorobenzyl)-5-(oxazol-2-yl)-1H-pyrazol-3-yl)-7-methyl-7H-purin-8(9H)-one (51 mg, 0.13 mmol, 67% yield) as a pink solid. 1H NMR (400 MHz, DMSO): δ 11.57 (s, 1H), 8.31 (s, 1H), 7.41 (s, 1H), 7.35-7.31 (m, 2H), 7.25-7.20 (m, 1H), 7.12 (t, 1H), 6.96-6.93 (m, 1H), 6.65 (s, 2H), 6.01 (s, 2H), 3.45 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C(O)C.C(OCC)(=O)C.[OH-].[Na+:35]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:35]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C

Procedure:
Esomeprazole obtained in example 14 (54.5 g; 157.78 mmol), was dissolved in a solution of aqueous NaOH (136.24 g; 4.88% w/w) and DM water (30 ml). The solution was washed with methylene chloride twice (200 ml×2). The aqueous layer was filtered and concentrated completely under reduced pressure to yield viscous mass. Ethanol was added to the viscous mass and concentrated under reduced pressure. Thereafter, ethyl acetate was added and concentrated to dryness under reduced pressure to yield solid mass. Further, ethyl acetate (400 ml) was added and stirred the mixture under reflux for 30 min. Cooled the reaction mass to 20-30° C. and stirred for 3 h. The separated solid was filtered, washed with ethyl acetate and dried under reduced pressure at 40° C. to yield esomeprazole sodium.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[C:31]([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)CC1
Reactant: CC(C)(C)C(=N)NO
Product: CC(C)(C)c1noc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.51 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13](O)[CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]>C(OC(=O)C)(=O)C>[CH:1]([C:4]1[C:12]([CH:13]=[CH:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(O)c1c(C(C)C)nn2ccccc12
Solvent: CC(=O)OC(C)=O
Product: CC=Cc1c(C(C)C)nn2ccccc12
Yield: 78.5 %

Procedure:
Five grams of 2-isopropyl-3-(1-hydroxypropyl)pyrazolo[1,5-a]pyridine (Example 8) were dissolved in 50 ml of acetic anhydride. The mixture was heated to reflux for 4 hours and concentrated to dryness. Water was added to the residue. The mixture was brought to alkaline by the addition of potassium carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-benzene (1:4) to give 3.6 g of the desired compound as pale yellow oil.
Reaction SMILES: O.[ClH:2].[ClH:3].Cl.[CH2:5]([N:7]([CH2:33][CH3:34])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[N:22][C:21]1[C:16](=[CH:17][CH:18]=[C:19]([O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:20]=1)[CH:15]=2)[CH3:6].S(=O)(=O)(O)O.ClN1C(=O)CCC1=O>>[CH2:29]([N:28]([CH2:31][CH3:32])[CH2:27][CH2:26][O:25][C:19]1[CH:18]=[CH:17][C:16]2[C:21]([C:20]=1[Cl:2])=[N:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([O:10][CH2:9][CH2:8][N:7]([CH2:5][CH3:6])[CH2:33][CH3:34])[C:24]=1[Cl:3])[CH:15]=2)[CH3:30]
Reactant: Cl
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)cc3nc2c1
Agent: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(Cl)c3nc2c1Cl

Procedure:
A 2.148 g. portion of 3,6-bis(2-diethylaminoethoxy)acridine trihydrochloride monohydrate is dissolved in 8 ml. of concentrated sulfuric acid. This solution is cooled in an ice bath and 1.175 g. of N-chlorosuccinimide are added. The procedure of Example 3 is followed giving 1.5 g. of a reddish brown crude product. This product is dissolved in 100 ml. of dichloromethane and filtered through a 2 inch×21/2 inch bed of alumina. The filter bed is washed with one liter of dichloromethane, then one liter of ethyl acetate. The filtrates are combined, concentrated in vacuo and the residue is crystallized from 10 ml. of hexane giving 1.067 g. of the desired product as yellow crystals, m.p. 83°-84° C.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[CH3:36][C:37]([O:40][C:41]([NH:43][C@H:44](C(O)=O)[CH2:45][N:46]1[N:50]=[CH:49][CH:48]=[CH:47]1)=[O:42])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(#N)C.C(OCC)(=O)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:44]([NH:43][C:41]([O:40][C:37]([CH3:39])([CH3:38])[CH3:36])=[O:42])[CH2:45][N:46]2[CH:47]=[CH:48][CH:49]=[N:50]2)[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1cccn1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cn1cccn1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.7 %

Procedure:
To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (909 mg, 1.97 mmol) in anhydrous dichloromethane (6 mL) at room temperature and under an atmosphere of nitrogen was added trifluoroacetic acid (6 mL, 173 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown viscous oil was dissolved in anhydrous acetonitrile (2 mL) and added to a solution of L-N-Boc-3-pyrazol-1-yl-alanine (500 mg, 1.97 mmol), N,N-diisopropylethylamine (1.4 mL, 7.87 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (747 mg, 1.97 mmol) in anhydrous acetonitrile (10 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was cooled to 0° C. diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 then 2:1 to give the title compound (999 mg, 95%) as a white foam, as a 2:1 mixture of diastereoisomers. LCMS (m/z) 500.1 [M+H], Tr=2.71 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:36][CH2:37][CH3:38])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CCCBr
Product: CCCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with propyl bromide
Reaction SMILES: [Na].[CH2:2]([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][OH:22]>>[CH2:2]([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([O:22][CH3:21])=[CH:16][N:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: Brc1cnc(C2CCN(Cc3ccccc3)C2)nc1
Agent: [Na]
Product: COc1cnc(C2CCN(Cc3ccccc3)C2)nc1
Temperature: 110 °C
Yield: 27.2 %

Procedure:
Sodium (362 mg, 15.75 mmol) was added portionwise to methanol (15 mL) at 22° C. until a homogeneous solution was obtained. The solution was then treated with 2-(1-benzyl-pyrrolidin-3-yl)-5-bromo-pyrimidine (1 g, 3.15 mmol) and heated in a sealed tube at 110° C. for 24 h. The mixture was cooled, concentrated in vacuo. The residue was purified by column chromatography to afford 2-(1-benzylpyrrolidin-3-yl)-5-methoxypyrimidine (230 mg 27.2%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:31].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:31])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)N(C)C)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
To a stirred solution of 2-benzyloxy-N,N-dimethyl-5-vinylbenzamide (560 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of 9-borabicyclo[3.3.1]nonane (255 mg) in tetrahydrofuran (8 ml) at −20° C. under an argon atmosphere, and the mixture was stirred for 14.5 hours at room temperature. To the stirred reaction mixture were added 2N aqueous sodium hydroxide solution (3.0 ml) and 30% aqueous hydrogen peroxide solution (2.4 ml) under ice-cooling, and the resulting mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:hexane/diethyl ether/dichloromethane=1/2/2 and methanol/diethyl ether/dichloromethane=1/10/10) gave 2-benzyloxy-5-(2-hydroxyethyl)-N,N-dimethylbenzamide (300 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:23][OH:24])[CH:22]=2)=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].N1C=CC=CC=1.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl>ClCCl.O>[C:41]1([NH:47][C:48](=[O:49])[O:24][CH2:23][C:21]2[CH:22]=[C:17]([O:16][C:15]3[CH:28]=[CH:29][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:6])([F:5])[F:7])[C:2]([F:33])([F:34])[F:1])=[CH:13][C:14]=3[CH2:30][CH2:31][CH3:32])[CH:18]=[CH:19][C:20]=2[N+:25]([O-:27])=[O:26])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(CO)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(COC(=O)Nc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of (5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrophenyl) methanol (221 mg, 0.444 mmol) in dichloromethane (2.2 mL), pyridine (72 μL, 0.889 mmol) was added. Phenylisocyanate (97 μL, 0.889 mmol) was added thereto under ice-cold conditions, and the resultant mixture was stirred at room temperature overnight. The reaction solution was added with water and 5% aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 5-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrobenzyl phenylcarbamate (249 mg, yield 91%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH:23]1([C:26]2[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[N:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=3)=[O:21])[O:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: NCc1nc(C2CC2)no1
Product: O=C(NCc1nc(C2CC2)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-cyclopropyl-1,2,4-oxadiazole-5-methanamine (CAS Registry No. 428507-31-7) as starting materials; LC-MS (UV peak area/ESI) 97.6%, 454.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: Cc1ccc(-c2c(C(=O)c3ccccn3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-methylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 393 ([M+H]+); Anal. Calcd for C23H15F3N2O.0.2H2O: C, 69.76; H, 3.92; N, 7.07. Found: C, 69.73; H, 3.79; N, 6.99.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Yield: 22 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.2 mL of a 0.46 M solution in toluene, 0.552 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.307 g, 1.1 mmol) were combined in toluene under nitrogen and heated to 110° C. After 4 h the toluene was replaced by xylenes (1 mL) and heating was continued under reflux overnight. After cooling to room temperature the crude reaction mixture was dissolved in CH2Cl2 and washed with saturated aqueous ammonium chloride solution then with brine. The organic layer was dired (MgSO4), filtered and evaporated to dryness. Chromotagraphy on silica gel eluting with 5% CH3OH in CH2Cl2 followed by a second chromatography step eluting with ethyl acetate provided 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 22%) as a yellow solid. MS (APCI); M++1: Calc'd, 580.32. Found 580.2. 1H NMR: 68 (400 MHz, DMSO) 8.50 (s, 1H), 8.26 (d, J=9 Hz, 1H), 7.94 (d, J=3 Hz, 1H), 7.39 (dd, J=3, 9 Hz, 1H), 6.78 (s, 1H), 5.89-5.98 (m, 1H), 4.15 (t, J=5 Hz, 2H), 3.86 (t, J=5 Hz, 2H), 3.56-3.62 (m, 6H), 3.09 (br t, J=5 Hz, 4H), 2.29-2.33 (m, 2H), 2.07-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.63-1.69 (m, 2H), 1.47 (s, 9H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[C:21](=[O:34])[N:20]([CH3:35])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:75][N:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1>O.CN(C)C=O>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([N:79]5[CH2:80][CH2:81][N:76]([CH3:75])[CH2:77][CH2:78]5)=[O:30])=[CH:32][CH:33]=4)[C:21](=[O:34])[N:20]([CH3:35])[CH:19]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)O)cc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCN(C)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic acid (7) (80 mg; 0.16 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (69 mg; 0.16 mmol), N,N-diisopropylethylamine (0.09 mL; 0.48 mmol), and N,N-dimethylformamide (1 mL) was stirred at room temperature for 0.5 hr. N-Methylpiperazine (80 mg; 0.8 mmol) was added and the mixture was stirred at room temperature for 16 hr. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was slurried with diethyl ether and filtered to give 4-tert-butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide (8) as a cream solid (50 mg), MS 593.35 (M+H)