Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.C1C2CC(=[O:22])C(C2)C1.N1CCOCC1>C1(C)C=CC=CC=1>[O:22]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: O=C1CC2CCC1C2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 6.6 g (0.06 mole) of norcamphor and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction. toluene was removed under reduced pressure, and the remaining chromanone compound was recrystallized from acetone, and the chromanon compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° C. to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.1 g of a chromene compound represented by the following formula: ##STR71##
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].C(O)C>O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1
Reactant: CCCCCCc1ccc2nc(-c3ccc(OC(C)=O)cc3)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.3 %

Procedure:
To 0.7 g (2.0 mM) of 2-(p-acetoxyphenyl)-6-hexylbenzothiazole, 0.25 g (6.0 mM) of sodium hydroxide and 50 ml of ethanol, followed by stirring for 10 hours at room temperature. After the reaction, the reaction mixture was poured into water, and 2 ml of concentrated hydrochloric was added thereto to precipitate a crystal. The crystal was recovered by filtration and sufficiently washed with water, followed by drying to obtain 0.6 g of 2-(p-hydroxyphenyl)-6-hexylbenzothiazole (Yield: 96.5%).
Reaction SMILES: C([O:9][CH:10]([C:18]([F:21])([F:20])[F:19])[C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13])(=O)C1C=CC=CC=1.[Na+:22].[OH-].[Na+]>O>[OH:9][CH:10]([C:18]([F:21])([F:19])[F:20])[C:11]([F:16])([F:17])[S:12]([O-:15])(=[O:14])=[O:13].[Na+:22]
Reactant: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reaction time: 1 h

Procedure:
In 43 g of water was dissolved 14.6 g of sodium 2-benzoyloxy-1,1,3,3,3-pentafluoro-propane-1-sulfonate synthesized in Synthesis Example 9. The solution was stirred under ice cooling. To the solution, 7.4 g of a 26% sodium hydroxide aqueous solution was added dropwise at a temperature below 10° C. The reaction solution was aged for 1 hour at the temperature and for a further 1 hour at room temperature. The solution was washed with toluene, from which an aqueous layer was separated. It was an aqueous solution of the target compound, sodium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate. Without further isolation, the aqueous solution was directly analyzed by NMR spectroscopy and TOFMS for confirming the formation of the target compound.
Reaction SMILES: [OH-].[Li+].[Cl:3][CH2:4][CH2:5][O:6][CH:7](P(OCC)(OCC)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)[CH:28]=O.C(O)C>C1COCC1.C(OCC)(=O)C.O>[Cl:3][CH2:4][CH2:5][O:6]/[C:7](=[CH:28]\[C:27]1[CH:30]=[CH:31][C:32]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]2)=[C:25]([O:24][CH3:23])[CH:26]=1)/[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CCOP(=O)(OCC)C(OCCCl)C(=O)OC(C)(C)C
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(/C=C(\OCCCl)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.9 %

Procedure:
Lithium hydroxide (52.1 mg) was added to a solution of tert-butyl 2-chloroethoxy-(diethoxyphosphoryl)acetate (240 mg) synthesized by a technique described in a document (see C. J. Moody et al., “Tetrahedron”, 1992, vol. 48, p. 3991, for example) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (173 mg) in a mixture of THF (5.0 mL) with ethanol (1.0 mL), and the reaction solution was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system) to obtain 51 mg of the title compound.
Reaction SMILES: O[N:2]=[C:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:12][C:4]1[C:3]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:2][O:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1onc(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 117.4 %

Procedure:
Ethyl 4-(hydroxyimino)-3-methyl-2-oxo-4-(pyridin-4-yl)butanoate (4.68 g, 18.7 mmol) and triethylamine (3.4 mL, 24.3 mmol) were added to 120 mL of CH2Cl2. Mesyl chloride (1.9 mL, 24.3 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with CH2Cl2 and saturated sodium bicarbonate solution was added. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was washed with brine and dried over MgSO4. The solvent was removed in vacuo to afford 5.1 g of the title compound. MS: (+) m/z 233.35 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C@H:20]([CH:40]([OH:42])[CH3:41])[C@:21]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)([O:28][Si](C)(C)C)[CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1.O>O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@:21]([OH:28])([C@H:20]([CH3:19])[CH:40]([OH:42])[CH3:41])[CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:34][CH:35]=1
Reactant: CC(O)[C@@H](C)[C@@](Cn1cncn1)(O[Si](C)(C)C)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)[C@@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
0.35 ml (0.35 mmole) of tetrabutylammonium fluoride (as a 1 molar tetrahydrofuran solution) was added to a solution of 85.4 mg (0.233 mmole) of (2R*,3R*)-3-methyl-2-(4-chlorophenyl)-2-(trimethylsilyloxy)-1-(1H-1,2,4-triazol -1-yl)-4-pentanol (prepared as described in Preparation 7) in 2.5 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 64 mg (93%) of the title compound. Judging from the NMR spectrum, this compound is thought to be about a 5:1 mixture of the (2R*,3R*,4S*) isomer and the (2R*,3R*,4R*) isomer.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:10](Cl)[CH:11]=[CH2:12].C1CCCCC1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:7][CH2:12][CH:11]=[CH2:10])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCl
Reactant: OCc1ccco1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: C=CCOCc1ccco1

Procedure:
14 g of benzyltrimethylammonium chloride and 490 g of furfuryl alcohol are added in succession to 800 g of 50% strength sodium hydroxide solution at 45° C. 425 g of allylchloride are added dropwise over a period of about one hour, the reaction mixture heating up slowly and later boiling under reflux. The reaction is allowed to go to completion for an additional hour at a bottom temperature of about 80° C., and 100 ml of cyclohexane and 700 ml of water are added. The salt phase is separated off and the organic phase is washed 3 times with 200 ml of water and then freed from water by azeotropic distillation. The crude product is fractionated over a short column, 548 g of approximately 96% pure allyl furfuryl ether being obtained at 69° C. to 70° C./13 hPa, the structure of which is confirmed by the 1H-NMR spectrum (furfuryl signals at δ=7.39; 6.33; 6.31; 4.45 ppm). The remaining 4% comprises dioxatricyclodecene as an internal cyclo addition product from the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (39 mg, 36%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.C(O)(=O)C.[ClH:42].O>O1CCOCC1>[ClH:42].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C

Procedure:
The title compound is prepared using the previously described procedures and the following reagants: 1.17 g (2.3 mmoles) t-butyloxycarbonyl-isoleucyl-valyl-tryptophan, 10 ml glacial acetic acid and 10 ml 6.07 HCl in dioxane. Total yield was 0.91 g. (88 percent). Analysis calculated for C22H32N4O4.HCl. H2O: C, 56.10; H, 7.49, N, 11.90. Found: C, 56.34; H, 7.48; N, 11.72.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:11]=2[O:10][CH:9]=1)=[O:6].[H-].[Na+]>CN(C)C=O>[CH3:23][S:20]([NH:19][C:17]1[C:16]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][C:12]2[C:13](=[O:14])[C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][O:10][C:11]=2[CH:18]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Nc1cc2occ(NC(=O)CCCCl)c(=O)c2cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2occ(N3CCCC3=O)c(=O)c2cc1Oc1ccccc1

Procedure:
3-(4-Chlorobutyrylamino)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with sodium hydride in N,N-dimethylformamide to obtain 7-methylsulfonylamino-3-(2-oxopyrrolidin-1-yl)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O>>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.76 (s, 1H), 8.49 (d, J=9.3 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.64-7.42 (m, 3H), 3.75 (s, 3H). m/z (ESI) 485.0 (M+H)+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:20])(=O)[C:17]#[CH:18].[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.ClCCl.CO>ClCCl>[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]([NH:27][C:16](=[O:20])[C:17]#[CH:18])=[CH:25][CH:26]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: C#CC(=O)Nc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
9.38 g (45.5 mmol) of DCC are added batchwise to a solution of 2.89 g (41.36 mmol) of propynoic acid in 100 mL dichloromethane at −15° C. and stirred for 1 hour. Then a solution of 7 g (41.36 mmol) of biphenyl-4-ylamine-15° C. is added dropwise to 30 mL dichloromethane and stirred for 2 hours. After this time, the cooling bath is removed and the reaction mixture is allowed to come up to ambient temperature. 20 g of CELITE® filter aid is added to the reaction mixture and it is then filtered. The filtrate is evaporated down in vacuo. The residue is combined with acetonitrile and stirred. The suspension is filtered, the filtrate is evaporated down and the residue is stirred with petroleum ether and pentane. The solid is isolated by filtration. Yield: 5.5 g (60.1% of theory); C15H11NO (M=221.26); calc.: molecular ion peak (M+H)+: 222; found: molecular ion peak (M+H)+: 222; Rf value: 0.7 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:16]=1[CH2:17][N:18]1[CH2:22][CH:21]([CH:23]([OH:25])[CH3:24])[CH2:20][C:19]1=[O:26]>ClCCl.O>[CH3:1][S:2]([O:25][CH:23]([CH:21]1[CH2:20][C:19](=[O:26])[N:18]([CH2:17][C:16]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:15]=2[O:14][CH3:13])[CH2:22]1)[CH3:24])(=[O:4])=[O:3]
Reactant: COc1ccc(CN2CC(C(C)O)CC2=O)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN2CC(C(C)OS(C)(=O)=O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
MsCl (3.3 g, 28 mmol) and Et3N (3.8 g, 38 mmol) were added to a mixture of 1-(2,4-dimethoxybenzyl)-4-(1-hydroxyethyl)pyrrolidin-2-one (5.0 g, 19 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 10 hours then diluted with water and extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford 1-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl]ethyl methanesulfonate. 1H NMR (400 MHz, CDCl3) δ 7.10˜7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.76-4.78 (m, 1H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.36-3.42 (m, 1H), 3.12-3.19 (m, 1H), 2.98 (s, 3H), 2.23-2.59 (m, 3H), 1.26-1.42 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C16H24NO6S [M+H]+ 358. found 358.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:11]=1
Reactant: Brc1ccccn1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccccn1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-bromopyridine (Acros), the title compound was obtained as a beige powder after purification by precipitation in acetonitrile.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]1.S(=O)(=O)(O)O.[N+:27]([O-])([O-:29])=[O:28].[Na+]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:27]([O-:29])=[O:28])=[CH:4][C:3]=1[C@:9]1([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:16])([F:17])[F:18])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: NC1=N[C@](CF)(c2cccc(F)c2F)C[C@@H](C(F)(F)F)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC1=N[C@](CF)(c2cc([N+](=O)[O-])cc(F)c2F)C[C@@H](C(F)(F)F)O1
Reaction time: 0.25 h

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.62 g, 5.19 mmol) in sulfuric acid (24 mL, 450 mmol) was added sodium nitrate (0.573 g, 6.75 mmol) in one portion. After stirred for 15 min, The ice bath was removed and the mixture was stirred for 3 h at room temperature. Reaction was cooled with ice bath, quenched with ice water and basified by addition of potassium carbonate (50 g) in small portion. The resulted suspension was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and dried in vacuum to afford crude (4S,6S)-4-(2,3-difluoro-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as yellow oil. It was carried to next step without purification. Assume theoretical yield. MS m/z=358.1 [M+H]+. Calculated for C12H9F6N3O3: 357.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:6]3[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([F:1])[CH:7]=3)[CH2:31][CH2:32]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: NS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzenesulfonamide (1.56 g) and 1-((4′-chlorobiphenyl-2-yl)methyl)piperazine (2.32 g) in dimethylsulfoxide (20 mL) was added N,N-diisopropylethylamine (5 mL). The mixture was stirred at 120° C. overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3×) brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a column and eluted with 40% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:19])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccccc1NC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(CC)C(=O)c1ccccc1N(C)C(C)(C)C
Temperature: 40 °C
Yield: 72.2 %

Procedure:
A mixture of N,N-diethyl-2-(N-tert-butylamino)benzamide (4.2 g, 17 mmol), potassium carbonate (3.1 g, 22 mmol), and MeI (3.1 g, 22 mmol) in DMF (75 mL) was heated overnight at 40° C. The reaction was not complete, so additional MeI (3.1 g, 22 mmol) was added and the reaction heated at 40° C. for 1 d, then was partitioned between EtOAc and water. The EtOAc was dried (MgSO4), concentrated, and purified by HPLC with 1:4 ethyl acetate/cyclohexane to afford 3.22 g of N,N-diethyl-2-(N-methyl-N-tert-butylamino)benzamide as a yellow oil, a 72% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dichloro-5-methyl-pyrimidine (3.61 g, 22.15 mmol), triethylamine (7.02 mL, 50.34 mmol) in DMF (15 mL) was slowly added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 5.00 g, 20.13 mmol). The resulting reaction solution was stirred at rt for 2 h, then diluted with ethyl acetate (400 mL), washed with water (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20–80% ethyl acetate in hexane) to give 4-[(2-Chloro-5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):375.36
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]2[C:6]([CH:12]=[CH:13][C:14]([CH3:15])=[N:9]2)=[CH:7][CH:8]=1
Reactant: C/C=C/C=O
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2ccc(N(C)C)cc2n1
Yield: 42.1 %

Procedure:
Referring to FIG. 21, a mixture of N,N-dimethyl-meta-phenylene-diamine (800 mg, 3.8 mmol) and 6 N HCl (12 mL) was stirred at reflux. Crotonaldehyde (0.31 mL, 3.8 mmol) dissolved in toluene (1 mL) was added dropwise to the purple solution. The reaction mixture was stirred for 2 h, cooled and neutralized with solid NaOH, and extracted with toluene, then chloroform (×5). The extracts were combined, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (EtOAc) to obtain 13a (304.3 mg, 1.6 mmol, 43% yield): 1H NMR (CDCl3) δ 7.84 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=8.8 Hz), 7.09 (2H, m), 6.98 (1H, d, J=8. Hz), 3.06 (6H, s), 2.66 (3H, s); 13C NMR (CDCl3) δ 159.3, 151.5, 149.9, 135.8, 128.6, 119.2, 118.2, 115.5, 106.8, 40.8, 25.6; FTIR (neat) 2918, 2804, 1620, 1600, 1514, 1379, 1155, 1062, 827 cm−1.