Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]([NH:14][S:15]([CH2:18][CH:19](O)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.O>ClCCl>[CH3:13][C:7]([NH:14][S:15](/[CH:18]=[CH:19]/[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])([CH3:6])[CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)CC(O)c1cccnc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Methanesulfonyl chloride (2.1 mL, 27 mmol) in dichloromethane (10 mL) was added dropwise over 15 minutes to a solution of 2-hydroxy-2-pyridin-3-yl-ethanesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.67 g, 18 mmol) and triethylamine (15 mL, 108 mmol) in dichloromethane (40 mL) at 0° C. The mixture was warmed to ambient temperature and stirred for a further 1 hour. Water (50 mL) was added in one portion to the reaction mixture and the whole was extracted with dichloromethane (2×50 mL). The organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate:heptane 1:1 to ethyl acetate) to afford (E)-2-pyridin-3-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide as a pale yellow solid (3.91 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Cs+].[C:29]([O:32][CH2:33]Br)(=[O:31])[CH3:30]>CC(C)=O>[C:29]([O:32][CH2:33][O:12][C:11](=[O:13])[C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCBr
Reactant: CC(C)(C)OC(=O)NNC(C)(Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(=O)OCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Temperature: 44 °C
Reaction time: 16 h

Procedure:
To a suspension of compound 102 (170 mg, 0.5 mmol) and cesium bicarbonate (99 mg, 0.5 mmol) in acetone was added bromomethyl acetate (170 mg, 0.5 mmol) and the mixture stirred at 44° C. temperature for 16 h. After removing the solvent under reduced pressure, the residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated, dried over MgSO4 and concentrated to afford the crude product, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:8][CH2:9][CH2:10][CH3:11])[CH2:6][NH2:7])[CH2:2][CH3:3].Br[CH2:13][CH:14]1[O:18][CH:17]([CH3:19])[CH2:16][O:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][NH:7][CH2:13][CH:14]1[O:18][CH:17]([CH3:19])[CH2:16][O:15]1)[CH2:10][CH3:11]
Reactant: CCCOC(CN)OCCC
Reactant: CC1COC(CBr)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCOC(CNCC1OCC(C)O1)OCCC
Temperature: 25 °C

Procedure:
2,2-Dipropoxyethylamine (0.11 mole), 2-bromomethyl-4-methyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](OC)=[O:11])(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][OH:11])(=[O:4])=[O:3]
Reactant: COC(=O)C1CCCN1S(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCCC1CO
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Methyl 1-(methylsulfonyl)pyrrolidine-2-carboxylate (1.1 g, 4.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added slowly to a stirring suspension of lithium aluminum hydride (0.259 g, 6.8 mmol) in anhydrous tetrahydrofuran (10 mL) kept at 0° C. with an external ice bath. After fifteen minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature and stirred for an additional hour. The mixture was cooled to 0° C., and water (1 mL) was added dropwise, followed by 15% aqueous sodium hydroxide (1 mL), and water (3 mL). The mixture was stirred for 15 mins at room temperature, followed by the addition of magnesium sulfate and additional stirring. The mixture was filtered through Celite, washed three times with ether, and the combined organic fractions concentrated under reduced pressure to afford a yellow oil (0.7 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 3.78-3.57 (m, 3H), 3.49-3.36 (m, 2H), 2.87 (s, 3H), 2.64 (br s, 1H), 2.09-1.82 (m, 4H).
Reaction SMILES: O.[OH:2]C1C=CC([N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=O)C(N)=N)=CC=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O)[C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.[ClH:40]>>[OH2:2].[ClH:40].[OH:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([N-:9][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:13][CH2:14][CH2:15][CH3:16])=[O:39])[C:29]([NH2:31])=[NH:30])=[CH:26][CH:27]=1
Reactant: N=C(N)N(CCCCCC(=O)O)c1ccc(O)cc1
Agent: Cl
Solvent: O
Product: CCCCCCCCCC[N-]C(=O)CCCCCN(C(=N)N)c1ccc(O)cc1
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
2.7 g of ε-(N-p-hydroxyphenylguanidino)caproic acid hemihydrate was dissolved in dilute hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in 30 ml of N,N-dimethylformamide and to the solution kept at 0° to 5°C was added dropwise 0.96 ml of ethylchloroformate and then 1.39 ml of triethylamine. After the mixture was stirred for 15 minutes, 1.6 g of n-decylamine was added dropwise to the mixture at 0° to 5°C. Thereafter, the reaction was carried out in the same manner as in Example 1. The resultant reaction mixture was concentrated under reduced pressure and cold 1N sodium hydroxide was added to the residue to separate precipitated oily substance. The precipitated oily substance was washed with ether and extracted with chloroform after being turned acidic by addition of hydrochloric acid. The chloroform layer was washed with water and dried with sodium sulfate, followed by concentration. Recrystallization of the residue from chloroformether gave 2.8 g of ε-(N-p-hydroxyphenylguanidino) caproyl-n-decyl amide hydrochloride monohydrate having a melting point of 73° to 75°C. The yield was 60.8%.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C@@H:44]([CH2:49][OH:50])[CH2:45][CH:46]([CH3:48])[CH3:47]>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:43][C@@H:44]([CH2:49][OH:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:9]
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)NC(=O)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
5-Bromo-6-chloro-nicotinic acid (2.0 g, 8.46 mmol) was dissolved in DMA (20 mL). To the solution was added TBTU (3.1 g, 9.3 mmol), N,N-diisopropylethyl amine (7.4 mL, 42 mmol) and (D)-leucinol (1.1 g, 9.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (cyclohexane/ethyl acetate gradient) to yield 2.6 g of the title compound as a yellow oil, MS (ISP) 337.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([CH3:13])([CH3:12])[CH3:11].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(OCC2CO2)c(C(C)(C)C)c1
Yield: 84.6 %

Procedure:
In 150 ml of methyl ethyl ketone were dissolved 4.5 g (0.025 mole) of 4-hydroxy-3-tert-butylanisole and 8 g of epichlorohydrin, and 7.0 g of potassium carbonate is added to the resultant solution, followed by heating under reflux for 8 hours. The precipitated inorganic salt is filtered out, and the filtrate is concentrated. The oily-formed residue is extracted with ethyl acetate, and the extract is washed successively with 1% aqueous sodium hydroxide and water, and the ethyl acetate is distilled off to give about 5 g of 4-(2,3-epoxypropoxy)-3-tert-butylanisole in the form of oily substance. The oily substance and 4.6 g of tert-butylamine are dissolved in 100 ml of methanol, followed by heating under reflux for 10 hours, and the solvent is distilled off. The oily residue is admixed with 200 ml of water, and the mixture is made acid with hydrochloric acid, stirred and extracted with isopropyl ether to remove the unreacted materials. The resulting aqueous solution is concentrated under reduced pressure, and the white crystals that crystallize out are recovered by filtration. Recrystallization from water gives 1.3 g of the objective compound, m.p. of 177° to 179° C.
Reaction SMILES: ClS(O)(=O)=O.[N+:6]([C:9]1[CH:25]=[CH:24][C:12]([O:13]/[C:14](=[CH:19]\[C:20]([O:22]C)=O)/[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].[N+](C1C=CC(O/C(=C/C(OC)=O)/C(OC)=O)=CC=1)([O-])=O>>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][C:20](=[O:22])[C:24]=2[CH:25]=1)([O-:8])=[O:7]
Reactant: COC(=O)/C=C(\Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: COC(=O)/C=C(/Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: O=S(=O)(O)Cl
Product: COC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2o1
Temperature: 60 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 79.3 parts by weight of chlorosulfonic acid and warmed to 60° C. Thereto 20.2 parts by weight of a mixture (content: 55.8% by weight, isomer ratio=52/48) containing dimethyl 2-(4-nitrophenoxy)fumarate and dimethyl 2-(4-nitrophenoxy)maleate was added at an inner temperature of 60° C. The inner temperature was raised to 100° C. and the mixture was stirred and kept at the same temperature for 6 hours to obtain a reaction solution containing 6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield: 95%). The reaction solution was poured gradually into 120 parts by weight of water at 60° C. and the mixture was kept at an inner temperature of 60° C. for 1 hour and then cooled gradually to an inner temperature of 25° C. Precipitated crystals were filtered and dried to obtain 10.8 parts by weight of a crystalline mixture of 6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and 6-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of 6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 23.0% by weight; the content of 6-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 58.5% by weight). The yield of 6-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 24.9% and the yield of 6-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 58.5%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([C:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH:51]=4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([CH:46]1[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]1)[CH:28]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C1
Yield: 113.3 %

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate (0.009 g, 0.01 mmol), in 1.5 mL of MeOH was hydrogenated, in the presence of 10% Pd on carbon (3.5 mg), under a hydrogen balloon at room temperature for 1 h. The mixture was filtered and the filtrate was evaporated under vacuum to give tert-butyl {(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate (0.0065 g, 90%). LCMS calc. for C32H44N7O3 [M+H]+: m/z=574.3. found: 574.5.
Reaction SMILES: [Cl:1][C:2]1[C:7](O)=[C:6]([CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:13])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]2[O:12][CH2:11][CH2:10][CH2:9][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c2c1CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
Under nitrogen atmosphere, a solution of 6-chloro-2-(3-hydroxypropyl)-3-methylphenol (7c) (6.74 g, 33.6 mmol) in anhydrous tetrahydrofuran (500 mL) was cooled to 0° C. Triphenylphosphine (11.45 g, 43.7 mmol) was added, followed by diisopropyl azodicarboxylate (8.60 mL, 43.7 mmol). The reaction mixture was stirred for 16 hours at room temperature. After concentration in vacuo, the residue was dissolved in diethyl ether and the precipitate was filtered off. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 90/10), to provide 8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran (7d) (5.74 g, 31.4 mmol, 94%), as a light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:17]=[C:16]([O:18]C(=O)CC)[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[C:8]=1C(=O)CC)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.CCOCC.C(Cl)Cl>O>[CH2:1]([C:3]1[O:4][C:5]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[CH:8]=1)[CH3:2]
Reactant: CCC(=O)Oc1ccc2c(=O)c(C(=O)CC)c(CC)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCc1cc(=O)c2ccc(O)cc2o1
Reaction time: 9 h
Yield: 59.9 %

Procedure:
A suspension of 6.5 g (21.5.10-3 mol) of 2-ethyl-7-(1-oxopropoxy)-3-(1-oxopropyl)-4H-1benzopyran-4-one and 5 g (47.403 mol) of sodium carbonate in 65 ml of water is kept at a temperature of 150° C. for 9 hours. The reaction mixture is hydrolyzed with a 1N solution of hydrochloric acid. The product is extracted with ethyl acetate. After purification by chromatography on silica gel using an ether/methylene chloride mixture (1/2 v/v) as the eluent, 2.45 g (yield: 61%) of the expected product are obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(=O)[CH2:22][N:23]([S:31](=[O:43])(=[O:42])[NH:32][C:33](OCC[Si](C)(C)C)=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=1.CCOC(C)=O.CCCCCC>C1COCC1>[I:30][C:26]1[CH:25]=[C:24]([N:23]2[S:31](=[O:43])(=[O:42])[NH:32][C:33](=[O:34])[CH2:22]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CN(c1cccc(I)c1)S(=O)(=O)NC(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CN(c2cccc(I)c2)S(=O)(=O)N1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of tetrabutylammonium fluoride (5.88 g, 18.67 mmol) in THF (40 mL) is added a solution of the title A compound, N-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(3-iodo-phenyl)glycine methyl ester (2.33 g, 4.5 mmol) in THF (50 mL). The reaction is heated at 90° C. and monitored by reverse phase HPLC (YMC CombiScreen Pro C18, 50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 at 7.0 min. Starting material has a retention time of 4.82 min and the product has a retention time of 2.81 min. After 24 h, the reaction is poured into 500 mL of 1N aqueous HCl and extracted with EtOAc. The organic solution is dried over anhydrous MgSO4, filtered and concentrated to give a yellow solid. Trituration with EtOAc/hexane yields 5-(3-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: (M−H)−=336.9.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-])=O)(=[O:9])=[O:8]>CCO.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:18])([F:17])[F:19])[CH:14]=[CH:15][C:10]=1[S:7]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])[CH3:23])(=[O:8])=[O:9]
Reactant: CN(C)CCCN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
To an argon purged solution of N-(3-(dimethylamino)propyl)-N-methyl-2-nitro-4-(trifluoromethyl)benzenesulfonamide (255 mg, 0.69 mmol) in EtOH (10 ml) was added Pd/C (73 mg, 0.069 mmol, 10%). The reaction mixture was placed under an atmosphere of H2 gas and allowed to stir for 2 h. The reaction mixture was purged with argon and filtered through Celite. The reaction was washed with EtOH (10 ml) and concentrated under reduced pressure to afford 2-amino-N-(3-(dimethylamino)propyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide as a dark oil. MS m/z=340.1 [M+H]+. Calc'd for C13H20F3N3O2S: 339.4.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>C1COCC1.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>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])/[CH:17]=[CH:16]/[C:15]([CH3:19])([CH3:18])[CH3:14])[CH2:11][CH2:12][CH3:13]
Reactant: C#CC(C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/C(C)(C)C)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tributyltin hydride (1.637 mL, 6.09 mmol) was added dropwise to a solution of 3,3-dimethylbut-1-yne (500 mg, 6.09 mmol) and Pd(Ph3P)4 (70 mg, 0.06 mmol) in THF (4 mL) at 0° C. in the dark. After 30 minutes of stirring the reaction mixture was warmed to room temperature and was stirred for 16 hours. The solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 100% iso-hexane afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N+:6]([O-])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[NH2:1][C:2]1[C:7]([Cl:13])=[N:6][CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1c[n+]([O-])cc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnc(Cl)c(N)n1

Procedure:
A suspension of 2-amino-6-methoxypyrazine 4-oxide in freshly distilled phosphorus oxychloride is refluxed for one hour. Thin layer chromatography indicates that the starting material is no longer present. The excess of phosphorus oxychloride is removed in vacuo and the residue is treated with crushed ice. After decomposition is complete the solution is made alkaline with 10% sodium hydroxide and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and evaporated to give the product which may be recrystallized from a suitable solvent such as ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:30][OH:31]>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:30][OH:31])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)C(F)(F)F)cc3)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C(=NO)C(F)(F)F)cc3)c2)CCOCC1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 69, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α,α,α-trifluoroacetophenone was reacted with hydroxylamine hydrochloride to give 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α,α,α-trifluoroacetophenone oxime in 70% yield, m.p. 131°-133° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1I.[Br-].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Zn+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(I)c1
Reactant: [Zn+]c1ccccn1
Agent: [Br-]
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure B was performed using N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (88 mg, 0.2 mmol) with 2-pyridylzinc bromide (1 mL, 0.5 mmol, 0.5 M in THF). Purified by silica gel chromatography (10-80% ethyl acetate/hexanes) to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide as a yellow solid: TLC Rf=0.28 (35% ethyl acetate/hexanes); TLC Rf=0.28 (35% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) 8.88 (bs, 1H), 8.41 (d, 1H), 7.96 (dd, 1H), 7.74 (m, 4H), 7.52 (d, 1H), 7.22 (m, 1H), 2.75 (s, 3H); MS (Q1) 392 (M)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](OB(O)O)=[C:12]([CH3:20])[CH:11]=1>CCOC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[C:12]([CH3:20])[CH:11]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1cc(Cl)ccc1OB(O)O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1cnc(N)cn1

Procedure:
The product was prepared analogously to Example 48.1a from 2.61 g (15.0 mmol) of 5-bromopyrazin-2-ylamine and 2.56 g (15.0 mmol) of 4-chloro-2-methylphenylboric acid. Yield: 1.70 g (52% of theoretical); C11H10ClN3 (M=219.670); calc.: molpeak (M+H)+:220/222 (Cl); found: molpeak (M+H)+:220/222 (Cl); Rf value: 0.35 (silica gel, PE/EtOAc 7:3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:23]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]([OH:15])[CH3:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid (3.0 g, 13.69 mmol) in DMF (50 mL) was added K2CO3 (3.73 g, 27.39 mmol) and stirred at RT for 15 min. (Bromomethyl)benzene (2.81 g, 16.43 mmol) was added and stirred at RT for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 20% EtOAc/hexane as eluent to afford benzyl 2-(tert-butoxycarbonylamino)-3-hydroxybutanoate 10 (2.8 g, 66%).