Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[H][H]>CO>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: [H][H]
Solvent: CO
Product: CC(C)=CCCC(C)CCO
Reaction time: 5 h
Yield: 97775.1 %

Procedure:
Into a 200-ml stainless steel-made autoclave were placed 16.1 g (0.104 mmole) of geraniol, 17.7 mg (0.0208 mmole) of Ru(OAc)2 ((-)-OcH-BINAP) as obtained in Example 7, and 18 ml of methanol. This mixture was stirred at a hydrogen pressure of 100 kg/cm2 and a temperature of 25° C. for 5 hours. After completion of the reaction, the solvent was removed by evaporation, and the residual crude product was subjected to vacuum distillation using a Claisen distillation flask, thereby obtaining 15.89 g of citronellol. The percent yield was 98%, and the optical purity of the citronellol was 98.3% ee.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([CH2:84][CH3:85])[CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][N:81]([CH2:84][CH3:85])[CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCC(N)CC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCN(CC)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a mixture of 0.0644 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0273 g (0.211 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0596 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(1-ethyl-piperidin-4-yl)-benzamide (I-216) as a white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.CI>CN(C)C=O>[Cl:7][C:8]1[C:9]([N:23]([CH3:1])[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: CCS(=O)(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
Potassium tert-butoxide (67.5 mg, 1.1 mmol) was added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)ethanesulphonamide (Preparation 4) (200 mg, 0.55 mmol) in dry dimethylformamide (3 ml) under nitrogen at 20° C. After 5 minutes, methyl iodide (38 μl, 1.1 mmol) was added and the mixture was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate and water, and the combined organic extracts were washed with dilute aqueous sodium hydroxide. The solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methyl)ethanesulphonamide (150 mg, 79%).
Reaction SMILES: [Li].C([N:9]1[C:18]2[CH2:17][CH2:16][CH:15](O)[CH2:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1.C(N1C2C(CC(O)CC=2)CCC1)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:9]1[C:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCC2=C(CCCN2Cc2ccccc2)C1
Agent: OC1CC=C2C(CCCN2Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C1=C2NCCCC2CCC1

Procedure:
106 g. of the above mixture were dissolved in 1 l. of THF and the solution cooled in an ice-water bath. 40 g. of lithium aluminumhydride were added thereto in portions. After the addtion had been completed, the reaction mixture was heated to refluxing temperature under a nitrogen atmosphere for about 4 hours. The reaction mixture was then cooled and excess lithium aluminumhydride destroyed by the addition of ethyl acetate. 10 percent aqueous sodium hydroxide was added to decompose any organometallic compounds present in the mixture. At this point, the reaction mixture was diluted with water. The resulting aqueous mixture was extracted several times with chloroform. The chloroform extracts were separated and combined. The combined extracts were washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform yielded a residue comprising a mixture of 1-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1-benzyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydroquinoline. (Both the 2-oxo group and the 6-benzoyloxy group reacted with the lithium aluminum hydride to yield an octahydroquinoline with a free alcohol at C-6). The mixture of compounds thus obtained was dissolved in ether, the ethereal solution cooled, and gaseous anhydrous hydrogen chloride passed into the solution, thus forming the hydrochloride salts of the quinoline isomers. The quinoline hydrochlorides were insoluble and were separated by decantantation of the ether. The residual salts were dissolved in 100 ml. of methanol and 400 ml. of THF. The solution was cooled and 30 g. of sodium cyanoborohydride added thereto in portions. After the addition had been completed, the cooling bath was removed and the reaction mixture stirred at ambient temperature for 1.25 hours, after which time it was poured into a mixture of 1 N aqueous hydrochloric acid and ice. The acidic solution was extracted with ether, and the ether extract discarded. The acidic solution was then made basic with 10 percent aqueous sodium hydroxide and the alkaline mixture extracted several times with a chloroform-isopropanol solvent mixture. The organic extracts were combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded trans-dl-1-benzyl-6-hydroxydecahydroquinoline formed in the above reaction; yield=53.6 g. Total yield in 6 steps was 73 percent based upon recovered 4-benzoyloxycyclohexanone starting material.
Reaction SMILES: C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3:22].[CH2:23]1[CH2:61][CH2:60][N:59]([OH:62])[C:57](=[O:58])[CH2:56][CH2:55][C:53](=[O:54])[NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][N:46]([OH:63])[C:44](=[O:45])[CH2:43][CH2:42][C:40](=[O:41])[NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([OH:64])[C:31](=[O:32])[CH2:30][CH2:29][C:27](=[O:28])[NH:26][CH2:25][CH2:24]1>C(OCC)(=O)C.O>[CH2:23]1[CH2:61][CH2:60][N:59]([O-:62])[C:57](=[O:58])[CH2:56][CH2:55][C:53](=[O:54])[NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][N:46]([O-:63])[C:44](=[O:45])[CH2:43][CH2:42][C:40](=[O:41])[NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([O-:64])[C:31](=[O:32])[CH2:30][CH2:29][C:27](=[O:28])[NH:26][CH2:25][CH2:24]1.[Fe+3:22]
Reactant: O=C1CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC(=O)N([O-])CCCCCNC(=O)CCC(=O)N([O-])CCCCCNC(=O)CCC(=O)N([O-])CCCCCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5.29 g (15 mmol) of iron(III) acetylacetonate in 300 ml of ethyl acetate is added to a suspension of 5.26 g (10 mmol) of desferrioxamine E in 500 ml of water, and the mixture is efficiently stirred for 5 hours at room temperature. The aqueous phase is then extracted repeatedly with ethyl acetate and then lyophilised to give ferrioxamine E.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([NH:7][C:8]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6])C.[OH-].[Na+]>O>[C:14]([C:13]1[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:16])=[O:3])=[N:9][CH:10]=[CH:11][CH:12]=1)#[N:15]
Reactant: CCOC(=O)C(=O)Nc1ncccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cccnc1NC(=O)C(=O)O

Procedure:
(3-Cyano-2-pyridyl)oxamic acid ethyl ester (0.005 mole) is stirred in 50 ml. water and 5.0 ml. of N NaOH is slowly added. After one half hour the solution is filtered and the filtrate is acidified to pH 2 with N HCl, giving the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([CH2:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([C:24]([O:26]CC)=[O:25])[CH:16]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([S:9]([CH2:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([C:24]([OH:26])=[O:25])[CH:16]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCn1nc(C(=O)OCC)cc1CCCS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCn1nc(C(=O)O)cc1CCCS(=O)(=O)c1ccccc1
Yield: 85.4 %

Procedure:
Sodium hydroxide (12 mL, 6M) was added to a solution of ethyl 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylate (13.3 g, 35.1 mmol) in 100 mL of ethanol and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 100 mL of water. The aqueous layer was extracted with several portions of ethyl acetate. The pH of the aqueous layer was adjusted to approximately 2-3 with aqueous hydrochloric acid and was then extracted with several portions of ethyl acetate. The combined organic layers originating from extraction of the aqueous layer were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 10.5 g of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [C:1]([CH:3]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:13][CH2:14][OH:15])[C:5]=1[F:16])#[N:2].[NH4+]=[S:27].O>O1CCCC1.CO>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][CH:3]([C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:13][CH2:14][OH:15])[C:5]=2[F:16])[C:1]([NH2:2])=[S:27])=[CH:25][CH:24]=1)#[N:23]
Reactant: COc1cc(OCCO)c(F)c(C(C#N)Nc2ccc(C#N)cc2)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
The crude product of 4-({cyano[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)benzonitrile (2.77 g) obtained in Example 30 was dissolved in tetrahydrofuran (4.26 mL) and methanol (4.26 mL), and 20% aqueous ammonium sulfide solution (8.54 mL, 25 mmol) was added dropwise thereto at room temperature, and the resulting mixture was stirred at the same temperature. After completion of the reaction, water (4.26 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred at the same temperature for 0.5 hours. The precipitated solid was filtered. The filtrate obtained was sequentially washed with water and tert-butyl methyl ether, and dried to obtain the captioned compound (1.87 g) as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][NH2:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:25][C:26](=[O:27])[NH:28][CH2:29][CH2:30][NH:31][C:17]([NH:16][C:14]1[CH:15]=[C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:11]=[CH:12][C:13]=1[O:19][CH3:20])=[S:18])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N=C=S
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)NCCNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The product from Example 26, Step A, [5-(1H-indol-2-yl)-2-methoxy-phenyl]-isothiocyanate, (0.272 g, 1.0 mmol) and mono-tert-butyloxycarbonyl ethylenediamine (0.156 g, 1.0 mmol) were heated briefly to 50° C. in ethyl acetate (20 mL). The reaction mixture was allowed to stand 1 hour at room temperature and was then concentrated. The residue was filtered through silica gel using hexanes/ethyl acetate as eluant The purest product-containing factions were combined, concentrated, and triturated with 3/1, hexanes/ethyl acetate, v/v, to give the product as an off-white solid (0.09 g), mp 159-160° C.
Reaction SMILES: [S-2:1].[Na+].[Na+].[S].[OH-].[Na+].[F:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11](N)=[CH:10][CH:9]=1.Cl.N([O-])=O.[Na+].N([O-])=O>O>[F:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([SH:1])=[CH:10][CH:9]=1
Reactant: [S-2]
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(F)ccc1S
Temperature: 6 °C
Reaction time: 0.33 h

Procedure:
A mixture of crystallized sodium sulfide (1.8 g, 0.01 mole) and powdered sulfur (0.24 g) was dissolved by heating and stirring in 2 cc of boiled water. A solution of 0.3 g of sodium hydroxide in 1 cc of water was then added and the mixture was cooled stepwise as detailed above. Four cc of water, 1 g (0.007 mole) of 5-fluoro-anthranilic acid and 1.4 cc of concentrated hydrochloric acid were added to a separate beaker which was set by a freezing mixture to 0° C. The mixture was stirred and cooled to about 6° C. Meanwhile, 0.48 g (0.007 mole) of sodium nitrite were dissolved in 2 cc of hot water and the solution was cooled on ice. When the temperature dropped to 5° C., the nitrite solution was run through a separatory funnel into the anthranilic solution. About 3.5 g of cracked ice were added at a rate that kept temperature below 5° C. The diazo solution was then added to the alkaline sulfide solution (which was kept at a temperature of 2°-4° C.) along with 10 g of ice and temperature was kept below 5° C. The mixture was allowed to warm up to room temperature, and when evolution of nitrogen ceased (about 2 h), concentrated hydrochloric acid (˜1.5 cc) was added until the solution was acid to Congo red paper. The precipitate of disulfide was filtered and washed with water. To remove the excess sulfur, the precipitate was dissolved by boiling with a solution of 0.5 g of anhydrous sodium carbonate in 15 cc of water and the mixture was filtered while hot. The solution was then acidified with hydrochloric acid, the precipitate was filtered and the cake was sucked to dryness. The cake was dried by addition of toluene followed by azeothropic evaporation. This procedure was repeated twice. The cake was mixed with 0.2 g of zinc dust and 2 cc of glacial acetic acid, and the mixture was refluxed for overnight. The mixture was cooled and filtered with suction. The filter cake was washed once with water and transferred to a 10 cc beaker. The cake was suspended in 2 cc of water and the suspension was heated to boiling. The hot solution was made strongly alkaline by the addition of about 0.3 cc of a 33% sodium hydroxide solution. The alkaline solution was boiled about 20 min. and the insoluble material was filtered. The product was then precipitated by the addition of concentrated hydrochloric acid to make the solution acid to Congo red paper. The product was filtered with suction, washed once with water, and dried in an oven at 100°-130° C.; mp was 185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[CH3:23][NH:24][C:25](=[O:35])[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1[F:34].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:32][C:31]1[CH:30]=[C:29]([F:33])[CH:28]=[C:27]([F:34])[C:26]=1[C:25]([N:24]([CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(Br)n2)CC1
Reactant: CNC(=O)c1c(F)cc(F)cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C(=O)c1c(F)cc(F)cc1F)c1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 43.9 %

Procedure:
Heat a mixture of 2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (152 mg, 0.41 mmol), N-methyl-2,4,6-trifluorobenzamide (92.6 mg, 0.49 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), BINAP (12.4 mg, 0.02 mmol), sodium t-butoxide (55 mg, 0.57 mmol) in anhydrous toluene (10 mL) at 85° C. for 16 hrs. Cool the reaction to room temperature and add another aliquot of N-methyl-2,4,6-trifluorobenzamide, Pd2(dba)3, BINAP and sodium t-butoxide in the same amount. Re-heat the reaction at 85° C. for 16 more hours. Extract the reaction mixture with ethyl acetate and aqueous NaOH (0.1N). Collect and dry the organic layers. Concentrate and purify the crude product by chromatography (silica gel, 10%-30% ethyl acetate/hexane) to obtain 2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (86 mg, 44% yield).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:4])(=[O:3])=[O:2].[OH:14]O>ClCCl.S(=O)(=O)(O)O>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][OH:14])=[O:9])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(OO)c1cccc(S(=O)(=O)O)c1
Temperature: 42 °C
Yield: 64.2 %

Procedure:
To a suspension of 3-sulphobenzoic acid (5 g, 2.5×10-2 moles) in dichloromethane (60 ml) containing a trace of sulphuric acid (5×10-5 moles) was slowly added hydrogen peroxide (3 g; 85%). The suspension was boiled under reflux (42° C.) for 1 hour after which it was cooled to room temperature, the dichloromethane was decanted off and the residue treated with saturated aqueous magnesium nitrate (25 ml). The resultant precipitate was filtered off, dried over phosphorous pentoxide under vacuum to yield the magnesium salt of 3-sulphoperoxybenzoic acid (3.5 g; 5.31% Avox as O; Magnesium content of 4.7%) compared with a theoretical yield of 5.67 g. The IR spectrum was again substantially the same as for the other preparations.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=2)[CH2:4][CH2:3]1.Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:34][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[CH:33][C:24]=2[O:23][CH2:22][CH2:21][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]4[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=4[CH:19]=3)[CH2:4][CH2:3]2)[N:29]=1
Reactant: O=C1COc2ccc(CC3CCNCC3)cc2N1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cccc2n1
Yield: 26.5 %

Procedure:
A mixture of 6-(4-piperidinylmethyl)-4H-benzo[1,4]oxazin-3-one hydrochloride (0.10 g, 0.35 mmol), 5-(2-bromoethoxy)-2-methylquinoline (0.11 g, 0.42 mmol), diisopropylethylamine (1 mL) and isopropanol (10 mL) was heated at reflux under argon for 48 h, cooled, then evaporated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (50 mL) and dichloromethane (3×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The resulting oil was purified by chromatography on silica eluting with 50% ethyl acetate-hexane followed by 0–25% methanol-ethyl acetate gradient elution, to give the title compound (0.04 g, 26%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][CH:9]=1
Reactant: Clc1nccn2ccnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Clc1nccn2c(Br)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 8-chloro-imidazo[1,2-a]pyrazine (1.53 g, 0.01 mol) in DCM (30 mL) is added N-bromosuccinimide (1.78 g, 0.01 mol) and the reaction is stirred at room temperature for 2 h. After this time the solution is washed with saturated aqueous solution of Na2CO3 (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (2.11 g, 96%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][N:31]([CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OC(CCl)COc1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Product: OC(COc1ccc(OCc2ccccc2)cc1)CN1CCC(O)(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from (RS)-1-chloro-3-[4-(benzyloxy)phenoxy]-2-propanol and 4-benzyl-4-hydroxy-piperidine.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)[N:3]=1.NC(N)=[S:20].Br>C(O)(=O)C>[N:4]1([CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([SH:20])([CH2:11]4)[CH2:9]2)[CH2:15]3)[CH:5]=[CH:6][CH:2]=[N:3]1
Reactant: Brc1ccn(CC23CC4CC(CC(C4)C2)C3)n1
Reactant: NC(N)=S
Agent: Br
Solvent: CC(=O)O
Product: SC12CC3CC(C1)CC(Cn1cccn1)(C3)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 26A (2.0 g) and thiourea (2.0 g) in a solvent mixture of acetic acid (20 mL) and 48% aqueous HBr solution (10 mL) was heated to 100° C. for 24 hours. The reaction was concentrated to dryness, and the residue was dissolved in 20% v/v ethanol in water (100 mL). Solid sodium hydroxide (10 g) was added, and the mixture was stirred overnight. The solution was acidified to pH 1 with concentrated HCl solution, and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 10-50% ethyl acetate in hexane, to give the title product.