Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17](=[O:27])[NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)[OH:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[Pb](Br)(Br)[Br:30].C(Cl)Cl.C(O[CH2:39][CH3:40])C>>[CH2:1]([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([Br:30])([C:17](=[O:27])[NH:18][C:19]2[CH:20]=[C:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[CH:24]=2)[O:16][CH2:39][CH3:40])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Br[Pb](Br)Br
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(O)C(=O)Nc2cc(C)cc(C)c2)cc1
Reactant: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(C(Br)(OCC)C(=O)Nc2cc(C)cc(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring solution of 2-{4-[(3,5-Dimethyl-phenylcarbamoyl)-hydroxy-methyl]-phenoxy}-2-methyl-propionic acid ethyl ester (1.4 g, 3.6 mmol), in dry diethyl ether (10 mL) under nitrogen at 0° C. was added lead tribromide in methylene chloride (4.4 mL, 4.4 mmol) drop wise. The reaction mixture was further stirred at room temperature for 4 hr and concentrated. Water (100 mL) added and the product extracted with Ethyl acetate (3×50 mL), dried and evaporated to yield 1.0 g of 2-{4-[bromo-(3,5-dimethyl-phenylcarbamoyl)-ethoxy-methyl]-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C([Li])CCC.[B:22]([O:31]C(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([O:23][B:22]([OH:31])[OH:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCC1CCC(c2ccc(I)cc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC1CCC(c2ccc(OB(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 20.2 %

Procedure:
To a mixture of 4-(4-methoxymethylcyclohexyl)-1-iodobenzene (297 mmol) and 250 ml of THF, was added dropwise 200 ml of a solution of n-butyl lithium (corresponding to 312 mmol) in hexane at −78° C. in 3.0 hours, and stirred at the same temperature for 1.2 hours. To the solution was added dropwise 100 ml of a solution of triisopropyl borate (594 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 270 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with heptane to give a white solid of 4-(4-methoxymethylcyclohexyl) phenyl boric acid (60.1 mmol).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32]>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:1]([C:2]2[CH:3]=[CH:4][N+:5]([O-:8])=[CH:6][CH:7]=2)=[O:10])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
A suspension of isonicotinic acid 1-oxide (4.16 g, 29.9 mmol) and 1,1'-Carbonyldiimidazole (5.33 g, 32.9 mmol) in dry dimethylformamide (50 ml) was stirred for 40 minutes under an air-lock and treated with 4-chloro-3-trifluoromethylbenzenamine (6.43 g, 32.9 mmol). The reaction mixture was heated at 100° for 5.3 hours and cooled to room temperature. The solution was evaporated in vacuo and the residue triturated with ethanol (2×20 ml) to give the title compound (5.379 g), m.p. 263°-265°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][Br:6].[Zn:11]>>[Br-:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][Zn+:11]
Reactant: [Zn]
Reactant: Clc1ccc(CBr)cc1Cl
Product: Clc1ccc(C[Zn+])cc1Cl
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-dichlorobenzyl bromide (0.47 g, 1.96 mmol) and Rieke Zinc (3.0 ml, 5 g/100 ml THF, 2.35 mmol) was stirred overnight at r.t. in a flame-dried Schlenk tube and decanted to provide a 0.65M stock solution of 3,4-dichlorobenzyl zinc bromide. A solution of 8-bromo-9-butyl-9H-purin-6-ylamine (42.7 mg, 0.158 mol), Pd(dppf)Cl2 (16.8 mg, 0.020 mmol), and 3,4-dichlorobenzyl zinc bromide (0.61 ml, 0.65M in THF) was stirred in a flame-dried Schlenk tube at 66° C. overnight, quenched with sat. aq. NH4Cl and sat. aq. EDTA., extracted into EtOAc, dried and concentrated. Preparative TLC purification (EtOAc/CH2Cl2/MeOH 14:14:2) provided the title compound as a colorless oil (approx. 15 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:12])[CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([NH2:12])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(N)c(C(=O)O)cc1C
Product: COC(=O)c1cc(C)c(C)cc1N

Procedure:
0.41 g Sodium nitrite in water is added to 1 g 4,5-dimethyl-2-nitroaniline in 3 mL conc. HCl and stirred for 1 hour at +4° C. This solution is added to a mixture of 0.67 g copper (I) cyanide, 0.98 g sodium cyanide, 0.32 g sodium carbonate, 25 mL of water and 3 mL toluene. The mixture is stirred for 12 hours at room temperature and worked up to give 0.45 g 4,5-dimethyl-2-nitrobenzonitrile. 4,5-Dimethyl-2-nitrobenzonitrile is reduced with iron powder in acetic acid to yield 4,5-dimethyl-2-aminobenzonitrile. 4,5-Dimethyl-2-aminobenzonitrile is heated at reflux for 12 hours in conc. HCl to give 4,5-dimethyl-2-aminobenzoic acid. 4,5-Dimethyl-2-aminobenzoic acid is reacted with trimethylsilyl diazomethane to yield methyl 4,5-dimethyl-2-aminobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
2.5 g of sodium triacetoxyborohydride (12.0 mmol) was added to a solution of 1.87 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (10.0 mmol), 10.7 g of 2-methylaniline (10.0 mmol) and 0.57 ml of acetic acid (10.0 mmol) in methylene chloride (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 2.43 g of the title compound (yield: 87%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(#N)C>[Cl-:1].[CH3:16][N:17]1[CH:21]=[CH:20][NH+:19]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=2)=[O:4])[CH2:18]1
Reactant: Cn1ccnc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCl)cc1
Solvent: CC#N
Product: CN1C=C[NH+](CC(=O)c2ccc(NS(C)(=O)=O)cc2)C1
Product: [Cl-]
Temperature: 25 °C

Procedure:
Heat a mixture of 160 g (0.646 mole) of N-[4-(2- chloro-1-oxoethyl)phenyl]methanesulfonamide, 55.7 g (0.678 mole) of 1-methyl-1H-imidazole and 2.1 L of acetonitrile at reflux for about 16 hours. Cool the mixture to room temperature and collect the solid and wash with 2 L of acetonitrile. Drying provides the title compound, which may be recrystallized from aqueous ethanol.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH:12]([CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:11][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:20][CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccccc1
Product: CCC(NC(=O)Cc1ccccc1)C(=O)OCC(C)C

Procedure:
Following General Procedure H above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by chromatography on silica gel using 9:1 toluene:EtOAc as the eluant.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28].[Cl-]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:23]([O:30][CH3:31])=[O:29])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(C)=O)c1
Reactant: C#CCCCC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)CCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O
Temperature: 20 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A mixture of methyl 3-acetamido-4-trifluoromethane-sulfonyloxybenzoate (1.43 g), methyl 5-hexynoate (582 mg), palladium(II) chloride (14 .9 mg), triphenylphosphine (43.8 mg) and cooper(I) chloride (32 mg) in diethylamine (18 ml) was stirred at 20° C. for 14 hours. The solvent was evaporated in vacuo an the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (1:2) to give methyl 3-acetamido-4-(5-methoxycarbonyl-1-pentynyl)-benzoate (1.15 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][OH:22])[N:9]=1.C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][O:22][S:36]([CH3:35])(=[O:38])=[O:37])[N:9]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCO)n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOS(C)(=O)=O)n2)c1
Temperature: 0 °C
Yield: 35 %

Procedure:
Compound 93, 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethanol (680 mg., 2 mmol) was dissolved in methylene chloride (10 mL) and to the reaction mixture was added diisopropylethylamine (0.6 mL, 3 mmol). The reaction was chilled to 0° C. To the reaction was added methanesulfonyl chloride (251 mg., 2.2 mmol). After fifteen minutes, the reaction was washed with saturated aqueous ammonium chloride (2×2 mL), dried with sodium sulfate, and purified by column chromatography to give Compound 95, methanesulfonic acid 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethyl ester (290 mg., 0.7 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[N:27]([S:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:36])=[O:35])[CH:26]=4)[CH:23]=3)[C:18](=[O:43])[NH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(#N)C>ClCCl>[C:37]1([S:34]([N:27]2[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:33]3[C:25]([C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:43])[NH:17][N:16]=[C:15]4[CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:26]2)(=[O:35])=[O:36])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2n[nH]c(=O)c3ccc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc23)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(CC2CCNCC2)c2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)ccc12

Procedure:
A solution of EXAMPLE 9B (272 mg, 0.45 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (1 mL) at ambient temperature for 1 hour. Acetonitrile (10 mL) was added and the solution was concentrated on a rotary evaporator. The residue was purified by HPLC (Zorbax C-18, 0-100% gradient of acetonitrile in water containing 0.1% trifluoroacetic acid) to yield the title compound. MS (ESI) m/z 500 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 1.49-1.66 (m, 2H), 2.01-2.16 (m, 2H), 2.26-2.37 (m, 1H), 2.93-3.05 (m, 2H), 3.10 (d, J=7.12 Hz, 2H), 3.39 (d, J=12.54 Hz, 2H), 7.41 (dd, J=8.14, 4.75 Hz, 1H), 7.55-7.61 (m, 2H), 7.64-7.72 (m, 1H), 8.18-8.24 (m, 3H), 8.24-8.27 (m, 1H), 8.33 (dd, J=7.97, 1.53 Hz, 1H), 8.39 (s, 1H), 8.45 (dd, J=4.92, 1.53 Hz, 1H), 8.47-8.52 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:25]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Solvent: O=CO
Product: CN1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
A suspension of 1.3 g (4.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, 13.3 ml of 37% formalin and 13.3 ml of 88% formic acid was refluxed for four hours. The resulting solution was evaporated in vacuo. The residue was suspended in aqueous ethanol, the resulting precipitate removed by filtration, washed with water and dried in vacuo to give 1.24 g of the title compound, mp 236°-237° C.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH2:10]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].FC(F)(F)S(O[CH2:39][C:40]([F:52])([F:51])[C:41]([F:50])([F:49])[C:42]([F:48])([F:47])[CH2:43][O:44][CH2:45][CH3:46])(=O)=O>O.CN(C)C=O>[CH2:10]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:39][C:40]([F:51])([F:52])[C:41]([F:49])([F:50])[C:42]([F:48])([F:47])[CH2:43][O:44][CH2:45][CH3:46])=[CH:30][CH:31]=2)=[N:24][CH:25]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCC)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
0.4 g of sodium hydride (97% pure), 15 ml of toluene and 15 ml of anhydrous N,N-dimethylformamide were placed in a 100 flask fitted with a magnetic stir bar and water-cooled condensor with a dry nitrogen inlet. Then 3.3 g (0.0106 moles) of 5-decyl-2-(4-hydroxyphenyl)pyrimidine was slowly added. After stirring for 30 minutes at room temperature, 3.9 g (0.0106 moles) of 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (made essentially as in Example 3) was added and the contents stirred overnight at room temperature. The contents then were poured into a separatory funnel containing 30 ml of water. The funnel was shaken and the two layers formed were allowed to separate. The aqueous layer was extracted twice with two 15 ml aliquots of toluene. The organic layers were combined, then washed four times with 20 ml aliquots of deionized water, dried with anhydrous sodium sulphate, and stripped of solvent using a rotary evaporator. The resulting oil was chromatographed on silica gel (chloroform) to obtain 2.07 g of 5-decyl-2-(4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14](O)=[O:15])=[CH:4][CH:3]=1.CN(C)C=O.O=S(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([Cl:26])=[O:15])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1Oc1ccc(Cl)cc1

Procedure:
[2-(4-chloro-phenoxy)-phenyl]-acetic acid (IX) (47.3 grams; 180 mmol) was suspended in toluene (140 ml) at 48° C. To this suspension dimethyl-formamide (4.0 ml) and SOCl2 (19.8 ml; 271 mmol; 1.5 eq) in toluene (18 ml) were added. After 10 min the reaction mixture was concentrated under vacuo and stripped twice with toluene, to yield a brownish oil of [2-(4-chloro-phenoxy)-phenyl]-acetyl chloride. The oil was suspended in toluene (75 ml). To the suspension was added at 5° C. a solution of sarcosine methylester (30.3 grams 217 mmol) and triethylamine (57 ml) in a mixture of dimethyl-formamide (236 ml) and toluene (47 ml). The brownish suspension was stirred for 2 hours at room temperature. To the reaction mixture water (750 ml) was added and the mixture was extracted twice with ethyl acetate (500 ml). The organic phase was washed with saturated brine (700 ml) and dried on magnesium sulphate. The solvent was removed in vacuum to yield methyl-N-[2-(4-chloro-2-phenoxyphenyl)-1-oxethyl]-N-methylglycinate (X) (61.3 grams, 202 mmol) as a brownish oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:28][O:27]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[C@H:29]([CH2:31][OH:32])[CH2:28][O:27][C:26]4=[O:25])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)c(C)c1
Yield: 54.4 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (530 mg) described in Preparation Example 145 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (466 mg), the title compound (315 mg) was obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]Br)[CH3:12]>CN(C=O)C.O.CCOCC>[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCC(CC)COc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
Sodium hydride (60% dispersion in oil, 17.4 g, 435 mmol) was added in portions to a cold (ice-bath) solution of 4-bromophenol (49.0 g, 283 mmol) in dry DMF (780 cm3). The mixture was stirred at that temperature for 2 h and the ice bath was removed. A solution of 2-ethylhexylbromide (54.4 cm3, 306 mmol) in 150 cm3 of dry DMF was added dropwise through an addition funnel to the reaction mixture and the reaction was stirred at room temperature overnight (21 h). The resultant mixture was diluted with water (400 cm3) and ether (500 cm3). The two phases were separated. The aqueous layer was extracted with ether (3×300 cm3) and the organic portion and the ether extracts were dried over anhydrous MgSO4, filtered and the filtrate was collected and evaporated under reduced pressure to leave yellow oil. Column chromatography over silica gel (half amount each time) with light petroleum as eluent afforded R1 (54.1 g, 67%) as colourless oil; λmax(CH2Cl2)/nm 284 (ε/dm3mol−1cm−1 1251), and 291 sh (1001); δH(400 MHz; CDCl3) 0.83-0.97 (6H, m, Me), 1.30-1.57 (8H, m, CH2), 1.68-1.79 (1H, m, CH), 3.78-3.84 (2H, m, ArOCH2), 6.74-6.80 (2H, m, ArH), and 7.33-7.40 (2H, m, ArH); δC(100 MHz; CDCl3) 11.1, 14.1, 23.0, 23.8, 29.1, 30.4, 39.3, 70.7, 112.4, 116.3, 132.1, and 158.5.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C(O)C.C([O-])(=O)C.[Na+]>O>[OH:15][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: NO
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=NO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a mixture of 3.00 g of 4-methyl-3-nitrobenzaldehyde, 1.64 g of hydroxylamine hydrochloride, 30 ml of ethanol and 15 ml of water was added 2.24 g of sodium acetate at room temperature, followed by stirring at room temperature for 1 hour. The reaction mixture was added to water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2.77 g of 5-hydroxyiminomethyl-2-methylnitrobenzene. 5-Hydroxyiminomethyl-2-methylnitrobenzene
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][N:13]([C:14]([C:16]4[C:17]([CH3:21])=[N:18][O:19][CH:20]=4)=[O:15])[C:7]3([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:6][N:5]2[CH:30]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][N:13]([C:14]([C:16]5[C:17]([CH3:21])=[N:18][O:19][CH:20]=5)=[O:15])[C:7]4([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:6][N:5]3[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(C23Cn4cc(N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C23Cn4cc(NC5CCCCC5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1

Procedure:
To a solution of 7-amino-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (33 mg, 0.081 mmol) in CH2Cl2 (0.5 mL) was added cyclohexanone (9 μL, 0.081 mmol), acetic acid (7 μL, 0.12 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). After stirring the mixture for three further hours, cyclohexanone (20 μL, 0.18 mmol) was added followed by the addition of additional acetic acid (20 μL, 0.34 mmol). The mixture was quenched with a saturated aqueous solution of NaHCO3. Additional CH2Cl2 (3 mL) was added and the organic layer separated, the aqueous layer was further extracted with CH2Cl2 (3 mL). The organic layers were combined dried (Na2SO4), filtrated, concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient 0-10% MeOH in EtOAc) and reverse phase chromatography (Biotage SP4, 12 g C18 cartridge; gradient ACN in water). The compound 7-(cyclohexylamino)-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (112) was isolated as a solid (1.6 mg, yield 1%).