Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCO)cc1
Yield: 83.1 %

Procedure:
Methyl 4-iodobenzoate (9.0 g, 34.4 mmol) was dissolved in 90 ml of diethylamine. The solution was stirred vigorously and, sequentially, 121 milligrams of bis(triphenylphosphine) palladium chloride and 65 milligrams of cuprous iodide were added, each in a single portion, followed by 1.93 grams of propargyl alcohol. The resultant mixture was stirred for about 20 hours at room temperature in an argon atmosphere. At the end of this period, diethylamine was removed by concentration in vacuo. The residue was diluted with 200 ml of water and extracted three times with 100 ml of benzene and 75 ml of ethyl acetate. The organic extracts were combined, dried over Na2SO4, and concentrated in vacuo, yielding a brown solid. This crude residue was purified by flash chromatography. Elution with a 2 to 1 (V:V) mixture of hexane and ethyl acetate yielded 5.44 grams (83% yield) of a pale yellow solid melting at 81 to 82° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:18](O)(=O)C.C(N)=N>C(O)C>[Cl:8][C:5]1[N:4]=[C:3]2[N:9]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[CH:18]=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: N#Cc1cccc(Nc2nc(Cl)ccc2N)c1
Agent: N=CN
Solvent: CCO
Product: N#Cc1cccc(-n2cnc3ccc(Cl)nc32)c1

Procedure:
In step 1-3, a solution of 3-(3-amino-6-chloropyridin-2-ylamino)benzonitrile (1.07 g, 4.38 mmol) and foramidine acetate (1.37 g, 13.1 mmol) in ethanol was refluxed for 3 hours. The reaction mixture was concentrated and purified to afford 3-(5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile (1-3) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: OCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To the solution of (4-(4-fluorophenoxy)phenyl)methanol (7 g, 32.1 mmol) and pyridine (5.19 mL, 64.2 mmol) in dichloromethane (DCM) (100 mL) was added sulfurous dichloride (7.63 g, 64.2 mmol) dropwise at 0° C. After addition the mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3 solution (40 mL×2) and brine (40 mL), the organic phase was dried over Na2SO4, filtered and concentrated to leave the crude product, which was purified by column chromatography (silica-gel, elution with PE: EtOAc=6:1) to afford the pure 1-(chloromethyl)-4-(4-fluorophenoxy)benzene (2.2 g, 8.83 mmol, 27.5% yield) as light yellow oil. LCMS: rt=1.56 min, [M+H+]=237
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reaction time: 2.5 h

Procedure:
To a solution of 428 g (959 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 151, Step A) in dichloromethane (4.55 L) was added 25.9 mL (1.44 mol) of water. A solution of 610 g (1.44 mol) of Dess-Martin periodinane in dichloromethane (4.55 L) was added slowly over a 25 min period so as to maintain an internal reaction temperature not exceeding 25° C. The white slurry was stirred for 2.5 h and then was quenched by cautious, slow addition of saturated aqueous sodium thiosulfate (5.2 L) so as to maintain an internal reaction temperature below 30° C. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4×) and then saturated aqueous sodium chloride (1×), dried over Na2SO4, filtered and the filtrate was concentrated to afford a yellow oily solid. A mixture of ethyl ether and DCM were added, and precipitated solids were filtered off. The precipitation/filtration process was repeated. The filtrate was concentrated to provide the title compound as a white solid. The crude product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.Cl[S:29]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(=[O:31])=[O:30]>>[CH:22]1([C:17]2[CH:16]=[C:15]([C:14]3[C:4]4[C:3]([CH3:27])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:20]=[CH:19][C:18]=2[O:21][S:29]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([OH:37])=[O:36])(=[O:31])=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: Cc1sc2cc3ccccc3c(-c3ccc(OS(=O)(=O)c4cccc(C(=O)O)c4)c(C4CCCC4)c3)c2c1C
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 9, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.300 g, 0.805 mmol) and commercial 3-chlorosulphonylbenzoic acid (0.600 g, 2.71 mmol). Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with 20% EtOAc/hexane followed by trituration with hexane gave 0.154 g (20%) of the title compound as a white solid, mp 120-128° C. 1H NMR (DMSO-d6) δ 1.23-1.36 (m, 2 H), 1.42-1.52 (m, 6 H), 1.55-1.69 (m, 3 H), 2.42 (s, 3 H), 2.96 (quintet, 1 H), 7.23-7.29 (m, 3 H), 7.33 (d, 1 H), 7.39 (ddd, 1 H), 7.47 (ddd, 1 H), 7.90 (t, 1 H), 7.97 (d, 1 H), 8.23 (dd, 1 H), 8.27-8.29 (m, 1 H), 8.37-8.39 (dt, 1 H), 8.50 (s, 1 H), 13.6-13.9 (br s, 1 H). IR (KBr) 3400, 2950, 1700, 1380 and 1190 cm-1. mass spectrum (-ESI) m/z 555 (M-H). Anal. Calcd. for C32H28,O5S2.0.65H2O: C, 67.62; H, 5.20; N, 0.00. Found: C, 67.60; H, 4.90; N, 0.09.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH:30]([N:26]1[CH2:27][CH2:28][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25]1)([CH3:32])[CH3:29]
Reactant: CC(C)=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A suspension of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (59.8 mg, 0.152 mmol) in 1,2-dichloroethane was treated with acetone (0.1 mL, 1 mmol) and acetic acid (0.1 mL, 2 mmol), stirred for one hour at ambient temperatures, under nitrogen, treated with sodium triacetoxyborohydride (66.3 mg, 0.313 mmol), stirred for 4 hours, diluted with chloroform and washed sequentially with 1.0 N sodium hydroxide and brine, treated with methanol to aid in solubility, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.2% ammonium hydroxide/2.0% methanol in chloroform to afford 5-(1-isopropyl-pyrrolidin-3-yloxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a very light yellow foam, 45.4 mg (68.6% yield). The foam was dispersed in methanol and chloroform, treated with isopropanolic HCL and concentrated in vacuo at 84° C. for 14 hours to give the title product as a light brown foam, 42.1 mg, Mass spectrum (+APPI, [M+H]+) m/z 436. 1HNMR (500 MHz, DMSO-d6): δ14.22 (d, 1H, J=4.76 Hz), 10.39-11.06 (m*, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.55-8.59 (m, 1H), 8.27 (d, 1H, J=8.18 Hz), 8.04 (d, 1H, J=7.93 Hz), 7.71-7.75 (m, 1H), 7.56-7.64 (m, 3H), 7.25-7.28 (m, 1H), 7.09-7.15 (m, 1H), 5.19-5.22 (m, 1H), 3.39-3.87 (m*, 4H), 3.20-3.25 (m*, 1H), 2.02-2.53 (m, 2H), 1.24-1.28 ppm (m, 6H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH2:15][C:16]1[CH:17]=[C:18]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:42][C:43]([CH3:45])=[CH2:44]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH:15]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:44][C:43]([CH3:45])=[CH2:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Reactant: C=C(C)CBr
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one from the previous step (6.0 g, 11.00 mmol) in dry THF (22 mL) at −78° C. was added sodium bis(trimethylsiyl)amide (NaHMDS) (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below −75° C. The resulting red solution was stirred at −78° C. for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature below −75° C. When the addition was near completion, the reaction mixture turned green. At this point the dry-ice bath was quickly removed and replaced with water-ice bath, and the addition was completed. The reaction mixture was stirred at 0° C. for an additional 30 min and quenched with saturated aqueous NH4Cl solution. The system was diluted with EtOAC (100 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.3 g, 95%).
Reaction SMILES: [CH:1](C(OC)(F)F)([C:6]([F:9])([F:8])[F:7])[C:2]([F:5])([F:4])[F:3].CCOCC.C1(C)C=CC=CC=1>[Ni].O>[CH2:1]([C:6]([F:9])([F:8])[F:7])[C:2]([F:5])([F:4])[F:3]
Reactant: COC(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: [Ni]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: FC(F)(F)CC(F)(F)F

Procedure:
A 100 g mixture containing 59.0% (CF3)2CHCF2OCH3 (ether A), 20% (CF3)2C=CFOCH3 (ether B), 15.9% toluene and 150 mL water was heated in a Hastelloy™ nickel alloy tube for 3 hours at 135° C. and 6 hours at 200° C. The volatiles were bubbled through a solution of aqueous NaOH and a CaSO4 drying column, and condensed in a dry ice cooled trap to give 12.9 g HFC-236fa identified by its infrared spectrum. The liquid contents of the tube contained two layers. The upper layer, 14.9 g, was shown by 1H and 19F NMR spectroscopy to contain 16.5 wt. percent HFC-236fa and toluene. The combined HFC-236fa from the volatiles and the toluene corresponded to a yield of 15.4 g, 29.0% based on the starting ethers.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=2)[O:17][CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[CH:25])[CH:22]=2)[O:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1ccc2c(c1)C(C)(C)CCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.47 g (24.41 mmol) of diisopropylamine in 40 ml dry tetrahydrofuran under argon at -78° C. was added dropwise 15.2 ml of 1.6M (24.32 mmol) n-butyl lithium in hexane. Mixture was stirred at -78° C. for 1 hour and then treated dropwise with a solution of 4.98 g (24.38 mmol) of 4,4-dimethyl-6-acetylchroman in 4 ml of dry tetrahydrofuran. After stirring at -78° C. for 1 hour, the solution was treated with 4.2 g (24.36 mmol) of diethyl chlorophosphate. The cooling bath was then removed and mixture stirred at room temperature for 2.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropyl amide (prepared as per Example 4) using 4.95 g (48.92 mmol) of diisopropylamine and 30.5 ml of 1.6M (48.8 mmol) n-butyl lithium in hexane in 80 ml dry tetrahydrofuran at -78° C. The cooling bath was removed and mixture stirred at room temperature for 18 hours and then quenched with 50 ml water and 25 ml of 3N hydrogen chloride. The mixture was extracted with 2×100 ml and 3×50 ml of pentane and the combined organic fractions washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl solution and then dried (MgSO4). Solvent was then removed in yacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by kugelrohr distillation (70° C.; 0.35 mm) to give the title compound as a colorless crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](N1CC2(CCCC2)NCC1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]([CH3:26])[CH:22]([NH2:25])[CH2:23][NH2:24].[CH3:27][C:28]([CH3:32])(O)[C:29]#N>>[C:1]([O:5][C:6]([N:25]1[CH2:27][C:28]([CH3:32])([CH3:29])[NH:24][CH2:23][CH:22]1[CH:21]([CH3:26])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(N)CN
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Product: CC(C)C1CNC(C)(C)CN1C(=O)OC(C)(C)C

Procedure:
2-Isopropyl-5,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 3-methyl-butane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[C:5](O)(=O)C.N[C:10]1[CH:11]=[CH:12][C:13]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:14]([CH:16]([CH:18]([C:28]([NH2:30])=[O:29])[C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH:15]=1.C=O>C(#N)C.CN(C)C=O>[CH3:5][N:2]([CH3:1])[C:10]1[CH:11]=[CH:12][C:13]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:14]([CH:16]([CH:18]([C:28]([NH2:30])=[O:29])[C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH:15]=1
Reactant: CC(c1cc(N)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(c1cc(N(C)C)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
A tenth of a gram (1.589 m mol) of sodium cyanoborohydride and, after two minutes, 0.056 ml of glacial acetic acid were added at 20° C. to a stirred solution of 0.20 gm (0.5242 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and 0.45 ml of 40% formalin in 2 ml of acetonitrile and 1 ml of absolute dimethyl formamide. After 1.5 hours the reaction mixture was evaporated in vacuo. The evaporation residue was dissolved in water by addition of hydrochloric acid at a pH of 2 to 3. After extraction with chloroform several times the aqueous phase was adjusted to a pH of 6 to 7 by means of saturated sodium bicarbonate solution and extracted several times with chloroform. This organic extract was dried and filtered. After evaporation in vacuo the evaporation residue was recrystallized from isopropanol. The colorless crystals were washed with absolute ether.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22].C(Cl)[Cl:24]>>[ClH:24].[ClH:24].[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: COc1ccccc1CBr
Reactant: ClCCl
Product: COc1ccccc1CN1CCNC(c2ccccc2)C1
Product: Cl
Temperature: -78 °C
Yield: 54 %

Procedure:
To a solution of (+,-)-2-phenyl-piperazine (2.83 g, 17.44 mmol) (described in Example 1) in dry CH2Cl2 (141.5 mL) at -78° C. was added slowly a solution of 1-bromomethyl-2-methoxy-benzene (3.507 g, 17.44 mmol) in dry CH2Cl2 (35 mL) under nitrogen. The reaction was stirred at -78° C. and gradually warmed to RT overnight. After completion, the product was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and filtered. The filtrate was removed under vacuum to give an oil. The product was purified by flash chromatography on flash grade silica gel (150 g), eluting with 4% MeOH/CH2Cl2 to give the title compound as an oil (2.68 gram, 54%). A portion of this oil (0.33 g, 1.168 mmol) was dissolved in CH2Cl2 (10.0 mL) and treated with 2.3M HCl (1.1 mL, 2.53 mol). After stirring at room temperature for 10 minutes, solvents were removed under vacuum to give a solid, m.p. 152°-156° C.; FAB MS [M+1]+ 283.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:15])([F:14])[C:11](O)=[O:12].O[N:24]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:15])([F:14])[C:11]([NH2:24])=[O:12]
Reactant: O=C(O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 23.4 %

Procedure:
In 20 ml of dioxane were dissolved 300 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid and 110 mg of N-hydroxysuccinimide. To the resulting solution was added 200 mg of N,N'-dicyclohexylcarbodiimide. Then, the resulting mixture was subjected to reaction at 15°-25° C. for 3 hours. The reaction mixture was subjected to filtration to remove the insolubles, and 4.5 ml of a concentrated aqueous ammonia solution was added to the filtrate. The resulting mixture was subjected to reaction at 15°-25° C. for 20 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 10 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=10/1) to obtain 70 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](CS([O-])(=O)=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])Cc1ccc(F)cc1
Reactant: CCOC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccccc1Nc1ccc(F)cc1
Temperature: 110 °C
Yield: 91 %

Procedure:
Following general procedure A, a mixture of 4-fluorophenylmethanesulfonate (95 mg, 0.5 mmol), ethyl 2-aminobenzoate (89 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-20% EtOAc/hexanes) to provide the title compound as a yellow oil (118 mg, 91%). 1H NMR (300 MHz, CDCl3) δ: 9.44 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.21 (m, 2H), 7.07 (m, 3H), 6.73 (t, J=7.5 Hz, 1H), 4.37 (q, J=7.5 Hz, 2H), 1.42 (t, J=7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 168.8, 161.3, 158.1, 148.8, 136.9, 136.9, 134.4, 131.9, 125.4, 125.3, 117.1, 116.5, 116.2, 113.6, 112.0, 60.9, 14.6 ppm. IR (neat, cm−1): 3316, 2982, 1683, 1583, 1513, 1455, 1260, 1233, 1082, 749. Anal. Calcd. for C15H14FNO2: C, 69.49; H, 5.44. Found: C, 70.14; H, 5.64.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13]>CN(C)C=O.O>[CH3:13][CH:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC(C)Br
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(C)N1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) and 2-bromooctane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:25]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[Cl-].[NH4+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]([N:11]([CH3:12])[CH3:13])=[O:10])[C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CN(C)C(=O)Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CN(C)C(=O)C(c1ccc(Br)cc1)C1(O)CCCCC1
Temperature: -78 °C

Procedure:
4-bromo-N,N-dimethylbenzene acetamide (15 g, 0.06 mole) was added to dry T.H.F. (250 ml) and the solution cooled to -78° C. under nitrogen. Straight chain butyl lithium in hexane (43.3 ml, 0.06 mole) was added dropwise, the temperature being maintained below -70° C. throughout. An orange coloured precipitate formed. After addition, the reaction mixture was maintained near -70° C. for 20 minutes and cyclohexanone (7.5 ml, 0.07 mole) was added. After a further 50 minutes at -78° C. the reaction mixture was poured into stirring saturated ammonium chloride solution. The layers were separated and the aqueous layer extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated. The product crystallised and was filtered with isopropanol (9.8 g, m.p. 140 °-144° C.).