Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[F:3][CH2:4][C:5]([CH2:10][F:11])([CH3:9])[C:6](=[O:8])[CH3:7]>C(Cl)Cl>[F:3][CH2:4][C:5]([CH2:10][F:11])([CH3:9])[C:6](=[O:8])[CH2:7][Br:1]
Reactant: BrBr
Reactant: CC(=O)C(C)(CF)CF
Solvent: ClCCl
Product: CC(CF)(CF)C(=O)CBr
Yield: 85.8 %

Procedure:
903 g of bromine were slowly added dropwise to a mixture of 757.0 g (5.58 mols) of 3,3-bisfluoromethyl-2-butanone and 4.5 liters of methylene chloride at 20° to 30° C., while cooling and stirring. The yellowish solution was subsequently stirred at 20° C. for a further 1 hour. After distilling off the solvent, the residue was distilled in vacuo. 1,030 g (86% of theory) of 3,3-bisfluoromethyl-1-bromo-butan-2-one of boiling point 49°-53° C./0.15 mm Hg were obtained. ##STR73##
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16][S:17][C:18]1[N:19]=[CH:20][C:21]2[C:26](=O)[O:25]C(=O)[N:23]([CH2:29][C:30]3[CH:38]=[CH:37][C:36]4[O:35][CH2:34][O:33][C:32]=4[CH:31]=3)[C:22]=2[N:39]=1.Cl>O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:23]([CH2:29][C:30]2[CH:38]=[CH:37][C:36]3[O:35][CH2:34][O:33][C:32]=3[CH:31]=2)[C:22]2[N:39]=[C:18]([S:17][CH3:16])[N:19]=[CH:20][C:21]=2[C:26]=1[OH:25])=[O:8])[CH3:11]
Reactant: CSc1ncc2c(=O)oc(=O)n(Cc3ccc4c(c3)OCO4)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2cnc(SC)nc2n(Cc2ccc3c(c2)OCO3)c1=O

Procedure:
To a solution of sodium ethoxide (1.6 g., 0.03 g. atom of sodium in 50 ml. of absolute ethanol) was added 4.8 g. (0.03 mole) of diethyl malonate. The ethanol was removed under suction in a rotary evaporator. To the residue was added 50 ml. of dry dimethyl formamide followed by 3.5 g. (0.01 mole) of 7-methylthio-1-piperonyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione. The reaction mixture was heated under reflux for 2 hours, cooled in ice and poured into 400 ml. of water. The reaction mixture was acidified with conc. hydrochloric acid. The resulting precipitateable amounted to 5.0 g.--m.p. 173°-178° C. Recrystallization from dimethyl formamide gave 3.4 g. of pure product--m.p. 187°-188° C.
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N+:40]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)([O-:42])=[O:41]>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.O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:47]4[CH:46]=[CH:45][CH:44]=[C:43]([N+:40]([O-:42])=[O:41])[CH:48]=4)=[CH:8][N:9]3[C:24]3[N:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=3)=[CH:14][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CNc1cc(-n2cc(Br)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cc(-n2cc(-c3cccc([N+](=O)[O-])c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 31.6 %

Procedure:
DMF (5 mL) was added to a mixture of 6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (200 mg, 0.49 mmol), K3PO4 (312 mg, 0.885 mmol) and 3-nitrophenylboronic acid (123 mg, 0.74 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (85 mg, 0.075 mmol), the mixture was stirred at 100° C. for 4 hours. After adding ethyl acetate and water and filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4-1:1). The target compound (70 mg) was obtained as white solid.
Reaction SMILES: COCCOCCOCCOC.C[Si](Br)(C)C.Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Br[C:28]1[N:29]=[CH:30][C:31]([C:34]([O:36][CH3:37])=[O:35])=[N:32][CH:33]=1.[Cl-].[Na+].Cl>CC(N(C)C)=O.[Zn].[Cu](Br)Br.C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:28]1[N:29]=[CH:30][C:31]([C:34]([O:36][CH3:37])=[O:35])=[N:32][CH:33]=1)([F:26])[F:25])[CH3:24]
Reactant: COC(=O)c1cnc(Br)cn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Br[Cu]Br
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: COCCOCCOCCOC
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)(F)c1cnc(C(=O)OC)cn1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a mixture of zinc powder (4.58 g, 0.070 mol) and triglyme (35 mL) was added TMSBr (0.91 mL, 0.007 mol) under nitrogen, and the mixture was stirred at 70° C. for 1.5 h. After the mixture was cooled to room temperature, ethyl bromodifluoroacetate (10.8 mL, 0.084 mol) was added while maintaining the internal temperature at 22 to 27° C., and the mixture was stirred at 20° C. for 30 min and then cooled to 0° C. After addition of the solution of methyl 5-bromopyrazine-2-carboxylate (II, 7.23 g, 0.033 mol) in DMA (106 mL) to the mixture, the resulting mixture was warmed to 20° C. Copper bromide (CuBr, 10.0 g, 0.070 mol) was added in fifth portions over 1 h followed by stirring the mixture for 30 min. The reaction mixture was transferred into a pre-cooled (ice bath) mixture of an aqueous sodium chloride solution (6.3%, 111 g), concentrated hydrochloric acid (29.4 mL) and toluene (140 mL), and the resulting mixture was vigorously stirred. The organic layer was separated and washed twice with aqueous sodium chloride solutions (5.7%, 70 g and 2.9%, 70 g) to afford 136 g of a toluene solution of methyl 5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrazine-2-carboxylate (III).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4](O)=[O:5])[CH3:3].B.C1COCC1>C1COCC1>[C:10]([O:9][C:7](=[O:8])[NH:1][C@@H:2]([CH3:3])[CH2:4][OH:5])([CH3:13])([CH3:11])[CH3:12]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
As described in literature (Stanfield; et al., JOC., 1981, 46, 4799-800), a solution of Boc-D-Ala-OH (50.0 g, 0.264 mol) in THF (250 mL) was added dropwise to a 0° C. solution of BH3-THF (1.0M in THF, 380 mL, 380 mmol). The mixture was stirred for 2 hours at 0° C. and quenched with a 10% solution of AcOH in MeOH (200 mL). The mixture was concentrated under reduced pressure, diluted with EtOAc (500 mL) and washed with 1N HCl (150 mL). The aqueous was extracted with EtOAc (100 mL) and the combined organic extracts were washed consecutively with H2O (150 mL) and 1N NH4HCO3 (150 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give ((S)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester as a colourless oil (43.6 g) that was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:51]=[CH:52][CH:53]=1)[CH2:14][N:15]1[C:19](=[O:20])[C:18]2([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[C:30]3[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:22][CH2:21]2)[N:17]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:16]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:41]([O:40][C:38]([C:30]1[N:29]([CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:18]3([N:17]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:16][N:15]([CH2:14][C:13]4[CH:12]=[C:11]([CH:53]=[CH:52][CH:51]=4)[C:9]([OH:10])=[O:8])[C:19]3=[O:20])[CH2:25][CH2:24]2)[C:37]2[C:32]([CH:31]=1)=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCN1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCc3ccccc3)c1)CN2c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCN1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Reaction time: 48 h
Yield: 30.1 %

Procedure:
To a solution of tert-butyl 1-(3-(3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-2-carboxylate (0.27 g, 0.32 mmol) in MeOH (5 mL), was added 10%/wt palladium on carbon (0.080 g). The reaction mixture was hydrogenated at 50 psi for 48 hours. It was filtered over Celite, and isolated by preparatory thin layer chromatography in 10% methanol in dichloromethane to obtain the title compound (0.060 g, 30%); 1H NMR (DMSO-d6): δ 1.56 (s, 9H), 1.66 (d, 2H, J=14 Hz), 1.95 (t, 2H, J=6.4 Hz), 2.50-2.66 (m, 4H), 2.88 (bs, 4H), 4.59-4.64 (m, 6H), 6.78 (t, 1H, J=7.2 Hz), 6.88 (d, 2H, J=8.4 Hz), 7.10 (t, 1H, J=7.2 Hz), 7.19-7.31 (m, 3H), 7.48-7.54 (m, 2H), 7.67 (t, 2H, J=8.4 Hz), 7.87 (d, 2H, J=6.4 Hz), 8.13 (s, 1H), 12.75 (bs, 1H); MS for C37H42N4O5 m/z 623.16 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].Cl.N([O-])=O.[Na+].[Cl-].[I-:16].[K+].S(=O)(=O)(O)O>O>[I:16][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: [I-]
Reactant: Cc1ccc(F)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(F)cc1I
Temperature: 100 °C
Yield: 82.1 %

Procedure:
2-Amino-4-fluorotoluene (68 g) is added dropwise to a stirred solution of 100 ml hydrochloric acid in 700 ml of water and after cooling to 0°-5° C., a solution of 46 g sodium nitrite in 100 ml water was slowly added dropwise. The resultant ice-cold solution of the diasonium chloride was added over 1 hour with stirring to a solution of 157 g potassium iodide and 35 ml of sulfuric acid in 250 ml water at 20°-25° C. The mixture was then stirred and heated for 2 hours at 100° C. After cooling, an oily product was separated and the remaining aqueous layer extracted with benzene. The separated product was dissolved in the benzene layer, the solution washed with a 5% sodium hydrogen sulfite solution, with water, 5% sodium hydroxide solution and again with water, dried with magnesium sulfate and filtered with charcoal. From the filtrate, benzene was evaporated under reduced pressure and the residue distilled. There were obtained 105.3 g of 2-iodo-4-fluorotoluene boiling at 92°-95° C./17 Torr.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:34]2[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=3)[CH2:36][CH2:35]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Reactant: CSc1ccc(CCN2CCNCC2)cc1
Product: CSc1ccc(CCN2CCN(C(=O)c3ccc(N(CCOC(C)C)C(=O)CCl)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.95 g of [2-(4-methylmercaptophenyl)ethyl]piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-methylmercaptophenyl)ethyl]piperazine. The hydrochloride thereof melts at 115°-116°.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:20]([C:18]1[S:19][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[CH:16][CH:17]=1)(=[O:21])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)c1Br
Yield: 40 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(2-pyridyl)thiophene-2-sulphonyl chloride in 40% yield. Purification was achieved by recrystallization from ethyl acetate to give a crystalline solid, m.p. 186-188° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[S:5][C:6]=1[C:7](=[O:9])[CH3:8].[NH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:7]([C:6]1[S:5][C:4]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[N:3][C:2]=1[NH2:1])(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CC(=O)c1sc(S(C)(=O)=O)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Temperature: 120 °C

Procedure:
390 mg (1.77 mmol) of 1-[4-amino-2-(methylsulfonyl)-1,3-thiazol-5-yl]ethanone (Example 48A) were dissolved in 5 ml of DMSO, and 209.6 mg (0.89 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 0.585 ml (3.54 mmol) of N,N-diisopropylethylamine were added. The mixture was heated in a microwave at 120° C. for 45 min. This gave, after purification by preparative HPLC, 162 mg (52% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) and 4-bromophenylboronic acid (80 mg) were dissolved in a mixed solution composed of dichloromethane (5 ml) and triethylamine (0.07 ml) to prepare a solution. Copper(II) acetate (50 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The stirred mixture was filtered, and the filtrate was then concentrated. The crude thus obtained was purified by chromatography on silica gel to give (4-bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:9]
Reactant: O=C(O)c1cc(F)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(F)ccc1OCc1ccccc1

Procedure:
A solution of 5-fluoro-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 20, 180 mg, 0.73 mmol), 3-pyridinamine (68.8 mg, 0.73 mmol), HOBT (134 mg, 0.88 mmol) and EDC (168 mg, 0.88 mmol) in DMF (10 ml) was stirred at room temperature overnight. Water (30 ml) was added and the mixture was filtered. The residue was dried to yield the title compound as a white solid. 100 mg.
Reaction SMILES: [OH-].[Li+].C[C@H]1[C@H](C2C=CC=CC=2)OC(=O)N1[C:16](=[O:27])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH3:18].C(OCC)(=[O:30])C>O1CCCC1.O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:17]([CH3:18])[C:16]([OH:27])=[O:30]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reactant: CCOC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
1.52 g of lithium hydroxide are added to a solution, cooled to +5° C., of 4.1 g of (4S,5S)-4-methyl5-phenyl-3-[(S)-2-(2-methoxyphenyl)propionyl]2-oxazolidinone in 60 cm3 of tetrahydrofuran and 30 cm3 of water. The reaction mixture is stirred for 3 hours at this temperature and then, after returning to room temperature, ethyl acetate is added, the mixture decanted, the aqueous phase is acidified with a 1N aqueous solution of hydrochloric acid, extracted with ethyl acetate and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from hexane, drained and dried. 0.4 g of (S)-2-(2-methoxyphenyl)propionic acid is obtained in the form of white crystals; melting point 102° C. [α]D20 =+84.6; (c=1; CHCl3).
Reaction SMILES: Cl.[CH:2]12[CH2:23][CH:5]([CH2:6][C@@H:7]1[NH:8][CH2:9][C@@H:10]([C:12]1[C:13]([CH3:22])=[C:14]3[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]3)[OH:11])[CH2:4][NH:3]2.[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:36][C@H:35]([C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[O:34])[O:31][CH2:32][C:33]=2[C:25]=1[CH3:24])[CH2:37][N:3]1[CH2:4][C@@H:5]2[CH2:23][C@H:2]1[CH:7]([NH:8][CH2:9][C@H:10]([OH:11])[C:12]1[CH:20]=[CH:19][C:18]3[C:17](=[O:21])[O:16][CH2:15][C:14]=3[C:13]=1[CH3:22])[CH2:6]2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN[C@H]2CC3CNC2C3)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNC2C[C@H]3C[C@@H]2N(C[C@H](O)c2ccc4c(c2C)COC4=O)C3)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[(1S,4S)-6-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}-2-azabicyclo[2.2.1]hept-2-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-((1R)-2-((6S)-2-azabicyclo[2.2.1]heptan-6-ylamino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 13] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[N:15][C:9]=2[NH:8][C:7]1=O)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[O:11]1[CH:6]([CH2:4][OH:3])[CH2:7][NH:8][C:9]2[N:15]=[CH:14][CH:13]=[CH:12][C:10]1=2
Reactant: CCOC(=O)C1Oc2cccnc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CNc2ncccc2O1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,4-dihydro-3-oxo-2H-pyrido[3,2-b]-1,4-oxazin-2-carboxylic acid ethyl ester (1.10 g, 5.0 mmol) in THF (50 mL) was added over 5 min to a stirred mixture of LiAlH4 (0.38 g, 10 mmol) and THF (20 mL) at 40° C. The mixture was stirred at 45° C. for 30 min and at reflux for 4 h. The mixture was allowed to attain room temperature and excess LiAlH4 decomposed with 50% aqueous NaOH. The mixture was filtered through Celite, and the filtrate was concentrated. The residue (0.42 g) was extracted with CH2Cl2 and the extract was concentrated and purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give the product as a white solid: yield 0.11 g (13%); mp 123-124° C. Anal. (C8H10N2O2) C, H, N.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.[Br:33][C:34]1[N:35]=[C:36]([CH:58]=[O:59])[N:37]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=1>C1COCC1>[Br:33][C:34]1[N:35]=[C:36]([CH:58]([C:5]2[C:6]([F:15])=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[OH:59])[N:37]([C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:38]=1
Reactant: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc(F)c(-c2ccccc2)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(-c2ccccc2)c(F)c(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -40 °C
Yield: 74.1 %

Procedure:
To a solution of Intermediate 228.2 (85 mg, 0.424 mmol) and PMDTA (0.10 mL, 0.478 mmol) in 4 ml THF at −78° C., was added BuLi (1.4 M in hexanes, 0.334 mL, 0.467 mmol). The mixture was stirred with warming to −40° C. over 30 min, recooled to −78° C., then a solution of Intermediate 175.1 (177 mg, 0.424 mmol) in 1.5 mL THF was added. The mixture was warmed to rt over 0.5 h. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 194 mg of Intermediate 228.3 as a colorless solid.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: COC(=O)[C@@H]1CC[C@H](CO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](CBr)C1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a 0° C. solution of 99 (6.6 gm, 50 mmol, 1 equi.) in 60 mL of DCM was added triphenyl phosphine (60 mmol, 1.2 equi, 15.72 gm) followed by carbon tetrabromide (60 mmol, 1.2 equi. 19.86 gm). The reaction mixture was stirred overnight allowing the temperature to rise to room temperature. Reaction was concentrated to dryness and the residue was diluted with ether/DCM (1:1, 20 ml) and filtered through a pad of celite. The filtrate was concentrated to dryness and the residue was purified by silica gel chromatography with (5% to 20% EtOAc in hexanes) to provide 3.5 g of (1R,3S)-methyl 3-(bromomethyl)cyclopentanecarboxylate 100.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][C@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:13][C@H:12](O)[CH:11]=1)([O-:3])=[O:2].CS(Cl)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C(Cl)Cl.C(OCC)(=O)C.CCCCCCC>[N:26]([C@H:12]1[CH2:13][C@@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:15][C:10]([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1cnccc1C1=C[C@@H](O)C[C@@H](C(F)(F)F)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1C=C(c2ccncc2[N+](=O)[O-])C[C@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of cis-3-(3-nitropyridin-4-yl)-5-(trifluoromethyl)cyclohex-2-enol (1.0 eq) in DCM (0.14 M) was added TEA (2.5 eq), and followed by MsCl (1.8 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed. The residue was dissolved in DMF (0.19 M), and then the mixture was added sodium azide (1.2 eq). The resulting mixture was stirred at room temperature for 1 hour. Another 1.2 eq of sodium azide was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and heptane, and washed with sat NaCl. The organic was dried over MgSO4, filtered and concentrated. The residue was purified by column (1:1 ethyl acetate and hexanes) to give cis-4-(3-azido-5-(trifluoromethyl)cyclohex-1-enyl)-3-nitropyridine (58%). LC/MS (m/z): MH+=314.1, Rt=0.96 min.