Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[O:16]([C:10]1[CH:11]=[CH:12][C:13]([C:3](=[O:4])[CH2:2][Br:1])=[CH:14][CH:15]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:3](=[O:4])[CH2:2][Br:1])=[CH:21][CH:22]=1
Reactant: O=C(Cl)CBr
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Oc2ccc(C(=O)CBr)cc2)cc1
Temperature: -15 °C
Reaction time: 0.05 h
Yield: 66.8 %

Procedure:
Bromoacetyl chloride (2.22 ml, 22 mmol) was added dropwise during 15 min with stirring at −15° C. to a mixture of aluminum chloride (6.0 g, 44.8 mmol) in methylene dichloride (40 ml). The reaction mixture was stirred at −15° C. for an additional 3 min. Diphenyl ether (1.87 g, 11.0 mmol) was added during 30 min with stifling at −15° C. and the reaction mixture was allowed to warm to room temperature and then stirred for 3 h. It was then poured into a mixture of concentrated hydrochloric acid and crushed ice and extracted with methylene dichloride (2×50 ml). The combined organic extracts were washed with 2% aqueous sodium hydrogen carbonate and water and dried over Na2SO4. Evaporation of the solvent under reduced pressure gave desired product 50 3.03 g (67%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:14])[N:6]([CH:11]3[CH2:13][CH2:12]3)[N:7]=2)[CH:3]=1.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>CS(C)=O.[Cu]I>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][N:25]([C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[C:5]([CH3:14])[N:6]([CH:11]5[CH2:13][CH2:12]5)[N:7]=4)[CH:3]=3)[C:24](=[O:28])[CH:23]=2)=[CH:18][CH:17]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cc1c2cc(Br)ccc2nn1C1CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1C1CC1
Yield: 38.9 %

Procedure:
To a suspension of 5-bromo-2-cyclopropyl-3-methyl-2H-indazole (320 mg), 4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (200 mg) and potassium carbonate (352 mg) in DMSO (20 ml) were added copper(I) iodide (162 mg) and N,N′-dimethylethylenediamine (112 mg), and the mixture was reacted at 150° C. for 1 hr under microwave irradiation. The reaction mixture was added to 28% aqueous ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (134 mg).
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCCCC.O1CCCC1>[CH:29]1([C:35]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)C1CCCCC1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.33 ml, 0.55 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (170 mg, 0.50 mmol) in tetrahydrofuran (5 ml) at 0 degrees under argon. After 10 minutes, cyclohexanecarboxylic acid chloride (74 microliter, 0.55 mmol) was added. The mixture was stirred at room temperature for 15 hours and quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 1000 u silica plate; developed with 5% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1C=CC(C([O-])=O)=C[CH:9]=1.ClCCOCCO.[OH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1
Reactant: O=C([O-])c1ccc(OCCOCCO)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: OCCOCCCl
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCOCCOCCO)cc1

Procedure:
These compounds were synthesized by a similar method. The representative synthesis of 4-(2-(2-hydroxyethoxy)ethoxy)benzoate (3) is presented. A solution of 2-(2-chloro ethoxy)ethanol 5.338 grams (0.04 mole) in 50 ml of acetonitrile was added dropwise to a solution of methyl 4-hydroxybenzoate 5.1 grams (0.036 mole) and 23.2 grams (0.168 mole) of powdered anhydrous potassium carbonate in 300 ml of acetonitrile at 80° C. After stirring the reaction mixture under reflux for 12 hours, 250 ml of the acetonitrile was then distilled and 250 ml dichloromethane was added. The reaction mixture was filtered through CELITE® and the solid was washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 40% diethyl ether in dichloromethane yielded 7.1 g (87%). 1H-NMR (CDCl3, TMS): d=2.62 (s, 1H, --OH), 3.81-4.25 (m, 8H, --(OCH2CH2)2 --), 3.85 (s, 3H, --COOCH3), 6.9 and 7.9 (2d, 4 aromatic protons).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:14]=[C:15]([CH:41]=[CH:42][CH:43]=1)[CH2:16][N:17]([S:29]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40])(=[O:31])=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl.C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:40][C:33]1[CH:34]=[C:35]([CH3:39])[CH:36]=[C:37]([CH3:38])[C:32]=1[S:29]([N:17]([C:18]1[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26](=[O:27])[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:22][CH:23]=1)[CH2:16][C:15]1[CH:41]=[CH:42][CH:43]=[C:13]([O:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][O:6]2)[CH:14]=1)(=[O:30])=[O:31]
Reactant: C1CCNC1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)N3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.6 %

Procedure:
A solution of pyrrolidine (11.7 μl, 0.14 mmol) in 0.3 mL methylene chloride was added to 3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethylbenzenesulfonyl)-amino]-phenyl}-acrylic acid (0.050 g, 0.09 mmol). Triethylamine (0.07 mL, 0.50 mmol), 1-propanephosphonic acid cyclic anhydride (0.056 mL of a 50 wt. % solution in ethyl acetate, 0.190 mmol), and catalytic DMAP were added. The reaction mixture was stirred at room temperature for 48 hr. PS-trisamine resin (0.050 g) and PS-isocyanate (0.050 g) resin was added, and the reaction mixture was stirred at room temperature for two hours. The resin was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to afford 0.021 g of the title compound of Step A.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24](B(O)O)=[CH:23][CH:22]=[C:21]3[CH2:20]1.C(N(CC)CC)C.COCCOC>C(Cl)(Cl)Cl.[Pd].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.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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[C:25]5[C:30]6[C:21]([CH2:20][CH2:19][C:29]=6[CH:28]=[CH:27][CH:26]=5)=[CH:22][CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc2c3c(cccc13)CC2
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c6c(cccc46)CC5)cc3CC[C@@H]12
Yield: 68.6 %

Procedure:
A 15mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 5-acenaphtheneboronic acid (154 mg, 0.78 mmol), 0.20 mL of triethylamine and 2 mL of DME, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL)and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 170 mg (69%) of the title compound as a white solid. mp>200° (decomp.) FDHS: m/e=381 α[D]589 =+61.47(c=0.84, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:25]([CH3:28])=[N:26][N:27]=[C:11]3[C@H:10]([CH2:29][C:30](O)=[O:31])[N:9]=2)=[CH:4][CH:3]=1.[CH3:33][CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C(N)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:25]([CH3:28])=[N:26][N:27]=[C:11]3[C@H:10]([CH2:29][C:30]([NH:35][CH2:34][CH3:33])=[O:31])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccccc3)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[(4S)-6-(4-Chlorophenyl)-1-methyl-8-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Intermediate 1) (29 mg) was dissolved in DMF (2 ml). DIPEA (23 μl), HATU (29.9 mg) and ethylamine hydrochloride (10.68 mg) were added to the reaction mixture. The reaction was stirred at room temperature overnight. The mixture was dissolved in ethyl acetate (10 ml) and washed with saturated hydrogen carbonate solution (5 ml). The organic phase was washed with water (5 ml) and brine (5 ml). The organic layer was dried and the solvent evaporated. The residue was chromatographed (0-5% methanol:DCM) and then further purified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide (7.5 mg) as a white oil. LCMS (formate): MH+ 470/472, RT 1.10 min
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15](OC)=[O:16])[CH2:3]1.[BH4-].[Na+].CCO>C1COCC1.CCOC(C)=O>[OH:7][CH2:6][C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:5][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][OH:16]
Reactant: COC(=O)[C@@H]1C[C@@H](C)C(=O)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (0.47 g, 1.8 mmol) in THF (4.0 mL) at −10° C., NaBH4 (0.207 g, 5.48 mmol) was added followed by EtOH (1.0 mL). After stirring at −10° C. for 1 h, the mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (25 mL) and brine (30 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product (0.39 g, 92%) was used directly in the next step without further purification. LCMS calc. for C11H24NO4 (M+H)+: m/z=234.2. found no ionization.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH2:12][C:13](=O)[CH3:14].C([OH:23])C1C=CC=CC=1.O[Li].O.Cl>ClCCl>[F:1][C:2]1[C:7]([OH:23])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[C:13]([CH3:14])[NH:9]2
Reactant: OCc1ccccc1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH.H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford 1.6 g of the desired compound which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 um 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH:water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:11]3[N:12]([C:14]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnc3c(C4CC4)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-cyclopropyl-3-iodo-imidazo[1,2-a]pyridine (example C.27 step 5) (592 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (230 mg, 2 mmol) according to general procedure II. Obtained as a yellow solid (128 mg, 22%). MS (ISP) 385.2 [(M+H)+],387 [(M+2+H)+]; mp 246° C.
Reaction SMILES: C(OC(=O)C)(=O)C.CS(C)=O.[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:31]1[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=1)([CH3:30])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=1)[OH:21])([CH3:15])([CH3:14])[CH3:13]>C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:31]1[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=1)([CH3:30])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=1)=[O:21])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(C)(c1ccc(Cl)nc1)C(O)c1ccc(Cl)c(F)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(C)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Reaction time: 18 h
Yield: 96.8 %

Procedure:
Acetic anhydride (2.3 ml, 24.7 mmol) was added to a dimethyl sulfoxide (8 ml) solution of the compound (1.14 g, 2.75 mmol) obtained in Step 4 above under ice cooling and the resulting mixture was gradually returned to room temperature while being stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with 6% aqueous sodium perchlorate solution, 10% aqueous sodium thiosulfate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=4:1 (v/v)] to give the title compound (1.10 g, 97%) as a pale yellow solid.
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NN[C:7]=2[CH:6]=CC=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([OH:53])=O)=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1.N[C@@H](CC)CO>C1COCC1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([NH:10][C@H:11]([CH2:3][OH:2])[CH2:7][CH3:6])=[O:53])=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@H](N)CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Hydroxybenzotriazole hydrate (45.3 mg, 0.29 mmol), N-ethyldiisopropylamine (253 μL, 1.45 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.7 mg, 0.29 mmol) were added at 0° C. to a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) and (S)-(+)-2-amino-1-butanol (34.0 μL, 0.35 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. Extraction with 1 N aqueous hydrochloric acid/ethyl acetate and chromatography (silica, ethyl acetate:heptane=0:100 to 100:0) afforded the title compound (75 mg, 62%) as a white solid. MS: m/e=414.2 [M−H]−.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[O:9][N:8]=1)(=O)=O.[Br-:18].[Li+].O>CC(C)=O>[Br:18][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[O:9][N:8]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ncccn2)on1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)=O
Product: BrCc1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(3-methanesulfonyloxymethyl-isoxazol-5-yl)-pyrimidine (19 gm), lithium bromide (13 gm) in acetone (190 ml) was stirred at 30° C. temperature over a period of 2 h. The reaction was monitored by TLC. The reaction mixture was evaporated under vacuum to provide a crude mass which upon stirring with water (150 ml) provided suspension. Filtration of suspension under suction afforded the title compound in 15.2 gm quantity (75.3%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:14]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cooled solution of 1.37 g (4.8 mmol) of trans-[4-(4-Hydroxy-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester and 0.95 ml NEt3 in 15 ml CH2Cl2 was added 0.5 ml (6.8 mmol) methanesulfonyl chloride. After stirring at RT for 2 h, the reaction mixture was partitioned between Et2O, 1M HCl and water. The ether-layer was concentrated in vacuo to give 1.745 g of clean trans-Methanesulfonic acid 4-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-butyl ester, that was treated in 5 ml CH2Cl2 with 5 ml of trifluoro acetic acid. After stirring the solution for 30 min at RT, the solution was evaporated under reduced pressure to dryness to give 2.25 g (quant.) trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[C:62]([C:64]([NH2:66])=[O:65])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[C:62]([C:64](=[O:65])[NH2:66])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: NC(=O)c1nc([C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.5 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (0.107 g; 0.341 mmol) was dissolved in methylene chloride/dimethyl formamide (5:1; 20 ml). 1-Hydroxybenzotriazole (0.046 g; 0.341 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.071 g; 0.369 mmol) were added. The reaction mixture was stirred 15 min at room temperature and 2-((1R)-1-amino-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide (0.106 g; 0.284 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. The reaction mixture was washed with water (20 ml), sodium hydrogensulfate (10%; 20 ml), sodium hydrogencarbonate (satd; 20 ml), water (20 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×15 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.22 g of ((1R)-1-((1R)-1-(4-carbamoyl-5-phenyl-1,3-thiazole-2-yl)-2-(2-naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccn(C)c(=O)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccn(C)c(=O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 4-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI+): m/z=425.1 ([M+H]+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([S:21](Cl)(=[O:23])=[O:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:21]([CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
To a solution of 10.0 g (50 mmol) of 4-bromophenethylamine and 7.6 mL (55 mmol) of triethylamine in 150 mL of dichloromethane was added a solution of 6.2 mL (55 mmol) of isopropylsulfonyl chloride in 40 mL of dichloromethane dropwise. The mixture was stirred at room temperature for 18 h. The mixture was washed with 100 mL of 1N aqueous hydrochloric acid, the organic layer was separated and the aqueous layer extracted one time with 100 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford 6.7 g (44%) of the title compound.