Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:15]([O:14][C:12]1[O:13][C@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][C@H:3]2[N:11]=1)[CH3:16]
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (±) trans-1-chloro-2-ethoxycarbonylaminoindane (B. J. Walker and P. J. Wrobel, J. Chem. Soc. Chem. Commun., 1980, 462)(4.0 g, 0.017 mol) in ethanol (125 ml) was treated with K2CO3 (2.4 g, 0.018 mol) and diluted with water (50 ml). After stirring at room temperature for 20 h, the reaction was concentrated under high vacuum to approximately one quarter the original volume, then diluted with water (25 ml) and extracted into diethyl ether (3×50 ml). The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a low melting solid (3.3 g), m.p 53°-54° C. (from diethyl ether/n-pentane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:9]2[O:10][CH2:12][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrClCH2 (4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs2CO3 (12.6 g, 39 mmol). The mixture was stirred at 60° C. overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/E.A.=10/1) to afford 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). 1H NMR (300 MHz, CDCl3) δ 9.78 (d, J=0.9 Hz, 1H), 7.26 (dd, J=1.5, 9.3 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 6.16 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[OH:9][C:10]1[CH2:15][CH:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([Br:24])[C:17]=2[CH3:25])[CH2:13][C:12](=[O:26])[C:11]=1[C:27](=O)[CH2:28][CH3:29].C(O)C>O>[CH2:2]([O:5][N:6]=[C:27]([C:11]1[C:12](=[O:26])[CH2:13][CH:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([Br:24])[C:17]=2[CH3:25])[CH2:15][C:10]=1[OH:9])[CH2:28][CH3:29])[CH:3]=[CH2:4]
Reactant: C=CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(Br)c2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(Br)c2C)CC1=O
Yield: 57.3 %

Procedure:
Allyloxyamine hydrochloride (0.17 g) and then a solution of sodium hydroxide (0.06 g) in water (1 ml) were added to a stirred mixture of 3-hydroxy-2-propionyl-5-(3-bromo-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.50 g, 1.37 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation under reduced pressure and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(allyloxyimino)propyl]-3-hydroxy-5-(3-bromo-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.33 g, 57.4%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([NH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=2)[C:19]([NH2:21])=[O:20])=[O:12])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To solution of (4-nitro-phenoxy)-acetic acid (50 mg, 0.25 mmol), 2-amino isonicotinamide (52 mg, 0.37 mmol) and DMAP (62 mg, 0.5 mmol) in DMF 6 ml was added PyBOP (684 mg, 1.31 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtOAc:n-Hexane:MeOH=1:2:1˜1:2:2) to afford 2-[2-(4-nitro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.04 g, 50% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O[Li].O>CO.O>[CH2:7]([O:6][P:4]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)c1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 7-f (100 mg, 0.33 mmol) in methanol (2 mL) and water (2 mL) was treated with LiOH—H2O (14 mg, 0.33 mmol), and the resulting reaction solution was stirred at room temperature overnight. The resulting mixture was concentrated and extracted by EA. The aqueous layers was added HCl (1 M) until pH 1˜2. The mixture was extracted by EA. Combined organic layers was washed by brine, dried over Na2SO4 and concentrated to afford the title compound, 7-g, as oil (35 mg, 37%). 1H NMR (300 MHz, CDCl3) δ1.30-1.34 (m, 6H), 1.52 (d, J=7.2 Hz, 3H), 3.79 (q, J=7.2 Hz, 1H), 4.07-4.17 (m, 4H), 7.39-7.43 (m, 2H), 7.71-7.78 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (0.51 g, 1.5 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (150 mg) in acetonitrile (10 mL) was heated to reflux for 12 hours. To the mixture, was added water (70 mL), and stirred at room temperature for 2 hours. The suspension was filtered and washed with ethyl acetate (10 mL). The solid in NMP (3 mL) was heated at 80° C. To the solution, was added water (1.5 mL), and the mixture was allowed to cool to room temperature. The suspension was filtered and washed with NMP (1 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (350 mg, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.18 min (99.9%); mp: 312-314° C.; 1H NMR (DMSO-d6) δ 2.14-2.21 (m, 1H, C W), 2.60-2.74 (m, 2H, 2CHH), 2.83-2.93 (m, 1H, CHH), 5.51 (brs, 1H, NCH), 7.68 (d, J=9 Hz, 1H, Ar), 8.03 (dd, J=2, 9 Hz, 1H, Ar), 8.24 (d, J=2 Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.45, 30.93, 55.49, 119.83, 122.96, 128.23, 129.65, 137.61, 146.52, 147.94, 158.66, 169.75, 172.46: LCMS: MH=336, 338; Anal Calcd for C13H11N3O3Br+0.3H2O: C, 45.72; H, 3.13; N, 12.30; Br, 23.39. Found: C, 45.46; H, 2.75; N, 12.15; Br, 22.81.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH3:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCC2)c1C
Temperature: 80 °C
Yield: 82.7 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclobutylamino)-2-methylbenzoate (0.7 g, 2.8 mmol) in acetonitrile-(10 mL), cesium carbonate (2.2 g, 6.8 mmol) and methyl iodide (3.9 g, 28 mmol) were added. The resulting reaction mass was heated at 80° C. for 8 h. On completion, the reaction mass was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give the title compound (0.62 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Cl:12][C:8]1[CH:7]=[C:3]2[C:2](=[C:10]([Cl:11])[CH:9]=1)[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:5]
Reactant: NC(N)=O
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Product: O=c1[nH]c(=O)c2cc(Cl)cc(Cl)c2[nH]1

Procedure:
Prepared according to general method C from 2-amino-3,5-dichlorobenzoic acid (3.0 g) and urea (8.8 g). Yield: 3.20 g (95%) of a solid. Although it contained a small amount of an impurity it was used in the next step without further purification. 1H-NMR (DMSO-δ6) δ (ppm) 10.13 (br s, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H).
Reaction SMILES: B(Br)(Br)[Br:2].CO[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COCc1ccccc1NC(=O)OC
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccccc1CBr
Reaction time: 2 h

Procedure:
38.6 g (150 mmol) of boron tribromide are added dropwise to 10 g (51 mmol) of methyl N-(2-methoxymethylphenyl)-carbamate (Example 2b) in 100 ml of methylene chloride. Stirring is carried out for 2 hours, after which the vigorously stirred reaction mixture is added dropwise to a solution of 11.8 g (0.17 mol) of NaHCO3 in water. The organic phase is separated off and the aqueous phase is extracted once with methylene chloride and once with ethyl acetate. The combined organic phases are dried over MgSO4 and evaporated down. 9.5 g (39 mmol=76%) of the title compound are obtained as a colorless solid. mp.=132° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CN(C1C=CN=CC=1)C.C1CCCCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: COC(=O)C1CCCC1=O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCCCC1
Product: O=C1CCCC1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
In a 4-liter flask fitted with a Dean-Stark apparatus and a condenser, methyl 2-oxo-cyclopentanecarboxylate (380 mL; 3 mol), benzyl alcohol (342 mL; 3.3 mol; 1.1 eq.) and DMAP (18.3 g; 0.15 mol; 0.05 eq.) are dissolved in 1800 mL of cyclohexane. The reaction mixture is stirred for 48 hours at reflux (temperature of the mixture: 90° C.) and the methanol formed is distilled off. After cooling, the reaction mixture is concentrated and taken up in 1500 mL of dichloromethane. The organic phase is washed with 1N hydrochloric acid, with water, and then with saturated sodium chloride solution. It is then dried, filtered and then evaporated.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46].N1C=CN=C1.[Na]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][O:43][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])([CH2:12][O:13]2)[C@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Na]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO[Si](C)(C)C(C)(C)C)(O3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol 28d (11.68 g, 18.9 mmol) in dichloromethane (40 mL) were added tert-butyldimethylsilyl chloride (3.4 g, 22.68 mmol), imidazole (2.57 g, 37.8 mmol) and a catalytic amount of 4-dimethylaminopyridine in turn at 0° C. The mixture was stirred at room temperature for 30 min and adjusted with saturated aqueous sodium bicarnonate till pH becomes 7. The resulting mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28e as a white solid (15.9 g, 100%). The crude product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].[I:20]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[I:20][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 h and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 5-iodo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (7.1 g, 50% yield). MS m/z 427 [M+1]. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.74 (d, J=6.57 Hz, 3H) 5.91-5.99 (m, 3H) 6.82 (d, J=1.26 Hz, 1H) 7.46 (t, J=8.72 Hz, 1H) 7.56 (dd, J=8.97, 4.93 Hz, 1H) 7.62 (d, J=1.52 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28]1[CH2:33][O:32][CH:31]=[CH:30][CH2:29]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH:31]3[CH2:30][CH2:29][CH2:28][CH2:33][O:32]3)[N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)nn1C1CCCCO1
Reaction time: 8 h

Procedure:
To a mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (2.44 g, 10 mmol) and 4-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) in THF (200 mL), was added DHP (4.25 g, 50 mmol). After stirring overnight, the reaction turned clear. After concentration, the residue was dissolved in ethyl acetate and washed with Na2CO3 saturated aqueous solution. The organic layer was then washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2,5-Dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine as light yellow solid, which was used in subsequent reactions without further purification; ESMS m/z 244 (M−THP+H+); TLC Rf=0.6 (Silica; 1:1 ethyl acetate/hexanes; starting material Rf=0.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[Sn](C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([O:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:22]=[CH:21]2>CN(C=O)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:32][CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=1)=[CH:18][CH:27]=[CH:26]2
Reactant: CC(C)(C)OC(=O)n1cccc1[Sn](C)(C)C
Reactant: OCCCOc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc2cc(OCCCO)ccc12
Temperature: 70 °C
Yield: 60 %

Procedure:
To N-tert-butoxycarbonyl-2-trimethylstannylpyrrole (3.0 g) and 6-bromo-2-(3-hydroxypropyloxy)naphthalene (2.55 g) in 20 ml of DMF was added dichloro bis(triphenylphosphino)palladium(II) (64 mg) under an argon atmosphere. The mixture was heated at 70° C. for 16 h. After cooling the mixture was washed with diethyl ether and water. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by column chromatography (silica, hexane/dichloromethane, 2/98, v/v) to give a pure oil in 60% yield [2-(6-(3-hydroxypropyloxy)-naphthyl)-N-tert-butoxycarbonylpyrrole]. To this oil (0.5 g) in 10 ml of DMF was added dropwise phophorusoxychloride (0.42 g) at 0° C. under an argon atmosphere. The mixture was heated at 60° C. for 2 h. After cooling the mixture was neutralized with aqueous sodium hydroxide (1 M) and heated at 80° C. for 1 h. After cooling the precipitate was filtered off and purified by column chromatography (silica, methanol/dichloromethane, 1/99,v/v) to give a 75% yield of 5-formyl-2-(6-(3-chloropropyloxy)-naphthyl)-N—H-pyrrole.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C@H:5]([OH:7])[CH3:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.O>CN(C)C=O>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][O:7][C@H:5]([CH3:6])[C:4]([F:9])([F:8])[F:3])[CH:13]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (77 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of (R)-1,1,1-trifluoropropan-2-ol (213 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and the mixture was stirred for 15 minutes. Then, a solution of 1-bromomethyl-3-chlorobenzene (311 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred at room temperature for 2.5 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (307 mg).
Reaction SMILES: [B-](F)(F)(F)F.CCN([S+](F)F)CC.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=O.[FH:32].[FH:33].F.C(N(CC)CC)C>ClCCl>[F:32][CH:14]([F:33])[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: F
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(C(F)F)CC1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a cooled (0° C.) solution of XtalFluor-E (4.50 g, 19.65 mmol) in dichloromethane (50 mL) was added a solution of 4-formyl-N-CBZ-piperidine (2.30 g, 9.30 mmol, Oakwood) in dichloromethane (7 mL) followed by triethylamine trihydrofluoride (3.00 mL, 18.40 mmol). The reaction was allowed to warm to room temperature overnight. Then the reaction mixture was cooled to 0° C. and quenched slowly with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco 40 g) eluting with (EtOAc):hexanes (0:1→1:1) to give benzyl 4-(difluoromethyl)piperidine-1-carboxylate as a light-yellow oil (1.16 g, 46% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].[Br:13][C:14]1[CH:26]=[C:25]([CH2:27][CH2:28]Br)[CH:24]=[CH:23][C:15]=1[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[Br:13][C:14]1[CH:26]=[C:25]([CH2:27][CH2:28][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH:24]=[CH:23][C:15]=1[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)COc1ccc(CCBr)cc1Br
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
A suspension of (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (475 mg), ethyl 2-[2-bromo-4-(2-bromoethyl)phenoxy]acetate (520 mg) and molecular sieves 4A powder (1.42 g) in N,N-dimethylformamide (4.7 ml) was stirred for 2 days at room temperature. Purification of the reaction mixture by medium pressure liquid column chromatography on aminopropyl silica gel (eluent:dichloromethane/methanol=10/1) gave ethyl 2-[2-bromo-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate (356 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=3)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCNCC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 70.4 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.332 g, 0.891 mmol) and tert-butyl piperidin-4-yl-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate (0.194 g, 0.891 mmol) gave tert-butyl (S)-{1-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperidin-4-yl}-N-[2-(4-trifluoromethylphenyl)-ethyl]carbamate (0.370 g, yield 70%) as a light yellow oil in the same manner as in Example 277.