Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH3:20])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(F)ccc1-c1cc(C(Cl)CC(C)C)c(C)o1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(F)ccc1-c1cc(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-methylfuran (442 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (188 mg, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[CH2:20]([Li])CCC.CI.O>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1ccc(NC(=O)C(C)(C)C)cc1OC
Reactant: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(NC(=O)C(C)(C)C)c(C)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of N-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide (500 mg, 1.87 mmol) in tetrahydrofuran (10 ml) was added dropwise 1.59M-n-butyllithium (2.94 ml, 4.68 mmol) at −15° C., and the resulting mixture was slowly warmed up to 0° C. After 2 hours, a solution of methyl iodide (0.175 ml, 2.81 mmol) in tetrahydrofuran (0.5 ml) was added dropwise thereto. After 1 hour, the resulting mixture was warmed up to room temperature. After 14 hours, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (30 ml×3), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain N-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide (424 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:13]([OH:15])=O)[CH2:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].ClC1C=C(Cl)C(Cl)=CC=1O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:13]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:15])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@H](CC1CCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N[C@H](CC1CCC1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.7 g (17.2 mmole) of ethoxycarbonyl-3-cyclobutyl-D-alanine (Example 1, Step D) is dissolved in 60 ml of tetrahydrofuran, cooled to 0° C., then 4.85 g (24.5 mmol) of 2,4,5-trichlorophenol and 5.06 g (24.5 mmol) of dicyclohexyl-carbodiimide are added. The reaction mixture is stirred at room temperature for 2 hours, filtered from the separated dicyclohexylurea and washed with tetrahydrofuran. The filtrate and the washings are pooled and evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 25 ml of diethyl ether-petroleum ether mixture (1:1), the insoluble dicyclohexylurea is filtered off and the filtrate is evaporated again [the filtered dicyclohexylurea amounts to 4.9 g (89%) and 0.6 g (11%), respectively]. The oily 2,4,5-trichlorophenyl ethoxycarbonyl-3-cyclobutyl-D-alaninate is dissolved in 40 ml of pyridine and 2.12 g (18.4 mmol) of finely pulverised L-proline is added together with 3.43 ml (24.6 mmol) of triethyl amine. The reaction mixture is stirred at room temperature for 3 hours, then evaporated at a pressure of 2.0-2.5 kPa. The residue is distributed between 50 ml of ethyl acetate and 50 ml of 1M HCl. The organic phase is washed first with 10 ml of 1M HCl then with 2×10 ml of water and is extracted with 3×100 ml of 5% NaHCO3. The pooled hydrocarbonate extracts are acidified to pH3 with 6M HCl and extracted with 3×20 ml of diethyl ether. The ethereal extracts are pooled, washed acid-free with water, dried over anhydrous sodium sulphate and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:30]3[CH2:31][CH2:32][CH:27]([F:26])[CH2:28][CH2:29]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC1CCNCC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC2CO2)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC(O)CN2CCC(F)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
A solution of 0.080 g (0.22 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one (example 166A) in 0.5 ml of MeOH was treated with 0.038 (0.26 mmol) of 4-fluoropiperidine hydrochloride and 0.15 ml (1.08 mmol) of Et3N in 0.5 ml of MeOH. The reaction was stirred for 24 h at RT, partitioned between aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phase was dried over Na2SO4 and evaporated to give after flash silica gel column (CH2Cl2/MeOH 98:2) 0.0099 g (10%) of the title compound as white foam. MS: 471.9 (MH+, 2Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH3:26][C:24]1[NH:23][N:22]=[C:21]([NH:20][C:12]2[N:11]=[C:10]([O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Cc1ccccc1O
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3C)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-methyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-o-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][C:14]([C:27]([F:30])([F:29])[F:28])=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][C:14]([C:27]([F:30])([F:28])[F:29])=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(C(F)(F)F)ccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(C(F)(F)F)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(trifluoromethyl)quinazolin-2-yl)methanone (500 mg, 1.2 mmol) in a 1:1 mixture of MeOH/THF (10 mL) at 0° C. was added NaBH4 (68 mg, 1.79 mmol). After 10 min of stirring at 0° C., 10 drops of water were added. The solvents were removed under vacuum and the residue was dissolved in a mixture of 1:1 of water EtOAc (20 mL), washed with brine and dried over sodium sulfate. The crude product (360 mg) was purified on reverse-phase preparative HPLC (elution gradient of 40-90% acetonitrile in water with 0.05% acetic acid) to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(trifluoromethyl)quinazolin-2-yl)methanol as white solid (140 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.2 (s, 3H) 5.9 (s, 1H) 6.55 (s, 1H) 7.35-7.5 (m, 3H) 7.9-8.0 (m, 1H) 8.05-8.3 (m, 4H) 11.1 (br. s, 1H) 12.25 (br. s., 1H) LC-MS (ESI) m/z 418 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:30])[CH2:11][CH2:12][N:13]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:14][C:15](OCC)=[O:16])[CH3:8].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([CH:11]1[C:15](=[O:16])[CH2:14][N:13]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:12]1)=[O:30])[CH3:8]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (2.52 g, 22.4 mmol, 1.4 equiv.) in toluene (50 mL) at 0° C. under nitrogen, was added diester 70 (5.41 g, 16 mmol) in toluene (10 mL) over a 10 min period. The solution was stirred for 30 min at 0° C. and 2 mL of glacial acetic acid was added, immediately followed by 10 g of NaH2PO4.H2O in 100 mL of ice-cold water. The resultant mixture was extracted with chloroform (3×150 mL), and the combined organic extracts were washed twice with phosphate buffer (2×25 mL, pH=7.0), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in toluene (200 mL), cooled to 0° C., and extracted with cold pH 9.5 carbonate buffer (3×150 mL) The aqueous extracts were converted to pH 3 with phosphoric acid, and extracted with chloroform (5×125 mL) which were combined, dried, and evaporated to a afford keto ester 71(2.2 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH:21]1OCCO1.Cl.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][N:30]1[CH2:31][CH2:32][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29]1
Reactant: Fc1cc(CCOc2ccc(C(F)(F)F)cc2)ccc1C1OCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCOc3ccc(C(F)(F)F)cc3)cc2F)CC1
Yield: 68.4 %

Procedure:
To a THF (10 mL) solution of 2-(2-fluoro-4-{2-[4-(trifluoromethyl)phenoxy]-ethyl}phenyl)-1,3-dioxolane (0.552 g) was added 6 M HCl (0.775 mL) at 0° C., then the resultant mixture was room temperature for 5 hours. The reaction mixture was evaporated to afford a pale yellow oil. To a CH2Cl2 (15 mL) solution of that pale yellow oil and tert-Butyl 1-piperazinecarboxylate (0.375 g) were added NaB(OAc)3 (0.657 g) at 0° C. The resultant mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 4/1) to afford tert-butyl 4-(2-fluoro-4-{2-[4-(trifluoromethyl)phenoxy]ethyl}benzyl)piperazine-1-carboxylate as a colorless oil (0.511 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.6 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.2 g, 0.642 mmol) in anhydrous dichloromethane (15 ml) was added dry triethylamine (220 ml, 1.4 mmol) and the resulting mixture was stirred at room temperature under an atmosphere of nitrogen until dissolution was complete. To this solution was added benzoyl chloride (82 ml, 0.706 mmol) and stirring was continued for 17 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and dilute citric acid (150 ml). The organic layer was washed successively with saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml) then dried (MgSO4) and evaporated to give the crude product (0.26 g) which was recrystallised from ethyl acetate/petroleum ether (bp 60°-80° C.) to give the pure title compound as colourless crystals (0.201 g, m.p. 258°-259° C.); δ (360 MHz, DMSO) 1.79 (1H, ddd, J= 13.3, 12.6 and 4.1 Hz, CHACHBHCCHD), 2.28 (1H, dm, J=13.3 Hz, CHACHBHCCHD), 3.73 (3H, s, --CO2CH3), 4.09 (1H, dm, J=12.6 Hz, CHACHBHCCHD), 5.28 (1H, m, CHACHBHCCHD), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.93 (1H, s, NH), 7.42-7.55 (3H, m, ArH), 7.89 (2H, d, J=7.1 Hz, ArH), 8.72 (1H, d, J=7.6 Hz, PhCONH-); m/e (CI+) 379 (M+1)+, 122 (100%); Found: C, 56.95; H, 4.30; N, 7.37; C18H16Cl2N2O3 requires C, 57.01; H, 4.25; N, 7.39%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]([CH2:9][OH:10])[CH2:6][CH:7]=[CH2:8].B(F)(F)F.CCOCC.CO[C:30](OC)([CH3:32])[CH3:31]>CC(C)=O>[OH:10][CH2:9][C@H:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][C@H:3]1[CH2:2][O:1][C:30]([CH3:32])([CH3:31])[N:11]1[C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: COC(C)(C)OC
Reactant: C=CC[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
tert-butyl (2S,4R)-1-hydroxy-4-(hydroxymethyl)hept-6-en-2-ylcarbamate (6.8 g, 26.2 mmol) was dissolved in acetone (150 mL) followed by the addition of BF3.Et2O (2.62 mmol). The reaction mixture was cooled to 0° C. and 2,2-dimethoxypropane (4.1 g, 39.4 mmol) was added. The resulting mixture was stirred at rt for 1 h, TEA (0.5 mL) was added and stirred for another 5 min before evaporating under reduced pressure. The residue was dissolved in Et2O (300 mL), washed with 1 N HCl (80 mL), sat. aq. NaHCO3 (80 mL), brine (80 mL) successively, and dried, filtered, and concentrated under vacuum to give crude (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (7.5 g, 96%). It was used for the next step without further purification. 1H NMR (CD3OD) δ 1.4-1.5 (m, 13H), 1.5-1.6 (d, 6H), 1.6-1.9 (m, 2H), 2.0-2.1 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 2H), 4.1-4.2 (m, 1H), 5.0-5.1 (m, 2H), 5.7-5.8 (m, 1H).
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:18]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:17][C@@H:9]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:51])C=1.CSC>C(Cl)Cl>[C:1]([O:7][C@H:8]1[C@@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:18]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:17][C@@H:9]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:51])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 75.4 %

Procedure:
To a solution of 36 (1.38 g, 2.27 mmol) in 65 mL of CH2Cl2 at -78° C. is added m-CPBA (612 mg, 64%, 2.27 mmol). The reaction mixture is allowed to warm to -15° C. and then quenched with dimethyl sulfide (1 mL, 13.6 mmol) and allowed to warm to room temperature. The reaction mixture is diluted with 50 mL of CH2Cl2, extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, and concentrated to afford a white solid. The sulfoxide is purified using flash chromatography (30% EtOAc/hexane) to afford 1.07 g (76%) of the title compound 37 as a mixture of diastereomers: Rf 0.35 and 0.38 (30% EtOAc/hexane).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=12.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CC#N.CCOC(C)=O>[C:21]1([O:20][C:18](=[O:19])[NH:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccn2ccnc12
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cccn2ccnc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-8-ylamine (397 mg, 2.98 mmol) in dry CH3CN (5.0 mL) was added pyridine (282 mg, 3.57 mmol) and phenyl chloroformate (467 mg, 2.98 mmol) and the reaction mixture was stirred at rt. After 4 h, the mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give imidazo[1,2-a]pyridin-8-yl-carbamic acid phenyl ester (409.1 mg, 54%). MS (ESI+): calcd for C14H11N3O2 m/z 253.09. found 254.1 (M+H)+.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1.[CH3:14]N(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C

Procedure:
Iodomethane (11.2 mL) was added to a mixture of compound 6b (32.6 g), DMF (100 mL), and potassium carbonate (62.5 g) at 0° C. The mixture was stirred and allowed to warm to RT over 2 hr. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to afford 1-(4-bromo-2-methoxyphenyl)-1-ethanone (compound 6c, 33.1 g) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.CC(C)([O-])C.[K+].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CCN(c2cc(F)cc(Br)c2)CC1
Temperature: 105 °C
Yield: 37.2 %

Procedure:
To a solution of 1,3-dibromo-5-fluorobenzene (LXI) (2.0 g, 7.88 mmol) in toluene (20 ml) was added potassium t-butoxide (2.65 g, 23.6 mmol) and 1-methylpiperazine (1.75 mL, 15.8 mmol). The reaction was heated at 105° C. overnight. The toluene was removed under vacuum and the residue was dissolved in water and extracted with EtOAc. The organic phase was separated, washed with brine, dried over MgSO4 and concentrated to dryness. The crude product was purified on a silica gel column (1:99 MeOH:CHCl3→7:93 MeOH:CHCl3) to produce 1-(3-bromo-5-fluorophenyl)-4-methylpiperazine (LXII) as an orange oil (800 mg, 2.93 mmol, 37.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.20 (s, 3H), 2.39 (t, J=5 Hz, 4H), 3.33 (t, J=5 Hz, 4H), 6.74-6.81 (m, 2H), 6.91 (s, 1H); ESIMS found for C11H4BrFN2 m/z 273 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].OS(O)(=O)=O.[C:20]([O-])([O-])=O.[K+].[K+].[CH3:26][C:27]([CH3:29])=[O:28]>CO>[O:28]1[CH2:26][C@@H:27]1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:20])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)=O
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@H]2CO2)c([N+](=O)[O-])c1

Procedure:
The material purchased from Aldrich, 4-hydroxy-3-nitrophenyl acetic acid, (0.500 g, 2.54 mmol) was dissolved in methanol (5 mL) and was treated with concentrated H2SO4 (0.25 mL) at reflux for 16 h. The mixture was cooled, evaporated, taken up in 5% NaHCO3 and extracted into ethyl ether. A mixture of this crude compound (0.512 g, 2.43 mmol), K2CO3 (1.0 g, 7.27 mmol) and 2R-(−)-glycidyl-3-nitrobenzenesulfonate (0.630 g, 2.43 mmol) in acetone (10 mL) was refluxed for 24 h. The mixture was cooled, concentrated and purified by flash column chromatography (50% EtOAc/Hexane) to afford the title compound (0.59 g) as an off-white foam. 1H-NMR (250 MHz, CDCl3): δ 2.84-2.93 (m, 2H), 3.37-3.450(m, 1H), 3.62 (s, 2H), 3.71 (s, 3H), 4.09-4.16 (m, 1H), 4.37-4.42 (m, 1H), 7.1-7.8 (m, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[CH2:10][CH:9]1[NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrB(Br)Br>ClCCl>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH:9]1[NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1Cc2ccc(OC)cc2C1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccc(O)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred and cooled (−10° C.) solution of ethyl 1-benzyl-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate (668 mg, 2.053 mmol) in dichloromethane (15 ml) under argon was added dropwise 1M tribromoborane (6.16 ml, 6.16 mmol) and stirred over night while the reaction mixture was allowed to warm up to room temperature. Poured into ice water, diluted with dichloromethane, separated organic layer and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed subsequently with water, sodium bicarbonate and brine, dried, filtered and evaporated to obtain ethyl 1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate as a brown solid. m=620 mg (97%)