Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C@@H:2]([C@@H:11]([OH:15])[CH:12]([CH3:14])[CH3:13])[CH:1]=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: CC(C)C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](O)[C@@H](C=O)Cc1ccccc1
Reaction time: 26 h
Yield: 75 %

Procedure:
A solution of freshly distilled hydrocinnamaldehyde (132 μL, 1.0 mmol) in 500 μL dimethylformamide was added slowly over the course of 24 h to a stirring suspension of isobutyraldehyde (272 μL, 3.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at room temperature. After 26 h, the resulting solution was diluted with ethyl acetate and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. Flash chromatography (3:1 hexanes:ethyl acetate) afforded the title compound as a clear, colorless oil in 75% yield (155 mg, 0.75 mmol), 91% ee and 95:5 anti: syn. IR (film) 3466, 3086, 3063, 3028, 2962, 2932, 2834, 2733, 1950, 1875, 1806, 1722, 1604, 1496, 1454, 1390, 1368, 1244, 1180, 1136, 1049, 1031, 993.0, 964.3, 849.7, 800.6, 739.8, 700.2 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.83 (d, 1H, J=2.1 Hz, CHO); 7.27 (m, 5H, Ar—H); 3.43 (ddd, 1H, J=6.6, 6.6, 4.5 Hz, CHOH); 3.06 (dd, 1H, J=13.2, 7.8 Hz, PhCH2); 2.92 (dd, 1H, J=13.2, 6.9 Hz, PhCH2); 2.81 (m, 1H, CHCH2); 2.15 (d, 1H, J=6.0 Hz, OH); 1.90 (m, 1H, CH(CH3)2); 0.96 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.92 (d, 3H, J=7.2 Hz, CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ 205.6, 129.2, 128.9, 128.6, 126.8, 76.9, 55.8, 33.4, 32.0, 19.7, 18.2; HRMS (CI) exact mass calcd for [M+H]+(C13H19O2) requires m/z 207.1385, found m/z 207.1386; [α]D=−7.9 (c=1.0, CHCl3). The product ratios were determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction) using a Chiracel OJ and OJ guard column (1.0% ethanol/hexanes, 1 mL/min); (2S,3S) anti isomer tr=7.5 min, (2R,3R) anti isomer tr=9.4 min, (2R,3S) and (2S,3R) syn isomers tr=6.3, 6.9 min.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.C[O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[NH2:23]>>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([N:10]([CH2:12][C:13]([NH:23][C@H:22]([C:21]([OH:31])=[O:20])[CH2:24][C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:15])[CH3:11])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N[C@@H](Cc2ccncc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)sarcosine was coupled to 3-(4-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-β-(4-pyridyl)alanine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[O:5][C:6]5[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=5[CH:8]=4)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(-c3ccccc3)coc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzo furan-5-acetate and 3-phenyl-6-hydroxy-7-propylbenzofuran as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.[CH3:8][N:9]([CH3:30])[C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27]C)[CH:19]=1>C1C=CC=CC=1>[CH3:8][N:9]([CH3:30])[C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=1
Reactant: COc1cc(C(=O)N[C@@H]2CCCC[C@H]2N(C)C)ccc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: c1ccccc1
Solvent: ClCCl
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of boron tribromide (7.52 g.; 0.03 mole) in 20 ml. of CH2Cl2 was added to a solution of trans-N-[2-(dimethylamino)cyclohexyl]-3-methoxy-4-nitrobenzamide (1.93 g.; 0.006 mole) in 50 ml. of CH2Cl3 keeping the temperature at -50° to -70°. It was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo at 30° to a small volume, ice-water was added followed by solid NaHCO3 to pH 8, then solid NaCl and extracted with ethyl acetate (5×100 ml). The extract was dried (MgSO4) and evaporated to give 0.657 g. of solid. The aqueous was extracted again with CHCl3 (4×100 ml.) to give 0.561 g. of solid. The last extraction was repeated to give 0.3 g. of solid. The three crops were crystallized from benzene to give 0.548 g. of orange prisms, m.p. 139°- 140°. The analytical sample melted at 138°-140° (efferv.). NMR analysis showed this product to contain ca. 30% of benzene. This impure titled product was heated at 120°-125° for 17 hours in a sublimation tube (the m.p. changed to 198°-199.5°) and was then sublimed at 170°-175° for 18 hours. The sublimate, orange prisms, melted at 202°-203.5°. uv λmax 238 nm nm (ε 11,600); 278 (7,900); 358 (2,350); 422 (2,850). ir NH/=CH/N+H/OH 3220, 3180, 3020, ~2900 broad, C=O 1655; C=C 1600; amide II/NO2 /C=C 1580, 1485, 1335; C--N/C--O 1260, 1240, 1220, 1155, 995. NMR in CDCl3 +d6DMSO (100 MHz) showed absence of benzene. Mass spectrum M+ 307.
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:10](OC)=[O:11])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[BH4-].[Na+].Cl>CO.[Co](Cl)Cl>[O:11]=[C:10]1[NH:2][CH2:1][C@H:3]([C:4]([O:6][CH3:7])=[O:5])[C@@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1
Reactant: COC(=O)CC(c1ccccc1)C(C#N)C(=O)OC
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COC(=O)[C@H]1CNC(=O)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To 1.0 L of a solution of 20.0 g of dimethyl 2-cyano-3-phenylpentanedioate and 36.4 g of cobalt chloride (TI) hexahydrate in methanol was added carefully 17.4 g of sodium borohydride under ice-cooling. After stirring at room temperature for 30 minutes, 1 M hydrochloric acid (1.0 L) was added thereto, followed by further stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to a half amount thereof, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 3.84 g of methyl rel-(3R,4S)-6-oxo-4-phenylpiperidine-3-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](OC2C=CC=CC=2)=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Br:26])=[CH:21][C:20]=1[Cl:27].[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:31][CH2:28][CH:29]=[CH2:30])=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Br:26])=[CH:21][C:20]=1[Cl:27]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2cc(Cl)c(Br)cc2Cl)cc1Oc1ccccc1
Solvent: C1COCCO1
Product: C=CCNc1cc(Oc2cc(Cl)c(Br)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 7 h

Procedure:
A mixture of 4.9 gm of 2-chloro-4-nitro-5-phenoxy-1-(2,5-dichloro-4-bromo-phenoxy)-benzene, 1.8 gm of allylamine and 10 ml of dioxane was stirred first for 7 hours at 40° C. and then for 3 hours at 60° C. Thereafter, the reaction solution was evaporated, the residue was taken up in chloroform, and the resulting solution was washed first with an acid solution and then with an alkaline solution, dried with sodium sulfate and evaporated. The raw reaction product thus obtained (5.6 gm) was purified on a silicagel column, yielding 3.0 gm (66.6% of theory) of the yellow crystalline title compound, m.p. 102.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].[C]=O.[OH-:10].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCl
Reactant: [OH-]
Agent: [C]=O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)OCC
Yield: 94 %

Procedure:
In a pressure vessel with a capacity of 7.5 liters, there are combined 20 g of Co2 (CO)8 in 2.5 liters of ethanol, and 612.5 g (5 moles) of chloroacetic acid ethyl ester, in a nitrogen atmosphere. Then the apparatus is scavenged three times with carbon monoxide, and a CO pressure of 7 bars is established. After the reaction temperature of 55° C. is reached, an 11.8% ethanolic solution of NaOH is pumped in by a proportioning pump at a CO pressure of 8 bars, in such a manner that a pH value of about 7.0 is sustained during the reaction. The reaction solution is constantly agitated during the reaction by means of a circulation pump. After 5 hours of reaction time a transformation of 79.2% is achieved. The reaction solution is separated from the NaCl on a rotary evaporator and distilled. 596 grams of malonic acid diethyl ester (94% yield) are obtained, and 20 g of acetic acid ethyl ester (5.7% yield) plus 127 g of chloroacetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[N:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[N:3]=1
Reactant: Clc1nc(N2CCc3ccccc32)c2nc[nH]c2n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Clc1nc(-n2ccc3ccccc32)c2nc[nH]c2n1
Reaction time: 60 h
Yield: 60.6 %

Procedure:
236 mg of product obtained in stage 1 of Example 1 in 20 ml of dioxane are heated over siliparite with 227 mg of DDQ (dichlorodicyanobenzoquinone), for 60 hours at 80° C. The dioxane is evaporated off and then purification is carried out by chromatography on silica with a CH2Cl2-MeOH: 95-5 mixture for eluent. 142 mg of expected product are obtained, in the form of beige-colored crystals.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH:17]=1.Cl>O>[CH3:11][CH:12]1[CH:17]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14][C:13]1=[O:18]
Reactant: O=S([O-])c1ccccc1
Reactant: CC1=CCCCC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1C(=O)CCCC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
Benzenesulfinic acid sodium salt (2.9 g) was added to a solution containing 1.5 g of 2-methyl-2-cyclohexen-1-one and 8 ml of water. Then 16 ml of 1N hydrochloric acid was added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and then, washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 2-methyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form of white crystals. Yield: 93%
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+].C(O)(=O)C>CO.O>[OH:18][CH2:19][C@@H:20]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 47.7 %

Procedure:
To a solution of (S)-di-tert-butyl (4-((tert-butyldiphenylsilyl)oxy)butane-1,3-diyl)dicarbamate (6.25 g, 11.51 mmol) in MeOH (100 mL) was added sodium hydroxide (1.38 g, 34.5 mmol) in water (20.0 mL). The mixture was heated to 70° C. for 18 h then cooled to room temperature and partially concentrated in vacuo. DCM was then added and the mixture was cooled to 0° C., whereupon acetic acid (2.31 mL, 40.3 mmol) was added. The organic layer was then separated, washed with saturated NaHCO3 (aq) and brine. The combined aqueous portions were extracted with DCM and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (1.67 g, 48%). LCMS: Rt=0.67 min, m/z=305.1 (M+1) Method 2m_acidic. 1H NMR (400 MHz, CDCl3) δ ppm 5.06 (br s, 1H) 4.83 (br s, 1H) 3.82-3.64 (m, 2H) 3.61 (dd, J=10.3, 4.9 Hz, 1H) 3.43-3.25 (m, 1H) 3.11-2.93 (m, 1H) 2.18 (br s, 1H) 1.79-1.65 (m, 1H) 1.64-1.58 (m, 1H) 1.51-1.36 (m, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-bromo-2,6-dimethoxyphenol (500 mg, 0.002 mol), phenylboronic acid (0.65 g, 0.0054 mol), TEA (1.8 mL, 0.013 mol), cupric acetate (0.62 g, 0.0034 mol) and DCM (30 mL, 0.4 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.77 (s, 6H), 6.82 (s, 2H), 6.86 (d, J=7.83 Hz, 2H), 6.96-7.04 (m, 1H), 7.22-7.27 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:25]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>C(Cl)Cl>[NH2:8][C@H:9]([C:25]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)C(=O)OCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Eighty percent TFA in CH2Cl2 (20 mL, v/v) was added to an ice-cooled solution of Boc-Tyr(OBn)-CO2CH2CH2TMS (14.8 g, 31.4 mmol) in CH2Cl2 (40 mL). The resulting mixture was stirred for 1.0 minute before concentrating in vacuo. The procedure was repeated once more, and the resulting residue was diluted with CH2 Cl2 and saturated aqueous NaHCO3. The resulting mixture was filtered through celite. The organic layer was then separated, washed with saturated aqueous NaCl, and dried (MgSO4). Filtration and concentration in vacuo provided an oil which was further purified by flash chromatography (SiO2, CHCl3 :MeOH eluent) to give the desired product;
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[N:35][C:34]([O:37][CH3:38])=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1
Yield: 10.3 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 35 mg of 2-methoxypyrimidin-5-yl-5-boronic acid via General Procedure A to give 7.2 mg of 203. MS (Q1) 514.3 (M)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].C1COCC1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[O:47]1[CH2:48][CH2:49][N:44]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]([C:12]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]5)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:45][CH2:46]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.0 g, 1.89 mmol) in DMF:THF (3 mL:4 mL) was added morpholine (1.8 mL, 20.6 mmol). The reaction mixture was stirred at RT for 2.5 h. The reaction mixture was concentrated in vacuo to remove volatiles. The residue was poured into ice-water and the resulting white solid was filtered and dried for several hours under high vacuum. The crude product re-crystallized using absolute EtOH to afford tert-butyl 5-(2-(3-(2-morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (830 mg, 75%)
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C.ClCCl>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3cccc(C)c3)cnc21
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1ncc2c3noc(-c4cccc(C)c4)c3cnc21
Yield: 75.4 %

Procedure:
4-Chloro-1-ethyl-5-(3-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (2.0 g) and hydroxylamine hydrochloride (6.0 g) were suspended in 200 ml of acetic acid, and to this was added 0.5 g of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed for 2 hours and then distributed between water and dichloromethane. The organic phase was washed four times with water and once with saturated sodium bicarbonate solution. It was then evaporated and chromatographed over 230-400 mesh silica gel, eluting with 10% ethyl acetate/dichloromethane. By combining the appropriate fractions, 1.40 g of product was obtained, mp 178°-179°. This product was combined with the product of another run and recrystallized from ethyl acetate to give product of mp 180°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:20])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:30])[NH2:20]
Reactant: NC(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC(=S)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid amide (1.74 g, 6.0 mmol), Lawesson's reagent (4.85 g, 12.0 mmol), toluene (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with 20-50% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carbothioic acid amide (1.38 g, 4.50 mmol). A mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carbothioic acid amide (921 mg, 3.00 mmol), 1,3-dichloroacetone (571 mg, 4.50 mmol) in toluene (30 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo, and the obtained crystals were washed with 10% dichloromethane (v/v) in n-heptane to give 7-chloro-3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-1H-indole (587 mg, 1.55 mmol).
Reaction SMILES: [Cl-].[Cl:2][C:3](=[O:9])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1/[CH:17]=[C:18]1\[C:19](=[O:29])[N:20]([CH2:27][OH:28])[C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2>>[Cl-:2].[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1/[CH:17]=[C:18]1\[C:19](=[O:29])[N:20]([CH2:27][O:28][C:3](=[O:9])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: C[N+](C)(C)CC(=O)Cl
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Agent: [Cl-]
Product: Cc1cc(C)c(/C=C2\C(=O)N(COC(=O)C[N+](C)(C)C)c3ccccc32)[nH]1

Procedure:
Following the procedure of Example 2, the title compound was prepared from 2-chloro-N,N,N-trimethyl-2-oxoethanaminium chloride and (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1).
Reaction SMILES: C([O:4][C:5]1[C:6]2[N:7]([C:11]([Br:15])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-].[Na+].Cl>CO>[Br:15][C:11]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[C:6]2=[N:13][C:12]=1[CH3:14]
Reactant: CC(=O)Oc1cccn2c(Br)c(C)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(O)cccn2c1Br
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 8-acetoxy-3-bromo-2-methylimidazo[1,2-a]pyridine (235 mg) in methanol (2.5 ml) was added 1N sodium hydroxide solution (2.0 ml) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was neutralized with 1N hydrochloric acid, and the resulting precipitates were collected by filtration and washed with water to give 3-bromo-8-hydroxy-2-methylimidazo[1,2-a]pyridine (150 mg) as brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:15])[CH2:13][CH3:14].[Br:16]N1C(=O)CCC1=O>CCOCC>[Br:16][CH:13]([CH3:14])[C:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[CH3:1])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1C
Solvent: CCOCC
Product: Cc1cc(C(F)(F)F)ccc1C(=O)C(C)Br
Yield: 74.6 %

Procedure:
Add 1-[2-methyl-4-(trifluoromethyl)phenyl]propan-1-one (0.805 g, 3.723 mmol), N-bromosuccinimide (0.662 g, 3.723 mmol), SCX-2® (1 mmol/g; 0.298 g, 0.298 mmol), and Et2O (11 mL) to a screw cap vial equipped with a stir bar. Stir the reaction at room temperature for 2 hours. Add N-bromosuccinimide (0.663 g, 3.723 mmol) and continue stirring at room temperature for 2 hours. Add more N-bromosuccinimide (0.663 g, 3.723 mmol), and continue stirring at room temperature for an additional 2 hours. Filter the reaction, and wash the solids with ample Et2O. Collect the filtrate, and concentrate the filtrate under reduced pressure. Place the resulting mixture in a freezer overnight. Purify the resulting material by flash chromatography (120 RediSep® silica gel column) eluting with a gradient of 0-30% DCM/pentane to give the title compound as a colorless oil (0.820 g, 75% yield). 1H NMR (399.80 MHz, d6-DMSO) δ 7.95 (d, J=8.0 Hz, 1H), 7.69-7.65 (m, 2H), 5.64 (q, J=6.5 Hz, 1H), 2.39 (s, 3H), 1.74 (d, J=6.5 Hz, 3H).