Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CO.COC>[C:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nccc2ccccc12
Agent: COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: c1ccc(-c2nccc3ccccc23)cc1
Temperature: 90 °C
Yield: 88.2 %

Procedure:
3.0 g of 1-chloro-isoquinoline (18 mmmol), 2.7 g of Phenyl boronic acid (21 mmol), 1.6 g of tetrakis-triphenylphosphine palladium (0.8 mmol %), and 2.9 g of potassium carbonate (21 mmol) were added into 100 ml of reaction bowl, and 50 ml of ethylene glycol-dimethyl ether as distilled solvent was added thereto under the flow of nitrogen, and then the reaction was performed in reflux at 90° C. for 12 hr. The mixture was cooled to room temperature, extracted by chloroform and distilled water, and then, separated by silica gel column chromatography (chloroform:hexane=1:3), to obtain 3.32 g of 1-phenyl-isoquinoline (yield: 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.COCCOC>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[CH:10]=[CH:11][C:12]=4[C:13]=3[N:14]=2)[CH:27]=[N:26]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3n2)cn1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
2-Bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (50 mg, 0.12 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.24 mmol), and PdCl2(dppf)-CH2Cl2 adduct (9.79 mg, 0.012 mmol) in a microwave vial was flushed with nitrogen. DME (2 mL) and aq. Na2CO3 solution (0.30 mL, 0.60 mmol, 2.0 M) were added, the vial sealed, and heated at 100° C. for 3.5 hr. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10 to 70% gradient over 20 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH gave 2-(1-methyl-1H-pyrazol-4-yl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (30 mg, 0.075 mmol, 63% yield) as a solid. MS (ESI) m/z 377.20 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.12 (1H, s), 8.36 (1H, br. s.), 8.25 (1H, s), 8.05 (1H, s), 8.01 (1H, s), 7.99 (1H, d, J=8.85 Hz), 7.79 (1H, s), 7.19 (1H, d, J=2.14 Hz), 6.98 (1H, dd, J=8.85, 2.14 Hz), 3.93 (3H, s), 3.77-3.84 (4H, m), 3.20-3.25 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[CH3:35])=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:27]3[CH:26]=[CH:25][C:24]([CH3:35])=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: Cc1ccc(C2CCNCC2)cc1NC(=O)C(C)C
Product: Cc1ccc(C2CCN(Cc3ccc(Oc4ccc(F)c(F)c4)cc3)CC2)cc1NC(=O)C(C)C

Procedure:
Prepared by Procedure AA and Scheme AJ using 4-(3,4-difluorophenoxy)benzaldehyde and 2-methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 479.2 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1([CH3:19])[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[S:11]1>C(Cl)Cl>[CH3:6][C:5]([C:17]1[CH:16]=[CH:15][C:13]2[S:14][C:10]([CH3:9])([CH3:19])[S:11][C:12]=2[CH:18]=1)=[O:7]
Reactant: CC1(C)Sc2ccccc2S1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)SC(C)(C)S2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/water, there were obtained 41.8 g of 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working-up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][O:21][CH3:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.[B:35](OC(C)C)([O:40]C(C)C)[O:36]C(C)C.[Li]CCCC>CCOC(C)=O>[CH3:22][O:21][CH2:20][O:19][C:14]1[CH:13]=[C:12]([O:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][C:15]=1[B:35]([OH:40])[OH:36]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution (0.30 M) of 4-bromo-3-(methoxymethoxy)phenyl 4-methylbenzenesulfonate in a mixture (1:3) of THF/toluene, triisopropyl borate was added and then the mixture cooled to −78° C. To the cold solution, n-BuLi (2.5 M in hexane; 1.5 eq) was added via syringe pump over 1.5 h. The mixture was stirred at −78° C. for a further 2 h and then left to warm to RT overnight. The mixture was diluted with EtOAc and washed with 1 N HCl, extracting the aqueous fraction a further two times with EtOAc. The combined organics were washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product, that could be used directly as crude or purified by FC (PE/EtOAc 9/1) to afford the title compound (43%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.42 (s, 3H), 3.31 (s, 3H), 5.06 (s, 2H), 6.64-6.69 (m, 2H), 7.44-7.49 (m, 3H), 7.74 (d, J 8.3, 2H); (ES+) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[C:30]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)OCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Yield: 24.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (56 mg, 0.21 mmol) was treated with benzyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (70 mg, 0.24 mmol), cesium fluoride (14 mg, 0.09 mmol), N,N-diisopropylethylamine (163 μl, 0.94 mol) according to Preparation 13 to give 27 mg (25% yield) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].C(O)C>O1CCCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]([CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 0 °C
Yield: 60.6 %

Procedure:
Sodium hydride (4.4 grams) and 10.7 grams of diethyl carbonate are suspended in 60 ml of tetrahydrofuran and 10 grams of 2-acetylfuran is gradually added thereto by keeping the inner temperature at 40°to 50° C. A small amount of ethanol is added thereto, heated to reflux for three hours, and the reaction is made stopped by addition of 20 ml of ethanol. The mixture is poured into ice water, extracted with ether, the ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom. The resulting oil is purified by distilling in vacuo to give 10 grams of pale yellow oily product, b.p. 90° C./3 mmHg.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH2:77])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:54][C:55]([N:57]1[CH2:58][CH2:59][N:60]([C:63](=[O:78])[C@@H:64]([NH:77][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH2:61][CH2:62]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 427 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 206 mg HOBt, 258 mg EDC and 0.43 ml DIPEA. After 5 minutes 420 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid butyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (70 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 37 mg MS (ES+): m/e=800.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[CH2:33][O:34][CH3:35])=[O:27])[S:25][C:18]=12.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:35][O:34][CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=3[CH:15]=2)[CH:23]=1)=[O:27]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)OC)c(C)sc4c3)c2s1
Yield: 40 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (85.8 mg, 0.386 mmole) with 7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (100 mg, 0.322 mmole) and Cs2CO3 (524 mg, 1.61 mmole) in a manner similar to that previously described for example 1 to give a brown solid (64 mg, 40%). 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (1H, d, J=4.90 Hz), 8.51 (1H, d, J=9.04 Hz), 8.15 (1H, s), 8.14 (1H, s), 7.54 (1H, dd, J=2.17, 8.95 Hz), 6.91 (1H, d, J=5.46 Hz), 4.47–4.38 (1H, m), 4.07–3.90 (2H, m), 4.03 (3H, s), 3.72–3.50 (2H, m), 3.42, 3.39 (3H, s), 2.94 (3H, s), 2.21–1.93 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][NH2:10])[CH:4]=1
Reactant: COc1ccnc(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccnc(CN)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 38.6 %

Procedure:
To a stirring solution of 949 mg of 4-methoxypicolinonitrile in 15 mL of THF at 0° C. was added about 0.6 g of LiAlH4. The reaction became very exothermic. The mixture was allowed to warm to r.t. and after 40 min., the following were added in succession: 0.4 mL of H2O, 0.4 mL of 15% NaOH (aq.), and 1.2 mL of brine. The mixture was stirred at r.t. for 75 min. and then filtered through Celite and concentrated to give 377 mg of (4-methoxypyridin-2-yl)methanamine which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:22])C1.OP([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([CH:18]=[O:22])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cc(C)cc3ccoc23)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(C=O)cc3ccoc23)cc1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of 7-(4-methoxyphenyl)-5-methyl-benzofuran (4.66 g, 19.58 mmol) in carbon tetrachloride (560 ml) was added NBS (3.83 g, 21.54 mmol) and AIBN (75 mg). The solution was brought to reflux for 4 h, cooled to room temperature, reduced by half, and the solids were filtered off. The solution was then concentrated to a yellow solid and anhydrous CH3CN (230 ml) was added. Then potassium benzeneselenite (5.34 g, 23.5 mmol), and K2HPO4 (4.09 g, 23.48 mmol) were added and then reaction was refluxed for 1.5 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and concentrated under high vacuum. Chromatography (100% CH2Cl2) afforded 3.3 g (67%) product as a light orange solid: mp 79–80° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.85 (3H, s), 7.13 (2H, d, J=8.8 Hz), 7.23 (1H, d, J=2.2 Hz), 7.88 (2H, d, J=8.8 Hz), 8.02 (1H, d, J=1.4 Hz), 8.23 (2H, m), 10.13 (1H, s); MS (ESI) m/z 253 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:25][C:16]1[C:17]2[C:22]([C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:8][CH:7]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: BrBr
Reactant: FC(F)(F)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1

Procedure:
5.7 g (18 mmol) of 9-(4-trifluoromethylphenyl)anthracene and 90 mL of carbon tetrachloride were put into a 500-mL three-neck flask and stirred. A solution in which 3.2 g (20 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 5.9 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 84%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH2:25])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reaction time: 1 h
Yield: 76.68 %

Procedure:
To a solution of 5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (133 mg, 0.33 mmol) in DCM was added pyridine (52 mg, 0.66 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (76 mg, 0.66 mmol, 2.0 eq.). The mixture was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was taken to the next step without further purification, yield 76.68% (125 mg); LC-MS (ESI): Calculated mass: 492.01; Observed mass: 493.0 [M+H]+ (rt: 1.72 min).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl[Sn]Cl>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(OCc2ccc(Br)cc2)c1
Agent: Cl[Sn]Cl
Product: Nc1cccc(OCc2ccc(Br)cc2)c1

Procedure:
The title compound was prepared by reduction of the product from Example 190a with SnCl2 following the procedure from Example 1f.
Reaction SMILES: C([N:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[C@@H:5]([C:7]([OH:9])=[O:8])[CH3:6])(=O)C.[ClH:18]>C(O)(=O)C>[ClH:18].[CH3:17][C:12]1[CH:11]=[C:10]([NH:4][C@@H:5]([C:7]([OH:9])=[O:8])[CH3:6])[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: CC(=O)N(c1ccc(C)c(C)c1)[C@H](C)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(N[C@H](C)C(=O)O)cc1C
Temperature: 25 °C

Procedure:
A solution of N-acetyl-3,4-dimethylphenyl-D-alanine (5.0 g) in a mixture of concentrated hydrochloric acid (50 ml) and acetic acid (50 ml) was stirred under reflux for 20 hours. After being cooled to room temperature, the resulting precipitates were collected by filtration and washed with ethyl acetate to give colorless crystals of 3,4-dimethylphenyl-D-alanine hydrochloride (3.75 g).
Reaction SMILES: N.C([O:5][C@@H:6]1[CH2:10][C@@H:9]([CH2:11][O:12]C(=O)C2C=CC=CC=2)[O:8][C@H:7]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1)(=O)C.OC1CCC(NC2N=CN=C3C=2N=CN3[C@H]2[C@H](O)C[C@@H](COC(=O)C3C=CC=CC=3)O2)CC1>CO>[OH:37][CH:34]1[CH2:35][CH2:36][CH:31]([NH:30][C:26]2[N:25]=[CH:24][N:23]=[C:22]3[C:27]=2[N:28]=[CH:29][N:21]3[C@H:7]2[C@H:6]([OH:5])[CH2:10][C@@H:9]([CH2:11][OH:12])[O:8]2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(NC3CCC(O)CC3)ncnc21
Agent: N
Agent: O=C(OC[C@@H]1C[C@@H](O)[C@H](n2cnc3c(NC4CCC(O)CC4)ncnc32)O1)c1ccccc1
Solvent: CO
Product: OC[C@@H]1C[C@@H](O)[C@H](n2cnc3c(NC4CCC(O)CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Methanol saturated with ammonia (20 mL) at 0° C. was added to a mixture of (5S,2R,3R)-2-{6-[(4-hydroxycyclohexyl)amino]purin-9-yl}-5-(benzoyloxymethyl)oxolan-3-yl acetate and (5S,2R,3R)-2-{6-[(4-hydroxycyclohexyl)amino]purin-9-yl}-5-(benzoyloxymethyl)oxolan-3-ol. The mixture was stirred at room temperature for 36 hours. The solvent was evaporated under reduced pressure, and the residue was purified on a Chromatotron to obtain (5S,2R,3R)-2-{6-[(4-hydroxycyclohexyl)amino]purin-9-yl}-5-(hydroxymethyl)oxolan-3-ol, a compound of Formula I.
Reaction SMILES: II.[CH2:3]1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[O:5][CH2:4]1.CO[CH:17]=[C:18]=[CH2:19].[Cl-].[NH4+]>C1COCC1.[Cu]Cl>[CH2:3]1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:19][C:18]#[CH:17])[CH:8]=2)[O:5][CH2:4]1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: C=C=COC
Agent: Cl[Cu]
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C#CCc1cccc(C2OCCO2)c1
Reaction time: 1 h

Procedure:
Dry Mg (0.74 g) under dry N2 in a flask is covered with THF (10 ml) and a crystal I2 added. 5 ml of a solution of 3-bromobenzaldehyde ethylene acetal (7.0 g) in THF (30 ml) is added and kept until it becomes warm, when it is cooled to 15°, and the remainder of the acetal solution added over 15 minutes, then stirred for an additional 1 hour. A mixture of methoxyallene (2.45 g), copper (1)chloride (0.30 g) and THF (30 ml) is cooled to -20°. The above Grignard solution (under moisture excluding conditions) is then added to this solution during 5 minutes, and allowed to warm to 20° with stirring over 30 minutes. Saturated aqueous ammonium chloride is added and the product is extracted with ether. The ether layer is washed with water, dried (MgSO4) and the residue distilled in vacuo. Yield 4.3 g (75%) 89°-96° (0.03 m Hg), nD20 1.5422.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[OH:11][C@@H:12]1[CH2:17][O:16][C:14](=[O:15])[CH2:13]1.[CH2:18](Cl)[CH:19]=[CH2:20].CN1CCN(C)C1=O.[Cl-].[NH4+]>C1COCC1>[CH2:20]([C@H:13]1[C@H:12]([OH:11])[CH2:17][O:16][C:14]1=[O:15])[CH:19]=[CH2:18]
Reactant: O=C1C[C@H](O)CO1
Reactant: C=CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1C(=O)OC[C@H]1O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Lithium hexamethyldisilazide (5.1 ml, 5.1 mmol) was loaded under argon gas in a reaction vessel. (S)-3-Hydroxy-γ-butyrolactone (0.250 g, 2.449 mmol) in THF (5 ml) was added thereto under cooling to −45° C. After stirring for 30 minutes at the same temperature, allyl chloride (0.24 ml, 2,94 mmol) and 1,3-dimethyl-2-imidazolidinone (0.7 ml) in THF (5 ml) was dropped thereto. After stirring for 30 minutes at the same temperature, an aqueous saturated ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and condensed in vacuo. The residue was purified by silica gel chromatography to give (2S,3S)-2-allyl-3-hydroxy-γ-butyrolactone (0.261 g, yield 75%).