Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:7]1[C:6]2[C:2]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:24][CH:25]=3)=[CH:3][S:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccc2scc(Br)c12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3ccnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A suspension of 3-bromothieno[3,2-c]pyridin-4-amine (13.7 g, 59.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (20 g, 62.7 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol) and Na2CO3 (13.3 g, 125 mmol) in tetrahydrofuran (150 mL), methanol (40 mL) and water (80 mL) was degassed, then stirred at reflux overnight. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate and the combined organics were dried (using MgSO4), filtered and the filtrate was concentrated. The residue was purified via silica gel chromatography eluting with 50 to 70% ethyl acetate-hexanes to give crude tert-butyl 4-(4-aminothieno[3,2-c]pyridin-3-yl)phenylcarbamate. A solution of the crude product (59.7 mmol based on 100% yield) in N,N-dimethylformamide (80 mL) was treated with N-iodosuccinimide (13.5 g, 59.7 mol-added in portions) and the resulting dark solution was stirred at room temperature for 2 hours, then partitioned between water (500 mL) and ethyl acetate (100 mL) with NaCl added to facilitate layer separation. The aqueous layer was extracted with additional ethyl acetate (2×75 mL) and the combined organics were washed with sodium thiosulfate (3×20 mL) and brine (50 mL), and then dried (using MgSO4), filtered, and concentrated. The crude material was treated with TFA (20 mL) and CH2Cl2 (5 mL), stirred at room temperature for 2 hours, concentrated under a stream of nitrogen, then concentrated in vacuo. The solid was dissolved in water (100 mL), carefully treated with solid Na2CO3 until gas evolution ceased and filtered, washing with additional water. The solid collected was dried to provide the title compound as a solid (contaminated by ca. 10% mole PPh3).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:47].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H:68]([NH:71][C:72](NCC4C=CC=CN=4)=[O:73])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.NC[C:104]1[CH:109]=[CH:108][N:107]=[CH:106][CH:105]=1>>[ClH:47].[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:72]([NH:71][CH2:68][C:109]4[CH:108]=[N:107][CH:106]=[CH:105][CH:104]=4)=[O:73])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCc1ccncc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)NCc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethylpyridine with 4-aminomethylpyridine. MS (ES+) m/e 762.54 (MH+).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].C(O)C.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:25]1([CH2:19][CH2:18][C:17]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: C1CCNC1
Reactant: C=CC(=O)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)CCN2CCCC2)c2ccccc21

Procedure:
6.3 gm (0.03 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3.3 gm (0.036 mol) of acrylic acid chloride were refluxed, while stirring, in 200 ml of toluene for 3 hours. The reaction mixture was then evaporated in vacuo. The dry residue was admixed with 200 ml of ethanol, and 2.5 gm (0.035 mol) of pyrrolidine were added dropwise, while stirring, to the boiling solution. Subsequently, the reaction mixture was heated for 20 minutes, then evaporated in vacuo to about 1/10 of its original volume, and discolored by filtration through activated charcoal/silica gel. The crude product was recrystallized from a little ethyl acetate.
Reaction SMILES: C([C:4]1[CH:18]=[CH:17][C:7]([N:8]=[C:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26](O)[CH3:27]>[Pd]>[NH:19]([CH:26]([C:13]1[CH:12]=[CH:11][C:10]([CH:9]([NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[CH:18][CH:17]=2)[CH3:16])=[CH:15][CH:14]=1)[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CCO
Reactant: CC(=O)c1ccc(N=C(C)c2ccccc2)cc1
Agent: [Pd]
Product: CC(Nc1ccccc1)c1ccc(C(C)Nc2ccccc2)cc1

Procedure:
A mixture of p-acetyl-N-(α-methyl benzylidene) aniline (XXIII) (40 g) prepared by the procedure described in example XXIXA and aniline (20 ml) was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. The crude product was crystallized from ethanol to give 1,4-Bis-(1-anilinoethyl) benzene (XXV). XXV had a melting point of 169°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=23)=[C:4]([F:21])[CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[C:25]([NH2:30])[N:24]=1.Cl.[OH-].[Na+]>O>[NH2:30][C:25]1[N:26]=[C:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[C:23]([Cl:22])[N:24]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(CCO)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]cc(CCO)c34)c(F)c2)n1

Procedure:
56 mg (0.17 mmol) of 2-[4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanol and 30 mg (0.18 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 25 μl of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is then adjusted to 10, resulting in the precipitation of crystals. The mixture is concentrated and filtered through silica gel. The product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 104 %

Procedure:
N,N-Dimethyl-L-prolinamide (2.50 g, 17.58 mmol) was dissolved in a mixture of CH2Cl2 (50 mL) and water (50 mL), then solid sodium bicarbonate (2.95 g, 35.16 mmol) was added, followed by benzoyl chloride (2.1 mL, 18.45 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide N,N-dimethyl-1-(phenylcarbonyl)-L-prolinamide (4.502 g, >99%). LCMS: (M+H)+: 247.2.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:33](=[O:42])[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:28][CH2:27]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[C:33](=[O:42])[NH:34][C:35]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:30][CH2:31]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 35 %

Procedure:
[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid (100 mg, 0.25 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (80 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 35% yield. High resolution MS m/e (M+H)+=606.1730.
Reaction SMILES: [CH2:1]([N:3]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].[ClH:27]>C(Cl)Cl>[ClH:27].[CH2:1]([N:3]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCN1CC2(CCNCC2)OCC1c1ccccc1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of tert-butyl 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (295 mg, 0.82 mmol) in DCM (3 mL) was added hydrogen chloride (2 mL of 4 M dioxane, 8.18 mmol). The reaction mixture was stirred for 1 hour. The solvent was decanted and the residue was triturated with methanol and hexanes. The solvent was concentrated in vacuo to obtain 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride salt (230 mg, 95%) as a fluffy solid. ESI-MS m/z calc. 260.2. Found 261.1 (M+1)+; Retention time: 0.2 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6](OC)=[C:7]([S:11]([OH:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[C:16]([O-:19])([O-])=O.[Na+].[Na+].[Cl:22][CH:23](Cl)C(O)=O>>[Cl:22][CH2:23][S:11]([C:7]1[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=[CH:9][C:8]=1[O:19][CH3:16])(=[O:12])=[O:13]
Reactant: O=C(O)C(Cl)Cl
Reactant: COc1c(S(=O)O)cccc1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C(C)(C)C)cc1S(=O)(=O)CCl

Procedure:
22.8 g (0.1 mol) of 3-(1,1-dimethylethyl)-2-methoxybenzenesulfinic acid, 23 g of Na2CO3 and 15 g (0.117 mol) of dichloroacetic acid are dissolved in 150 ml of H2. The solution is slowly evaporated to dryness at a bath temperature of 160° C. The residue is again taken up in H2O, and the solution is neutralized with a little dilute hydrochloric acid and extracted by shaking several times with ethyl acetate. After removing the solvent, the product is obtained as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc(I)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A mixture of 2-bromo-5-iodo-pyrazine (1.14 g, 4.0 mmol) and copper (I) iodide (80 mg, 0.42 mmol) in DMF/Et3N (2:1, 24 ml) was deoxygenated by evacuate/refill with nitrogen (×3). Ethynyl-trimethyl-silane (680 μl, 4.8 mmol) followed by Pd(PPh3)4 (230 mg, 0.2 mmol) were added and the mixture was deoxygenated again (×1). The reaction was stirred at RT for 16 hours, then partitioned between Et2O/H2O. The organic layer was washed with water (×1), brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (2∝34% Et2O/Petrol) to give the title compound (850 mg, waxy solid) as ˜3:1 mixture of mono coupled product to bis coupled. 1H NMR (400 MHz, CDCl3): 8.63 (1H, d), 8.43 (1H, d), 0.25 (9H, s), [Bis coupled product: 8.60 (s), 0.25 (s)] This material was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH:22]([OH:25])[CH2:23]O)[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:25][CH:22]([CH2:21][O:20][C:15]2[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=2[CH3:19])[CH2:23][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Cc1ccc(Cl)cc1OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(Cl)cc1OCC1COC(CBr)(c2ccc(Cl)cc2)O1

Procedure:
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 11.9 parts of 1-(4-chloro-o-tolyloxy)-2,3-propanediol, 2.5 parts of p-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed for 24 hours in a four-necked round-bottomed flask equipped with a watertrap. The benzene solution is washed successively with a diluted sodium hydroxide solution and with water. The solvent is removed in vacuo. The residue is crystallized from methanol and the less pure fraction is recrystallized from diisopropylether, yielding A-2-(bromomethyl-2-(p-chlorophenyl)-4-(4-chloro-o-tolyloxymethyl)-1,3-dioxolane; m.p. 102.5°C. The methanol filtrate is evaporated in vacuo, yielding B-2-(bromomethyl)-2-(p-chlorophenyl)-4-(4-chloro-o-tolyloxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.O>[Si:26]([O:20][CH2:19][C@@H:11]1[C@H:12]2[O:16][C:15]([CH3:17])([CH3:18])[O:14][C@H:13]2[C@H:9]([NH:8][C:4]2[CH:3]=[C:2]([I:1])[N:7]=[CH:6][N:5]=2)[CH2:10]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of {(3aR,4R,6R,6aS)-6-[(6-iodopyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (1.321 g, 3.38 mmol) and 1H-imidazole (0.552 g, 8.10 mmol) in DMF (16.9 mL) was added tert-butyldimethylsilyl chloride (0.534 g, 3.54 mmol) and the reaction was stirred overnight. The solution was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography (10 to 40% EtOAc/hexanes) to afford the title compound (1.465 g, 86%). LC/MS: Rt=2.47 min ES+ 506 (FA Standard).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:24][O:25][CH2:26][O:27][C:28]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:29]=1[C:30](OCOC)=[O:31]>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:7]1[C:2]([C:30](=[O:31])[C:29]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:28]=2[O:27][CH2:26][O:25][CH3:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCOC(=O)c1cc(C)ccc1OCOC
Reactant: Brc1ncccc1C1OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C)cc1C(=O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (3.50 g) in THF (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.5 ml), which was stirred for 20 minutes. This reaction mixture was added, at the same temperature under argon atmosphere, to a solution of methoxymethyl 2-methoxymethoxy-5-methylbenzoate (3.66 g) in THF (50 ml). The mixture was stirred for 40 minutes, then for further one hour while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(1,3-dioxolan-2-yl)-2-(2-methoxymethoxy-5-methylbenzoyl)pyridine (2.06 g) (Compound E-14). The physical properties and spectrum data are shown in Table 16 and Table 19.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:21]1([CH2:27][CH2:28]O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccccc2O)cc1
Reactant: OCCN1CCCCC1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NCCc2ccccc2OCCN2CCCCC2)cc1
Yield: 69 %

Procedure:
N-[2-(2-Hydroxyphenyl)ethyl]-4-methylbenzenesulfonamide is reacted with 2-piperidin-1-ylethanol by the method described under 3C. Yield 69%.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][OH:19])[CH2:4][CH2:3][CH2:2]1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=[CH:30]3)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=[CH:30]4)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Temperature: 100 °C
Yield: 24.6 %

Procedure:
To a solution of [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (150 mg, 0.503 mmol), methyl 6-(4-hydroxyphenyl)-1-naphthalenecarboxylate (140 mg, 0.503 mmol), triphenylphosphine (145 mg, 0.553 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.553 mmol) dropwise. The solution was heated in a microwave reactor at 100° C. for 10 minutes. The product was purified by chromatography (silica gel, 0-15% ethyl acetate in hexanes gradient elution) to afford a white solid (0.069 g, 25%). 1H-NMR (DMSO-d6,) δ 8.77 (d, J=9 Hz, 1H), 8.23-8.20 (m, 2H), 8.09 (d, J=9 Hz, 1H), 7.93 (d, J=11 Hz, 1H), 7.70-7.51 (m, 6H), 6.90 (d, J=9 Hz, 2H), 4.83 (s, 2H), 4.00 (quintet, J=9 Hz, 1H), 3.92 (s, 3H), 2.43-2.31 (m, 4H), 2.10-1.92 (m, 2H). APCI-LCMS m/z 558 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[C:42](Br)[CH:41]=1)[CH3:36]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:41]=[C:42]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)[C:43]([F:46])=[CH:44][CH:45]=1)[CH3:36]
Reactant: CCOC(=O)Cc1ccc(F)c(Br)c1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1ccc(F)c(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, (3-bromo-4-fluoro-phenyl)-acetic acid ethyl ester, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{-4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-6-fluoro-biphenyl-3-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: OCCC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)N1CCCCC1CCO
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Triethylamine (0.79 ml) and myristoyl chloride (1.270 g) were added to a solution of 2-(2-hydroxyethyl)piperidine (0.660 g) in methylene chloride (7 ml) under argon gas atmosphere while being cooled with ice. After being stirred for 2 hours, the reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.664 g) as white solid.