Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][N:21]1[CH2:38][C:39](O)=[O:40].C(N(C(C)C)CC)(C)C>ClCCl>[C:13]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:12][CH2:11][CH2:10][N:9]([C:39](=[O:40])[CH2:38][N:21]3[CH2:22][CH2:23][CH2:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:19])[CH2:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(C2(c3ccccc3)CNCCO2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCOC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,2-diphenylmorpholine (0.075 g, 0.313 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.097 g, 0.313 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.131 g, 0.345 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.082 mL, 0.470 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was loaded directly onto a silica gel column (Analogix®, SF15-24) and the product was eluted with a gradient of 5% to 100% ethyl acetate/hexanes over 25 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.60 (m, 20H), 4.43 (s, 2H), 3.50-3.70, m, 6H), 3.05-3.10 (m, 2H), 2.40-2.50 (m, 2H), 1.55-1.70 (m, 2H); MS (DCI+) m/z 531 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)c1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (230 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated. The residue was crystallized from EtOAc/hexane to give the title compound (79.4 mg) as colorless crystals.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=2)O1>>[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:40][CH:41]=1)(=[O:48])[CH3:47]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(=O)Nc1ccc(C2=COCCN2C(=O)OC(C)(C)C)cc1
Yield: 44 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (44% yield); 1H-NMR (d6-DMSO) 1.07 (9H, s), 2.02 (3H, s), 3.66 (2H, t), 4.08 (2H, t), 6.32 (1H, s), 7.09 (2H, d), 7.49 (2H, d), 9.88 (1H, s); MS ES(+) 263.0 (M+-tBu); HRMS m/z calcd for C17H22N2O4+H+ 319.1658 [M+H+]. Found 319.1658. IR λmax=1694 cm−1.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCN(CC)CC.ClC(O[CH2:30][CH:31]([CH3:33])[CH3:32])=O.N[C@H](C(O)=O)CC(C)C.Cl>C1COCC1.O.CC(O)=O>[CH2:12]([O:11][C:9]([N:1]([CH2:8][CH2:7][CH3:6])[C@H:2]([C:3]([OH:5])=[O:4])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)COC(=O)Cl
Agent: CC(C)C[C@H](N)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)OCc1ccccc1)[C@@H](CC(C)C)C(=O)O
Reaction time: 0.33 h

Procedure:
12.5 g (0.05 mol) of Cbz-Pro are dissolved in 70 cc of THF and 7.5 cc (0.05 mol) of Et3N, and then cooled to -10° C. 6.8 g (0.05 mol) of isobutyl chloroformate in 30 cc of THF are added dropwise, whereafter the mixture is stirred for 20 minutes at <10° C. A solution of 7.9 g (0.06 mol) of Leu and 12.6 cc (0.08 mol) of Et3N in 65 cc of water are added to the mixture and the reaction is allowed to continue for 90 minutes, allowing the temperature to rise to 20° C. The reaction mixture is acidified with 6N-HCl, the THF is removed under vacuum and the solid which is obtained is dissolved in 20 cc of AcOH and then precipitated with 200 cc of water. Recrystallisation takes place in CCl4. The product indicated in the heading is obtained, this having two melting points: either 118° C. or 136° C.
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]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.[C:45](=[O:48])([O-])[O-:46].[K+].[K+]>CN1C(=O)CCC1>[C:31]1([O:46][C:45](=[O:48])[NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[N:15]=[C:14]4[C:10]([N:11]=[CH:12][N:13]4[C@@H:16]4[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]4[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[N:8]=3)[CH2:3]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)Oc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture comprising N-((1S,2R,3S,4R)-4-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 22 step 4) (50 mg, 83 μmol) and potassium carbonate (46 mg, 332 μmol) in NMP (1 ml) is treated with phenylchlorofomate and stirred at room temperature for 90 minutes. This mixture was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:33])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Yield: 72.2 %

Procedure:
A mixture of 4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (610 mg, 1.69 mmol) and NBS (331 mg, 1.86 mmol) in CH2Cl2 (17 mL) was refluxed for 3 h and then concentrated. Residue was triturate with acetone (15 mL). Solid was collected and dried to provide the title compound 540 mg (1.22 mmol) in 73% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 11.90 (s, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.47 (m, 2H), 7.15 (m, 3H), 4.54 (br q, J=7.3 Hz, 2H), 1.49 (br t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH2:5]2.OS(O)(=O)=O.[N+:25]([O-])([O-:27])=[O:26].[K+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:25]([O-:27])=[O:26])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH2:5]2
Reactant: Cc1ccncc1N1CCc2cc(F)ccc2C1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccncc1N1CCc2cc(F)c([N+](=O)[O-])cc2C1=O
Yield: 60.1 %

Procedure:
6-Fluoro-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (83A: 350 mg, 1.38 mmol) was reacted with conc. H2SO4 (4 mL) and KNO3 (154 mg, 1.52 mmol) for 4 hours to afford 250 mg of the product (60.0% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25](=[O:32])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25](=[O:32])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCNC(=O)N(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCNC(=O)N(c1ccccc1)c1ccccc1

Procedure:
Batch size: 3.5 g (23.5 mmol) 3-(3-pyridyl)-acrylic acid, 4.0 g (31.5 mmol) oxalyl chloride and 6.0 g (21.1 mmol) 4-(3,3-diphenyl-ureido)-butylamine.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:24])[CH:13]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:45][C:41]4([CH2:44][O:43][CH2:42]4)[CH2:40]3)=[CH:35][CH:34]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O>[CH2:44]1[C:41]2([CH2:45][N:39]([C:36]3[CH:37]=[CH:38][C:33]([C:2]4[C:10]5[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:24])[CH:13]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)[C:14]6[CH:18]=[CH:17][S:16][CH:15]=6)[CH:9]=5)[NH:4][N:3]=4)=[CH:34][CH:35]=3)[CH2:40]2)[CH2:42][O:43]1
Reactant: CC1(C)OB(c2ccc(N3CC4(COC4)C3)cc2)OC1(C)C
Reactant: O=C(Nc1ccc2[nH]nc(I)c2c1)C(c1ccsc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2[nH]nc(-c3ccc(N4CC5(COC5)C4)cc3)c2c1)C(c1ccsc1)N1CCCC1
Temperature: 130 °C

Procedure:
The title compound was synthesized according to General Method C1 by utilizing N-(3-iodo-1H-indazol-5-yl)-2-(pyrrolidin-1-yl)-2-(thiophen-3-yl)acetamide (200 mg, 0.45 mmol), 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (160 mg, 0.53 mmol), PdCl2dppf.DCM (36 mg, 0.044 mmol) and 2 M aq Na2CO3 (0.5 mL) in PhMe/EtOH (12 mL, 2:1 mixture). The reaction mixture was heated under microwave irradiation at 130° C. for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (5 mL), dried (MgSO4) and concentrated under vacuum to give a crude product. Purification by flash chromatography (Biotage Isolera, 50 g HP-SIL, 100% EtOAc then 0-10% DCM in MeOH) followed by trituration with MeOH gave the title compound as a light brown solid (46 mg, 18%). 1H NMR (400 MHz, CDCl3) δ ppm 9.21 (br. s., 1H), 8.38 (s, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.48 (d, J=9.0 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.29-7.36 (m, 2H), 7.15 (d, J=4.8 Hz, 1H), 6.58 (d, J=8.3 Hz, 2H), 4.87 (s, 4H), 4.15 (s, 1H), 4.09 (s, 4H), 2.61-2.75 (m, 2H), 2.47-2.60 (m, 2H), 1.76-1.92 (m, 4H); MS ESI 500.3 [M+H]+, calcd for [C28H29N5O2S+H]+ 500.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:23]=[CH:24][C:3]([CH2:2][P:26]([CH3:25])(=[O:30])[O:27][CH2:28][CH3:29])=[CH:4][CH:5]=2)=[O:8])=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCOP(C)OCC
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Product: CCOP(C)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
90 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 45 μL of diethyl methylphosphonite in the microwave at 120° C. for 5 minutes. The reaction was evaporated to dryness and purified by reverse phase HPLC to give pure ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl(methyl)phosphinate. MS (Q1) 429 (M)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH:12]1[CH2:17][N:16]([C:18]2[S:19][C:20]3[C:25](=[O:26])[N:24]=[CH:23][NH:22][C:21]=3[N:27]=2)[CH2:15][CH2:14][O:13]1.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[Cl:37]>C1COCC1>[Cl:37][C:31]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:22]1[C:21]2[N:27]=[C:18]([N:16]3[CH2:15][CH2:14][O:13][CH:12]([CH3:11])[CH2:17]3)[S:19][C:20]=2[C:25](=[O:26])[N:24]=[CH:23]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC1CN(c2nc3[nH]cnc(=O)c3s2)CCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(c2nc3c(s2)c(=O)ncn3Cc2cccc(Cl)c2Cl)CCO1
Yield: 42.5 %

Procedure:
LiHMDS (0.9 N, 2.7 mL, 2.4 mmol) was added to a solution of 2-(2-methylmorpholino)thiazolo[4,5-d]pyrimidin-7(4H)-one (300 mg, 1.2 mmol) in THF (6.0 mL) at 0° C. The reaction mixture was stirred for an hour. 1-(bromomethyl)-2,3-dichlorobenzene (285 mg, 1.2 mmol) was added to the mixture and the resultant mixture was stirred for 18 hours. The reaction was quenched by water and extracted with dichloromethane. The organic layer was dried, concentrated and purified through silica gel chromatography to give the desired product as a solid (210 mg, 43%). 1H NMR (300 MHz, d6-DMSO) δ 8.48 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.35 (m, 1H), 7.18 (d, J=7.8 Hz, 1H), 5.47 (s, 2H), 3.89 (m, 1H), 3.82˜3.75 (m, 2H), 3.56˜3.52 (m, 2H), 3.26˜3.16 (m, 1H), 2.91 (m, 1H), 1.14 (d, J=6.0 Hz, 3H); LC-MS: 411 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([O:22]CC)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH3:26].[Cl-].[NH4+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Si:1]([O:18][CH2:19][C:20]1([OH:22])[CH2:26][CH2:25]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC1(O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 12 g (35 mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 200 ml of tetrahydrofuran (THF) and 2.2 ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 29.2 ml of ethylmagnesiumbromide (3.0M in THF), and the reaction solution was stirred for 12 hours at room temperature. 20 ml of saturated ammonium chloride was added to stop the reaction. About 150 ml of tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 200 ml of ethyl acetate. The ethyl acetate extract was distilled under reduced pressure to give 11.4 g (Yield 100%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzyloxy)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[Br:13]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]2[NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C1CCCc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(Br)ccc2N1

Procedure:
To a solution of the title compound from Example 2 Step B (17.0 g, 106 mmol) in N,N-dimethylformamide (500 mL) was added N-bromosuccinimide (25.2 g, 141 mmol) at room temperature, and then the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate (1 L), and the separated organic layer was washed with 0.1 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate=12:1 to 3:1) provided a crude product that was recrystallized from ethyl acetate and petroleum ether (v:v=1:10) to give the title compound: LCMS m/z=241 [M+2+H]+. 1H NMR (400 MHz, d6-DMSO): δ 9.56 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 2.65 (m, 2H), 2.12-2.07 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:18]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:8]1=[O:27])C.[OH-].[Na+].Cl>CO>[Cl:26][C:24]1[CH:23]=[CH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][N:9]3[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])[C:8]3=[O:27])[C:18]=2[CH:25]=1
Reactant: CCOC(=O)CCn1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCn1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
A solution of 3-[3-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid ethyl ester (50 mg, 0.12 mmol) in MeOH (3 mL) was added 2N NaOH (1 mL). The reaction mixture was stirred at room temperature for 1 h. The solution was then treated with 1M HCl solution until pH ˜4 and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 20 mg (42%) of the desired product as a white solid. LCMS (ESMS): m/z 387.89 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([Cl:31])[CH:33]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(F)c(Cl)c2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A mixture of 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1.04 g, 2.08 mmole), 3-chloro-4-fluorophenylboronic acid (726 mg, 4.16 mmole), cesium carbonate (2.04 g, 6.25 mmole) and tetrakis(triphenylphosphine)palladium (241 mg, 0.21 mmole) in dioxane (7 ml) was refluxed for 16 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (649 mg). MS: (+) m/z 551.26 (M+H+)
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([CH2:33][CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[CH:25]([O:26][C:27](=[O:35])[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)=[O:15].C1([Se](O[Se](C2C=CC=CC=2)=O)=O)C=CC=CC=1>ClC1C=CC=CC=1.C(OCC)(=O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([CH2:33][CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[CH:25]([O:26][C:27](=[O:35])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3)=[O:15]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4OC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: O=[Se](O[Se](=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4OC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F

Procedure:
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androstan-3-one-17β-carboxamide. (35 mg, 0.066 mmol, prepared according to the procedures of Example 8) in chlorobenzene (5 mL) was added benzeneseleninic anhydride (30 mg, 0.085 mmol). After stirring the reaction mixture at reflux temperature for overnight, the reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by prep. tlc (50% EtOAc/hexane). Mass spec. M+ 530(m+1, observed).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29]Br)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:26]
Reactant: CCOC(CBr)OCC
Reactant: NCCCCCCOCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNCCCCCCOCCCCc1ccccc1)OCC
Reaction time: 20 h
Yield: 42.6 %

Procedure:
To a solution of 2.77 g (11.12 mmol) 6-(4-phenylbutoxy)hexylamine in 20 ml DMF is added 1.54 g (11.16 mmol) K2CO3 and 1.68 g (11.17 mmol) bromoacetaldehyde diethylacetal. After allowing the mixture to stand for 20 hr at 80° C., DMF is distilled off at reduced pressure, and the resulting crude product in 30 ml CH2Cl2 is washed with 30 ml H2O. The CH2Cl2 phase is dried on anhydrous Na2SO4, concentrated to dryness and the residue is purified by column chromatography on silica gel (gradient CH2Cl2/AcOEt 1:1 to AcOEt), thereby yielding 1.73 g (42.6 %) N-diethoxyethyl-6-(4-phenylbutoxy)hexylamine as an oil.