Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[O:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C@@H:13]([OH:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccc(OCc2ccccc2)cc1
Temperature: -25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A solution of 23 g of (+)-diisopinocamphenylchloroborane dissolved in 30 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 12 g of 4-benzyloxyphenacyl bromide. The resulting mixture was stirred for 4 hours at -20° to -15° C. The reaction mixture was added to a mixture of 150 ml of diethyl ether and 100 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: hexane:toluene=1:2) to obtain 6.8 g of (R)-1-(4-benzyloxyphenyl)-2-bromoethanol.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][O:14][CH3:15])[C:6]=2[CH2:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:3]1.C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[CH2:5][C@@H:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:3][C@@H:2]([CH2:30][N+:27]([O-:29])=[O:28])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: COCOc1cccc2c1CC(c1ccccc1)OC2O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COCOc1cccc2c1C[C@@H](c1ccccc1)O[C@H]2C[N+](=O)[O-]
Yield: 11 %

Procedure:
A solution of 1.81 g (6.3 mmol) of 3,4-dihydro-1-hydroxy-5-methoxymethoxy-3-phenyl-1H-2-benzopyran (the product of Step 2 of Example 89) and 488 mg (1.8 mmol) of ammonium acetate in 30 mL of nitromethane was heated at reflux for 3 days and then concentrated in vacuo, the concentrate was poured into 30 mL of a 1M aqueous hydrochloric acid solution and the cloudy mixture was extracted with 2×150 mL of ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with hexane/diethyl ether (8:1 v/v) to give 230 mg (11% yield) of the title compound.
Reaction SMILES: OS([O-])=O.[Na+].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[NH2:25])[C:18]([O:20][CH3:21])=[O:19].O>C(O)C>[C:7]1([C:6]2[NH:25][C:24]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2[nH]c(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
An aqueous solution of NaHSO3 (21.0 mL, 40% in water) was treated benzaldehyde (2.00 mL, 20.0 mmol) and stirred at ambient temperature for 1 h. A solution of methyl 3,4-diaminobenzoate (3.32 g, 20.0 mmol) in ethanol (15.0 mL) was added and the solution was heated to reflux for 6 h. Upon cooling, the solution was poured into water and the resultant precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title compound as a grey solid (4.90 g; 97%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.85 (br. s., 1H) 8.35 (s, 1H) 8.11 (d, J=2.0 Hz, 1H) 8.10 (d, J=4.0 Hz, 1H) 7.97 (dd, J=8.6, 1.5 Hz, 1H) 7.63 (d, J=5.8 Hz, 1H) 7.46 (d, J=2.3 Hz, 2H) 7.45 (dd, J=5.5, 4.0 Hz, 1H) 3.94 (s, 3H). MS (ES+) m/e 253 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Cl.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20]Cl)[CH3:17]>CO>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCOc1ccc(-n2ccnc2)cc1

Procedure:
Dissolve 4-(1H-imidazol-1-yl)phenol (4.02 g, 25.1 mmol) in methanol (100 mL) containing potassium hydroxide (3.52 g, 62.74 mmol). Add 2-diethylaminoethyl chloride hydrochloride to this mixture and heat to reflux under nitrogen overnight. Cool the mixture and concentrate in vacuo. Dissolve the residue in water (50mL) and adjust the pH to 13 with 1N NaOH solution. Wash with 2×100 mL of methylene chloride, combine, dry (Na2SO4) and concentrate in vacuo. This residue is dissolved in ethanol and 37% hydrochloric acid is added until pH=1.0. Concentration affords crystals which are recrystallized from isopropanol/ethanol (ca. 4+1). Drying at 80° C. for 5 hr at 1.0 mm give the title compound.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(N)cc2)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)cc1
Reaction time: 22 h
Yield: 24 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (30 mg, 0.072 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:10) to furnish IV as a yellow oil (7 mg, 24%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:11]1[C:16](=[O:17])[S:15][CH2:14][C:12]1=[O:13].[OH-].[K+].Cl>O1CCOCC1.O>[OH:13][C:12]1[CH2:14][S:15][C:16](=[O:17])[C:11]=1[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: O=C1CSC(=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(CC2=C(O)CSC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a suspension of 4-methylthiobenzyl bromide (5.6 g. 25.8 mmol), thiotetronic acid (3.0 g, 25.8 mmol) in dioxane (50 ml), was added aqueous potassium hydroxide (25.8 mL). The mixture was stirred at temperatures in the range of 65°-70° C. for 3 hours. Then, the mixture was cooled to room temperature, poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 in MeOH) silica gel (eluting solvent hexane/EtOAc 1/3) gave a white solid (1.72 g, 26.5%): m.p. 206°-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:19][C:18]4([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:19][C:18]4([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(N5CC6(CCN(C(=O)OC(C)(C)C)CC6)C5)ccc43)cc2OC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CC6(CCNCC6)C5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a stirred solution of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.53 g, 0.88 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir at room temperature. After 1 h, the mixture was concentrated, and the residue partitioned between 3 M ammonium hydroxide solution and dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-15% methanol/dichloromethane elute) afforded 0.28 g (64%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.1 Hz, 1H), 7.80 (s, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.88-6.79 (m, 2H), 6.78-6.65 (m, 3H), 6.47 (dd, J=8.6, 2.1 Hz, 1H), 5.18 (s, 2H), 5.00 (s, 2H), 3.92 (s, 3H), 3.75 (s, 3H), 3.61 (s, 4H), 2.86-2.78 (m, 4H), 2.54 (b, 1H), 1.82-1.74 (m, 4H) ppm; (M+1)=500.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20]CC2C=CC=CC=2)[CH:19]=1)[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1)=[O:9])[CH3:3]>CO>[OH:20][C:18]1[CH:17]=[C:7]([CH:6]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:19]=1)[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1)=[O:9]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CO
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-[(1-Methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (51 g; 0.14 mol) was dissolved in methanol (500 mL) and THF (500 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (5.1 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite, and the filtrate concentrated in vacuo. Ethyl acetate was added and filtered to give the desired compound. (30.5 g). A second crop of material was obtained in the same way (4.0 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](Cl)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:33]=[C:34]([C:38]2[NH:39][O:40][C:41](=[O:43])[N:42]=2)[CH:35]=[CH:36][CH:37]=1>>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[NH:39][O:40][C:41](=[O:43])[N:42]=4)[CH:33]=3)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(-c2nc(=O)o[nH]2)c1
Reactant: O=C(Cl)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2nc(=O)o[nH]2)c1

Procedure:
reacting the [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl )-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetyl chloride with 3-(3-amino-phenyl)-2H-[1,2,4]oxadiazol-5-one; in an aprotic organic solvent; to yield 2-[5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-N-[3-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-acetamide, the compound of formula (Is).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:18][CH2:17]1
Reactant: OC1CCNCC1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: O=C1OCc2nc(CCCN3CCC(O)CC3)ccc21

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde and 4-hydroxypiperidine are reacted to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:9]=2[NH:8][C:7]=1[CH3:27])=[O:5])[CH3:2].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:24]1([CH2:23][O:22][C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[C:14]2[C:9]3[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:7]([CH3:27])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:25][CH2:26]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (example D.a2) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:43])[CH2:31][O:32][C:33]1[C:34]([F:42])=[C:35]([F:41])[CH:36]=[C:37]([F:40])[C:38]=1[F:39])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of N-[(1-methyl-indole-2-cabonyl)valinyl]-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (141 mg, 0.23 mmol) in CH2Cl2(5.0 ml) was added Dess-Martin periodinane (128 mg, 0.3 mmol) and the solution stirred for 10 min. at room temperature. The reaction was quenched with Na2S2O4, diluted with EtOAc, washed with NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (1:1 EtOAc/hexane) to give the titled product as a white solid (129 mg, 92%).
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH:10]([C:11]([OH:13])=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]1([S:7][CH:8]2[CH:10]([C:11]([O:13][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[C:18]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:19]=3)=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CC1(C)C(Sc2ccccc2)C1C(=O)O
Product: CC1(C)C(Sc2ccccc2)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1

Procedure:
Using the method of Example 3, 3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid is reacted with 4-fluoro-3-phenoxybenzyl bromide to yield 4-fluoro-3-phenoxybenzyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 4-chlorophenylboronic acid (116 mg, 0.74 mmol). Yield 150 mg (79%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1)([O-:8])=[O:7].[OH-].[Na+].CN([CH:29]=[O:30])C>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:23]=1[CH:29]=[O:30])([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2[N+](=O)[O-])nc2ccccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
In a dry flask charged with DMF (2.7 g, 37 mmol) and cooled to 0° C. was added slowly POCl3 over 5 minutes. The solution was stirred for 10 min at 0° C. was warmed to room temperature over 1 hour. To the deep red color solution recooled to 0° C. was added 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine (1.0 g, 4.18 mmol) in DMF (8 ml). The reaction was stirred for 5.5 hours; LC-MS indicated some product formation. A second addition of the Vilsmeier complex (from 2.7 g of DMF and 1.47 g POCl3) was charged and the reaction stirred overnight, then heated to 50° C. for 3 hours until reaction completion. The reaction was cooled to room temperature, poured onto ice, adjusted to pH=7 with 1N NaOH. The product was extracted into CH2Cl2 (3×50 ml), washed with brine, dried over Na2SO4 and concentrated to obtain the product as a white solid (1.03 g, 92% yield). (MS, M++H=268.0)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[N:61]=[C:60]([NH2:62])[CH:59]=[CH:58][N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:60]1[CH:59]=[CH:58][N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[N:61]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(Nc2nccc(N)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4nccc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N2-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([C:48](=[O:73])[CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[N:42]1([C:48](=[O:73])[CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)N1CCOCC1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester (54 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (35 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O6, 536.24. found 536.2.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)n[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(indole-2-sulfonyl)-pyridazine (0.58 mmol, 290 mg), conc. HCl (0.5 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue, and the resulting solid, 6-(indole-2-sulfonyl)-2H-pyridazin-3-one was collected and dried (83%, 133 mg); mp 248° C.-249° C.
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:9]([Si:6]([CH2:7][CH3:8])([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[Si:4]([CH2:15][CH3:16])([CH2:17][CH3:18])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Reactant: [Li][Si](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC[Si](CC)([Si](C)(C)c1ccccc1)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.58 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 49 mg (0.05 mmol) of undecasilane (8) obtained in Example 8 was treated with 7.5 mg (0.05 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to afford 1-(trifluoromethanesulfonyloxy)undecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C. and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 36 mg (41% yield) of hexadecasilane (9) as a colorless crystal.