Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.1 %

Procedure:
Sodium hydride (257 mg, (428 mg of 60% dispersion), 10.6 mmol, 2 eq) was added to a solution of p-bromobenzyl alcohol (1 g, 5.3 mmol) in dry toluene (30 mL). Once the concomitant effervescing had ceased, p-toluenesulphonyl chloride (2.04 g, 10.6 mmol, 2 eq) was added and the mixture stirred at room temperature, 12 hours. The toluene was removed in vacuo and the residue taken up in water and extracted into ethyl acetate portions. The combined organic layers were washed (brine), dried (MgSO4), filtered, and concentrated in vacuo to give the crude product which was purified by column chromatography (silica gel, eluant:ethyl acetate/heptane mixtures) to give the p-bromobenzyl tosylate as a white solid (yield: 400 mg, 22%);
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9](B(O)O)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]1[C:9]([C:14]2[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncccc1B(O)O
Reactant: Nc1cccc(Br)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: [Na+]
Solvent: COCCOC
Product: CCOc1ncccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
2-ethoxypyridine-3-boronic acid (0.123 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-10% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed from fractions containing product, resulting in 0.079 g in 80% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>[Fe].C1(C)C=CC=CC=1>[CH3:14][C:13]1[O:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cccc(C=C(C)[N+](=O)[O-])c1O
Agent: [Fe]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2cc(C)oc12
Temperature: 70 °C
Yield: 76.6 %

Procedure:
A mixture of 2.02 g of methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate, 4.75 g of iron powder and 40 ml of acetic acid is heated at 70° C. for 25 minutes. Toluene is added to the reaction mixture, and the mixture is filtered and washed with chloroform. The washings and the filtrate are combined and the mixture is evaporated under reduced pressure to remove solvent. 50 ml of toluene, 2.43 g of p-toluenesulfonic acid monohydrate and 1 ml of water are added to the residue. The mixture is refluxed for 50 minutes and further refluxed 20 minutes while removing water azeotropically. Ethyl acetate is added to the reaction mixture. The mixture is washed successively with water and an aqueous saturated sodium bicarbonate solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 1.24 g of methyl 2-methylbenzofuran-7-carboxylate as colorless oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O>CN(C)C=O>[Br:14][C:15]1[C:16]2[CH:17]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[S:3][C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(Br)cccc2s1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Methyl thioglycolate (42.35 g) was added under nitrogen at 80° C. to a solution of triethylamine (109 ml) in dimethylformamide (290 ml), the mixture was stirred at 100° C. for 15 minutes, then a solution of 2-bromo-6-fluorobenzaldehyde (81.35 g; prepared in a manner similar to that described above) in dimethylformamide (70 ml) was added. The mixture was stirred at 130° C. for 5 hours, then it was cooled to ambient temperature and poured into ice-water (3000 ml). The resulting solid was collected by filtration, washed with water (2×250 ml) and dried in air to give methyl 4-bromobenzo[b]thiophene-2-carboxylate (101 g) as a yellow solid which was used without further purification.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1>>[CH3:22][C:3]1[C:2]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Nc1ccccn1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Nc1ccccn1
Temperature: 22 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 61 mg, 0.206 mmol), pyridin-2-amine (97 mg, 1.029 mmol, Aldrich), and KHMDS in toluene (2059 μl, 1.029 mmol) stirring at 22° C. for 1 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2-(2-methyl-3-(pyridin-2-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (s, 3H) 2.85 (t, J=6.75 Hz, 2H) 3.44 (dt, J=6.85, 3.42 Hz, 2H) 5.86 (br. s., 1H) 6.99 (br. s., 1H) 7.06 (s, 1H) 7.15 (t, J=5.97 Hz, 1H) 7.53 (t, J=7.82 Hz, 1H) 7.70 (d, J=8.22 Hz, 1H) 7.78-7.83 (m, 1H) 7.86 (dd, J=7.04, 1.76 Hz, 1H) 8.02 (d, J=7.24 Hz, 1H) 8.52 (d, J=3.52 Hz, 1H) 9.32 (s, 1H). MS (ESI, pos. ion) m/z: 371.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([CH3:18])[CH:3]1[CH2:19][CH3:20].[Cl:21]Cl.[N+](C)([O-])=O>C(O)(=O)C.Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([CH3:18])[C:3]1([CH2:19][CH3:20])[Cl:21]
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C
Reactant: ClCl
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCC1(Cl)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C
Temperature: 0 °C
Yield: 93 %

Procedure:
To a suspension of (1-oxo-2-ethyl-3-methyl-6,7-dichloro-5-indanyloxy)acetic acid (3.5 g., 0.011 mole) in glacial acetic acid (75 ml.) and concentrated hydrochloric acid (2 drops) is added, with stirring, a solution of glacial acetic acid (50 ml.) and chlorine (0.9 g., 0.0127 mole) over a period of 10 minutes. During the addition the reaction vessel is heated on a steam bath. After the addition is complete, the mixture is stirred without heating for 30 minutes and then poured into ice water (600 ml.). The white solid that separates is collected by filtration, washed with water and dried. The yield of product is 3.6 g. (93% yield) of (1-oxo-2-ethyl-3-methyl-2,6,7-trichloro-5-indanyloxy)acetic acid which, after recrystallization from nitromethane, melts at 208.5°-210.5° C.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]#[C:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1)(C)C.[H][H].O>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1
Reactant: CCCCCCCC#CCC(OCOC)C1CCC(C2CCC(C(CC#CC=CCCCC(CC3=CC(C)OC3=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OCOC)O2)O1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCC(OCOC)C1CCC(C2CCC(C(CCCCCCCCC(O)CC3=CC(C)OC3=O)OCOC)O2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of {2R-[2α[2′R*, 5′R*(R*)],5β[1(S*), 2R*, 11R*]}-3-{2-[(1,1-dimethylethyl)diphenylsilyloxy]-11-methoxymethyloxy-11-[octahydro-5′-(1-(methoxymethyloxy)undec-3-ynyl) [2.2′-bifuran]-5-yl]-6-undecen-8-ynyl}-5-methyl-2-(5H)-furanone (64 mg, 70 mmole) in benzene (0.5 mL) is stirred at room temperature under a flow of nitrogen while tris(triphenylphosphine)rhodium chloride (14 mg, 15 mmole) is added. The mixture is charged with hydrogen gas and stirred at room temperature for two days. Water is added, and the layers are separated. The aqueous extracted with ethyl acetate (3×2 mL) and the combined organic fractions are washed (1×20 mL water) dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) affords the desired product.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@@H:13]([OH:25])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:18]([C@:14]1([OH:17])[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]1[OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@](O)(Cc2ccccc2)[C@@H](O)C1
Agent: [Pd]
Solvent: CCO
Product: O[C@H]1CNCC[C@@]1(O)Cc1ccccc1
Reaction time: 16 h
Yield: 110.6 %

Procedure:
(3S,4S)-4-Benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester 8.2 g (24 mmol) was dissolved in 250 ml EtOH and hydrogenated in the presence of 1.1 g Pd/C, (10%)under atmospheric pressure at r.t. After 16 hours the reaction was complete and the catalyst was filtered off and the solvent was removed under reduced pressure to give 5.5 g (quant., ˜95% purity) (3S,4S)-4-Benzyl-3,4-dihydroxy-piperidine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([NH:16][C:17]2[N:25]=[C:24]3[C:20]([NH:21][C:22](=[O:36])[N:23]3[C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH2:31][CH2:30][CH2:29]4)=[CH:19][N:18]=2)[CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:36])[N:23]2[C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n(-c3ccc4c(c3)CCCN4)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n(-c3ccc4c(c3)CCCN4)c2n1

Procedure:
A solution of tert-butyl 4-fluoro-2-(8-oxo-9-(1,2,3,4-tetrahydroquinolin-6-yl)-8,9-dihydro-7H-purin-2-ylamino)phenylcarbamate (obtained from tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidine-2-ylamino)phenylcarbamate and 1,2,3,4-tetrahydroquinolin-6-amine (J. Org. Chem. (2002), 67, 7890) using procedures outlined in Example 27) was stirred for 45 minutes in 1:1 TFA/DCM and concentrated to afford 2-(2-amino-5-fluorophenylamino)-9-(1,2,3,4-tetrahydroquinolin-6-yl)-7H-purin-8(9H)-one. The 2-(2-amino-5-fluorophenylamino)-9-(1,2,3,4-tetrahydroquinolin-6-yl)-7H-purin-8(9H)-one was stirred for 15 minutes in trimethylorthoformate and concentrated to afford 6-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)-3,4-dihydroquinoline-1(2H)-carbaldehyde, which was purified by silica gel chromatography (2→5% MeOH in DCM). This material was deformylated by refluxing for 1 hour in 11:2 1 M HCl:MeOH to provide the title compound as the HCl salt. 1H-NMR (300 MHz, CD3OD) δ 10.0 (s, 1H), 8.4 (s, 1H), 8.4 (dd, 1H), 7.8 (dd, 1H), 7.8 (s, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.4 (td, 1H), 3.6 (dd, 2H), 3.1 (t, 2H), 2.2 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:43])[O:14][CH2:15][C@@H:16]([N:29]([CH3:42])[C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1[Cl:41])=[O:31])[CH2:17][C:18]([CH3:28])([CH3:27])[CH2:19][O:20][P:21]([O:25]C)([O:23]C)=[O:22])=[CH:5]2.[Si](I)(C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:43])[O:14][CH2:15][C@@H:16]([N:29]([CH3:42])[C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1[Cl:41])=[O:31])[CH2:17][C:18]([CH3:27])([CH3:28])[CH2:19][O:20][P:21]([OH:23])([OH:25])=[O:22])=[CH:5]2
Reactant: COP(=O)(OC)OCC(C)(C)C[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)COP(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(dimethoxyphosphoryloxy)-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamate (0.5 g, 0.79 mmol) in acetonitrile (50 mL) was added TMSI (0.848 mL, 6.23 mmol) at 0° C. After stirred at 0° C. for 30 min, the reaction was quenched with MeOH. The solvent was removed and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and water (0.1% HCOOH buffer) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-dimethyl-5-(phosphonooxy)pentyl 6-fluoroisoquinolin-3-ylcarbamate (340 mg, 71.1%). LRMS (M+H+) m/z 615.5.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Si:4]([O:21][C@H:22]1[CH2:26][CH2:25][O:24][C:23]1=[O:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[Si:4]([O:21][C@@H:22]([CH2:26][CH2:25][S:2][CH3:1])[C:23]([OH:24])=[O:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.98 %

Procedure:
Sodium thiomethoxide (0.187 g, 2.67 mmol) was added to (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (CAS no. 220351-82-6: Klar, U.; Schwede, W.; Skuballa, W.; Buchmann, B.; Schirner, M. Ger. Offen. 1999 DE 19735575 A1) (0.826 g, 2.43 mmol) in DMF (2 mL) at 0° C. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was neutralised with 2M HCl and diluted with ethyl acetate. The organic layer was extracted with water (3×100 mL), the organic layer was dried (MgSO4) and evaporated to afford (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 16.98%) which was used without further purification. A solution of trimethylsilyldiazomethane (2M solution in ether, 0.412 ml, 0.82 mmol) was added dropwise to a stirred solution of methyl alcohol (0.167 ml, 4.12 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 0.41 mmol) in toluene (0.174 ml) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with acetic acid (0.071 ml, 1.24 mmol) and stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (0.120 g, 72.4%). 1H NMR (400 MHz, CDCl3) δ 1.09 (9H, s), 1.94-2.05 (5H, m), 2.48-2.60 (2H, m), 3.47 (3H, s), 4.33-4.36 (1H, m), 7.34-7.45 (6H, m), 7.62-7.67 (4H, m); m/z (ES+) (M-Ph)-=325; HPLC tR=3.63 min
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:37])=[C:11]([N:14]4[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]5[CH:27]=[CH:26][C:25]([N:28]6[CH2:32][C@H:31]([CH2:33][OH:34])[O:30][C:29]6=[O:35])=[CH:24][C:23]=5[F:36])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:38])[C:6]([C:39]([OH:41])=[O:40])=[CH:5]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH:48]1[CH:53]=[CH:52][C:51]([CH2:54]Br)=[CH:50][CH:49]=1>CN(C=O)C>[CH2:54]([O:40][C:39]([C:6]1[C:7](=[O:38])[C:8]2[C:13](=[CH:12][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:32][C@H:31]([CH2:33][OH:34])[O:30][C:29]5=[O:35])=[CH:24][C:23]=4[F:36])[CH2:18][CH2:19]3)=[C:10]([F:37])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1)=[O:41])[C:51]1[CH:52]=[CH:53][CH:48]=[CH:49][CH:50]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCC(COc4ccc(N5C[C@H](CO)OC5=O)cc4F)CC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cn(C2CC2)c2cc(N3CCC(COc4ccc(N5C[C@H](CO)OC5=O)cc4F)CC3)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
A solution of the compound of Example 2 (600 mg) in DMF (10 mL) was treated with K2CO3 (155 mg) and BnBr (160 μl) and stirred at 80° C. for 24 h. The solvent was evaporated under reduced pressure and the residue was worked up (DCM). The residue was stirred in ether (100 mL) and the resulting crystals were collected by filtration affording 612 mg (90.6% yield) of an off-white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nnc(Cc3ccc(C4CCNCC4OCc4ccc5ccccc5c4)cc3)o2)cc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine trifluoroacetate as a white powder; MS: 476 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[C:16]([F:42])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([S:21]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)(=[O:22])=[O:23])=[C:16]([F:42])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnc(N)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc([C@H]2CCC[C@@H]2Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)ccn1
Yield: 88 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (185 mg, 0.310 mmol) prepared in Example 36c, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (122 mg, 88%) as a colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([CH:19]=[N:20]O)[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1>C(OC(=O)C)(=O)C>[C:19]([C:9]1[C:8]2[CH:22]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:23]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)#[N:20]
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C=NO)c3cc2C2CC2)S(C)(=O)=O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C#N)c3cc2C2CC2)S(C)(=O)=O)cc1
Yield: 97.9 %

Procedure:
A mixture of Example 8A (1.3 g, 2.56 mmol) in acetic anhydride (40 mL) was heated at 140° C. for 16 hours, cooled and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed on an Isco 12 g silica cartridge eluting with hexane followed by 3:2 hexane/ethyl acetate to give the title compound as a white foam (1.23 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione (1 mmol) in anhydrous CH2Cl2 (20 mL), is added iodotrimethylsilane (6 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl1). The solvent is removed in vacuo to afford crude (S)-4-amino-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione. The product is purified by recrystallization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12](OC)=[O:13])[CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[BH4-].[Li+].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:12][OH:13])[CH2:10][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1(n2cc([N+](=O)[O-])cn2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2(CO)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.5 %

Procedure:
To a solution of methyl 1-(4-nitro-1H-pyrazol-1-yl)cyclopropanecarboxylate (1.0 g) obtained in Step A of Example 128 in tetrahydrofuran (50 mL) was added lithium tetrahydroborate (160 mg), and the mixture was stirred at room temperature for 10 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (620 mg).