Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:23])[CH:3]=1.[F-].[Cs+].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>O1CCOCC1.Cl.[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2]>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:3][C:4]=2[Cl:23])[CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(Br)cc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(-c2cncnc2)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 30 step ii) (0.20 g) which was dissolved in dry dioxane (10 ml). Cesium fluoride (0.15 g) followed by pyrimidine-5-boronic acid (0.058 g) and Palladium(diphenylphosphinoferrocene) dichloride (0.017 g) were added and the mixture was heated at 80 C for 10 hours. The mixture was diluted with 2M HCl, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20 g.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[BH4-].[Na+].C(OCC)(=O)C.[OH-].[Na+]>CO.[Co](Cl)Cl>[NH2:2][CH2:1][C:3]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1(C#N)CCOCC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(CN)CCOCC1
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a suspension of tert-butyl (4-cyanotetrahydro-2H-pyran-4-yl)carbamate (G14, 210 mg) and cobalt(II) chloride (241 mg) in methanol (9 mL), sodium borohydride (175 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, cobalt(II) chloride (241 mg) and sodium borohydride (175 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ethyl acetate and 1.0 mol/L aqueous sodium hydroxide were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)carbamate (G15, 195 mg).
Reaction SMILES: [C:1]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:29][OH:30]>CCO>[C:1]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[C:24](=[N:29]/[OH:30])/[NH2:25])=[CH:20][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(/C(N)=N/O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 85 °C
Yield: 95.5 %

Procedure:
Prepared using General Procedure 2: To a stirring solution (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate (1.0 g, 2.74 mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (572.2 mg, 8.22 mmol) and TEA (1.38 g, 13.7 mmol). The reaction was heated to 85° C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with water (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude material was crystallized from isopropanol (20 mL) to afford 1.04 g (95%) of (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl)propanoate (INT-2) as a white solid. LCMS-ESI (m/z): calcd for: C22H27N3O4, 397.2. found 398.1 [M+H]+, tR=2.26 min (Method 1). 1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.57 (s, 1H), 8.78 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.79-4.49 (m, 1H), 3.65 (s, 3H), 3.15 (dt, J=13.6, 6.0 Hz, 2H), 1.75 (d, J=13.6 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C(C)C)=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[OH:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([I:1])=[C:3]([C:14](=[O:16])[CH3:15])[CH:4]=1
Reactant: COc1cc(I)c(C(C)=O)cc1OC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(I)c(C(C)=O)cc1O
Temperature: 18 °C
Reaction time: 21 h
Yield: 75.3 %

Procedure:
A solution of ketone 9 (625 mg, 1.87 mmol) in dry CH2Cl2 (5 mL), was treated with AlCl3 (325 mg, 2.44 mmol) and the resulting mixture stirred at 18° C. under a nitrogen atmosphere for 21 h then partitioned between H2O (10 mL) and additional CH2Cl2 (10 mL). The separated aqueous phase was extracted with CH2Cl2 (1×10 mL) and the combined organic fractions were then dried (MgSO4), filtered and concentrated under reduced pressure. The ensuing residue was subjected to flash chromatography (1:4 v/v ethyl acetate/hexane elution) to afford the title compound 13 (411 mg, 75%) as a pale-yellow solid, m.p. 109.4-110.6° C., Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][CH3:21])[CH:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[NH:5][C:4]1=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([C@@H:31]([N:39]=[C:40]=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH:29]=[CH2:30].O>CN(C=O)C>[CH2:20]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[N:5]([C:40]([NH:39][C@H:31]([CH2:28][CH:29]=[CH2:30])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[O:41])[C:4]1=[O:19])[CH3:21]
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)COC)cc1
Reactant: C=CC[C@@H](N=C=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(=O)COC)cc1)c1ccc(C)cc1

Procedure:
To a solution of 1.64 gm (5.6 mmol) of 3,3-diethyl-4-(RS)-[4-(1-oxo-2-methoxyethyl) phenoxy]azetidin-2-one in 23 mL of dry DMF was added 78 mg (0.56 mmol) of powdered potassium carbonate and then 1.27 gm (6.8 mmol) of (R)-α-allyl-4-methyl-benzyl isocyanate, and the mixture was stirred for one hour. The solution was treated with 50 mL of water and was extracted with 100 mL of 50:50 hexanes: ethyl acetate, 80 mL of ethyl acetate and then 100 mL of hexanes: ethyl acetate. Each extract was washed with 10 mL of water and 10 mL of brine. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 240 gm of silica with 4 L of 70:30 hexanes: ethyl acetate to give a small amount of higher Rf material (3,3-diethyl-1-[(R)-α-(allyl)-4-(methyl)benzylaminocarbonyl]-4-(S)-[4-(1-(oxo)-2-(methoxy) ethyl)phenoxy]azetidin-2-one) and a substantial amount of mixed fractions. The mixed fractions were purified by flash chromatography on 173 gm of silica eluting with 4 L of 75:25 hexanes:ethyl acetate, and the mixed cuts from that chromatography were fractionated again under the same conditions. The pooled fractions containing mostly desired product were subjected to a final purification by flash chromatography on 143 gm of silica eluting with 3 L of 98:2 methylene chloride: ethyl acetate to give 1.40 gm of product as an oil.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:9]=2[CH2:10][NH:11]C(=O)C)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl>C(O)C>[NH2:11][CH2:10][C:9]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:8]=1[S:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)(=[O:6])=[O:7]
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)NC1CC1
Agent: Cl
Solvent: CCO
Product: NCc1cc(F)ccc1S(=O)(=O)NC1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
(Step 2) To a solution of N-[2-(cyclopropylsulfamoyl)-5-fluorobenzyl]acetamide obtained in Step 1 (2.22 g) in ethanol (20 ml) was added hydrochloric acid (10 ml) at room temperature, and the mixture was stirred overnight at 80° C. The reaction solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 2-(aminomethyl)-N-cyclopropyl-4-fluorobenzenesulfonamide (0.60 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:18][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1

Procedure:
A mixture of benzoic acid 2-chloro-5-methyl-phenyl ester (CAB02124, 2.47 g, 10.0 mmol), N-bromo-succinimide (1.96 g, 11.0 mmol) and dibenzoyl peroxide (10 mg) in carbon tetrachloride (25 mL) was heated to reflux for 1 hour (TLC-control). After cooling to room temperature water (50 mL) and diethyl ether (100 mL) were added. The organic layer was separated, washed with brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:hexane, 1:40, Rf: 0.21). Yield: 2.012 g (62%) colourless oil, which solidified after a few hours (contains ca. 10% benzoic acid 5-dibromomethyl-2-chloro-phenyl ester).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([O:26][CH2:27][CH2:28][CH2:29][C@@H:30]3[CH2:34][O:33]C(C)(C)[O:31]3)=[C:18]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:17]=2)([CH3:14])[CH3:13])[CH:8]=[C:7]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:6]=1[OH:45])([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[K+]>CO>[C:22]([C:20]1[CH:21]=[C:16]([S:15][C:12]([S:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:45])=[C:7]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:8]=2)([CH3:14])[CH3:13])[CH:17]=[C:18]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:19]=1[O:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:31])[CH2:34][OH:33])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OC[C@@H](CCCOc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OCCC[C@H](O)CO)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 2,6-di-tert-butyl-4-(1-{3,5-di-tert-butyl-4-[3-(2,2-dimethyl-[1,3]dioxo-lan-4(R)-yl)-propoxy]-phenylsulfanyl}-1-methyl-ethylsulfanyl)-phenol (Ex-11, 230 mg, 0.35 mmol) in 20 ml MeOH, was added 1.0 N HCl dropwise until the mixture turned cloudy. Then small amount of MeOH was added to the mixture until it became clear. The mixture was stirred at room temperature, and HPLC indicated that the reaction completed within 2 hours. The mixture was neutralized with 5N KOH and extracted with EtOAc. The combined organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The residue was purified by silica gel column chromatography to give 0.2 g (93%) 5-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-pentane-1,2(S)-diol as a white solid, mp 68–71° C. 1H-NMR (CDCl3) δ 7.53 (s, 2H), 7.45 (s, 2H), 5.36(s, 1H), 3.67–3.79 (m, 4H), 3.46–3.52 (m, 1H), 1.91–2.17 (m, 4H), 1.42–1.45 (m, 42H). MS m/z: 636.4119 ([M+NH4]+, 20%). Anal. calcd for C36H58O4S2: C, 69.86; H, 9.44; S, 10.36; found: C, 70.10; H, 9.15, S, 10.13.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[CH:17]([C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[C:22]([CH:29]([CH3:31])[CH3:30])[C:21]=1[S:32]([NH:35][NH2:36])(=[O:34])=[O:33])([CH3:19])[CH3:18]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3](=[N:36][NH:35][S:32]([C:21]1[C:22]([CH:29]([CH3:30])[CH3:31])=[CH:23][C:24]([CH:26]([CH3:28])[CH3:27])=[CH:25][C:20]=1[CH:17]([CH3:19])[CH3:18])(=[O:33])=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(c2cccc(C(F)(F)F)c2)C(F)(F)F)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
2,2,2-Trifluoro-3'-(trifluoromethyl)acetophenone (3.7 g, 0.15 mol) was dissolved in dichloromethane (15 ml, anhydrous) and the solution was cooled to 0° C. Titanium tetrachloride (15 ml, 1.0M in dichloromethane) was added to the solution dropwise and the resulting ochre suspension was stirred at room temperature for 12 h. 2,4,6-Triisopropylbenzenesulfonyl hydrazine (3.8 g, 0.015 mol) was added to the suspension and the reaction mixture was stirred for 2 h. The mixture was quenched with water and the organic phase was separated, washed with brine, dried and the solvent was removed in vacuo. The resulting solid was purified by column chromatography using 10-25% ethyl acetate in hexane as eluant. This afforded the product as a white crystalline solid (3.9 g). 1HNMR (250 MHz, CDCl3) δ 1.10-1.22 (m, 18H, (CH3)2), 2.86 (septet, 1H, C H(CH3)2), 4.02 (septet, 2H, C H(CH3)2), 7.14 (S, 2H, ArH), 7.40-7.48 (m, 2H, ArH), 7.64 (t, 1H, ArH), 7.72-7.80 (m, 1H, ArH), 8.72 (s, 1H, NH).
Reaction SMILES: C1COCC1.[BH4-].[Na+].CS(O)(=O)=O.[O:13]=[C:14]([N:28]1[CH2:33][CH2:32][N:31]2[C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=[C:30]2[CH2:29]1)[CH:15]=[C:16]([NH2:27])[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26]>CC(O)C>[O:13]=[C:14]([N:28]1[CH2:33][CH2:32][N:31]2[C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=[C:30]2[CH2:29]1)[CH2:15][CH:16]([NH2:27])[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 5 h

Procedure:
In a 250 mL round bottom flask THF (110 mL) was taken. It was cooled to less than −5° C. and NaBH4 (2.81 g) was added. After that methanesulfonic acid (17.8 g) was added dropwise at less than −5° C. over a period of 1 h. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (10.0 g) is mixed in a solvent mixture of THF (25 mL) and IPA (11 mL) and added into the reaction mixture, keeping the temperature below 0° C. It was stirred for 4-6 h below 5° C. After usual work-up procedure, product was extracted in a suitable solvent. Extract was washed and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-9.5 g, % Y-94.5%, % Purity by HPLC-94.6%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:5]=1[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=O.S(C)C>C1COCC1>[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:12]=[C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][C:4]=1[NH:3][CH3:1])([CH3:11])[CH3:10]
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC=O
Solvent: CSC
Solvent: C1CCOC1
Product: CNc1ccc(Oc2ccccc2)cc1C(=O)NC(C)C
Temperature: 50 °C
Yield: 29.6 %

Procedure:
A solution of 44A (55 mg, 0.19 mmol) in THF (1 mL) at 0° C. was treated with BH3.SMe2 (0.09 mL, 0.93 mmol). The resulting yellow solution was warmed to 50° C. for 1 hour, and then cooled to 0° C. and quenched with MeOH (0.25 mL). The resulting solution was treated with acetic acid (0.1 mL) and warmed to 50° C. for 6 hours. The solution was concentrated to dryness and purified by chromatography (SiO2, 10% MeOH in CHCl3) to afford 44B (16 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][NH:8][C:9]1[C:10]2[C:26]([CH3:27])=[CH:25][S:24][C:11]=2[N:12]=[C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:14]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][NH:8][C:9]1[C:10]2[C:26]([CH3:27])=[CH:25][S:24][C:11]=2[N:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=2)[N:14]=1
Reactant: Cc1csc2nc(-c3ccc(C(=O)O)cc3)nc(NCc3cccc([N+](=O)[O-])c3)c12
Agent: [Ni]
Solvent: CO
Product: Cc1csc2nc(-c3ccc(C(=O)O)cc3)nc(NCc3cccc(N)c3)c12

Procedure:
A solution of 4-[4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid in methanol is hydrogenated in the presence of Raney nickel. The catalyst is filtered off and the solution is concentrated. After recrystallization, 4-[4-(3-amino-benzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1c[nH]nn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cn2ccnn2)cc1
Temperature: 25 °C

Procedure:
4-Nitrobenzylbromide (25.4 g, 0.12 mol) was added to a solution of 1H-1,2,3-triazole (8.12 g, 0.12 mol) and triethylamine (11.88 g, 0.12 mol) in anhydrous acetonitrile. The mixture was refluxed for 1 h, cooled to room temperature and the precipitated NEt3. HBr filtered off. The solvent was removed under vacuum and the residue chromatographed through silica gel eluting with CH2Cl2 (100) to CH2Cl2 /MeOH (95.5) to give 2-products. The more polar product was identified as the title-1-isomer (13 g, 54%); mp 114°-116° C. δ (250 MHz, CDCl3) 5.72 (2H, s, CH2), 7.38 (2H, d, J=9 Hz, Ar-H), 7.64 (1H, s, Ar-H), 7.78 (1H, s, Ar-H), 8.18 (2H, d, J=9 Hz, Ar-H). The less polar, minor isomer was identified as the 2-alkylation product (2.25 g, 9%), mp 112°-113° C. δ (250 MHz, CDCl3) 5.72 (2H, s, CH2), 7.40 (2H, d, J=9 Hz, Ar-H), 7.66 (2H, s, Ar-H), 8.18 (2H, d, J=9 Hz, Ar-H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:30][N:31]1[C:35]([NH2:36])=[C:34]([NH2:37])[CH:33]=[N:32]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O>[NH2:36][C:35]1[N:31]([CH3:30])[N:32]=[CH:33][C:34]=1[NH:37][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cn1ncc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a suspension of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]propanoic acid (1.695 g) and 1-methyl-1H-pyrazole-4,5-diamine sulfate (1.05 g) in water (16 ml) were added triethylamine (1.4 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.73 g). The mixture was stirred at room temperature for 2 hours. The resulting suspension was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2-benzyl 1-tert-butyl {(2S)-3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxo-1,2-propanediyl}biscarbamate (1.78 g) as a solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[N:1]1[CH:2]=[C:3]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)=[O:29])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccc2[nH]c(SCc3cnc4ccccn34)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(Cc1cnc2ccccn12)c1nc2ccccc2[nH]1
Yield: 21.9 %

Procedure:
A suspension of 150 mg (0.54 mmole) of 2-[(imidazo[1,2-a]pyridin-3-ylmethyl)thio]-1H-benzimidazole (see Example 1) in 4.0 ml of dichloromethane was cooled in an ice bath. A solution of 120 mg (0.59 mmole) of ca. 85% m-chloroperbenzoic acid in the minimum amount of dichloromethane needed to form a solution was then added dropwise with stirring. The reaction was quenched with a few drops of dimethylsulfide. The mixture was washed with saturated aqueous sodium bicarbonate. The organic phase was concentrated in vacuo and chromatographed on silica gel (using ethanol-dichloromethane-triethylamine as eluent) to yield 35 mg of the title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1cccc2c1CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2c(OC)cccc2C1=O
Yield: 23 %

Procedure:
A solution of 21.5 g of 4-methoxy-1-indanone, 27.4 ml of 3-buten-2-ol and 210 mg of p-toluenesulfonic acid in 27.4 ml of 2,2-dimethoxypropane and 210 ml of anhydrous toluene was boiled under reflux for 16 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1). 6.42 g (23%) of (RS)-2-(2-buten-1-yl)-4-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(=O)([O-])O.[Na+]>[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(C(OC2CCCCO2)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Yield: 100.4 %

Procedure:
Stir a solution of 3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (12 g, 30.3 mmol), 3,4-dihydro-2H-pyran (3.6 mL, 39.4 mmol) and dichloromethane (250 mL) at room temperature. Add pyridinium p-toluenesulfonate (0.8 g, 3.03 mmol) and stir the resulting mixture 18 hours at room temperature. Dilute the reaction mixture with aqueous saturated sodium hydrogen carbonate (100 mL) and separate the layers. Extract the aqueous layer is washed with dichloromethane (2×50 mL), combine the organic layers, dry with magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with hexanes to 8:2 hexanes:ethyl acetate to afford the title compound (14.6 g, 100%) as a colorless oil. LCMS (m/z) 478 M−1.