Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15](=[O:21])[N:14]([CH3:22])[CH:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=2)[C:24]1=[O:36])(=[O:3])[CH3:2].C(O)(=O)C>[Zn].C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=3)[C:24]2=[O:36])=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH2:18])[C:15](=[O:21])[N:14]([CH3:22])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc([N+](=O)[O-])c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 122c (600 mg, 1.23 mmol), acetic acid (10 mL) and THF (5 ml). Zinc dust (1.56 g, 20.5 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 81% (460 mg) yield of 122d as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 1H, J=8.0 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.52 (s, 1H), 7.45 (t, 1H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 6.74 (d, 1H, J=2.0 Hz), 6.57 (d, 1H, J=2.0 Hz), 5.08 (s, 2H), 4.78 (s, 2H), 4.37 (s, 2H), 3.60 (s, 3H), 1.85 (s, 3H), 1.40 (s, 9H); MS (ESI+) m/z 460.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:20][C@H:21]([C@H:23]2[CH2:27][O:26]C3(CCCCC3)[O:24]2)[CH3:22])[N:7]=1.O>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:20][C@@H:21]([CH3:22])[C@H:23]([OH:24])[CH2:27][OH:26])[N:7]=1
Reactant: C[C@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(2-[(2,3-difluorobenzyl)thio]-6-{(1S)-1-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]ethoxy}pyrimidin-4-yl)azetidine-1-sulfonamide (the product of step ii) (43 mg) in DCM (4 ml) was added iron (III) chloride hexahydrate (73 mg). The reaction mixture was stirred at room temperature for 2 h after which time further iron (III) chloride hexahydrate (40 mg) was added. After 3 d at −18° C., H2O and DCM were added. The layers were separated and the aqueous material extracted with further DCM. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. TFA (1 ml) and DCM (4 ml) were added to the residue and the reaction mixture stirred at room temperature for 2 d. The mixture was partitioned between saturated aqueous sodium bicarbonate and DCM, then neutralised with 2M aqueous hydrochloric acid, the layers separated and the aqueous material extracted with further DCM. The DCM extracts were allowed to slowly evaporate and the resulting solid washed with minimal cold DCM to afford the title compound as a white powder. Yield: 11 mg
Reaction SMILES: [CH2:1]([S:8][CH:9]1[NH:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH2:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([S:8][CH:9]1[N:12]([CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCCCc1ccccc1)C(F)(F)F
Reactant: O=C1CC(SCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(SCc2ccccc2)N1CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A solution of 4-(benzylthio)azetidin-2-one (1.1 g, 5.5 mmol) in dry THF (10 ml) was added dropwise over 10 minutes to a suspension of NaH (0.13 g, 5.6 mmol) in dry THF (5 ml) at -20° C. under a N2 atmosphere. A solution of 3-phenyl-1-(trifluoromethanesulfonyloxy)propane (1.5 g, 5.6 mmol) in dry THF (10 ml) was added dropwise over 10 minutes at -55° C. After stirring for 1 hour, the mixture was poured into ice/water (50 g), filtered through hyflo, the THF evaporated under reduced pressure and the residue taken up in ethyl acetate. The solution was washed with brine (×2), dried (MgSO4), evaporated under reduced pressure and purified by flash chromatography on silica gel eluted with 5:1 petroleum ethemethyl acetate to give the title compound as a yellow oil (1.4 g, 81%). 1H NMR δ (CDCl3) 2.58 (2H, m, CH2), 2.58 (2H, t, J=15 Hz, CH2Ph), 2.9, 3.2 (each 2H, m, H-3 & NCH2), 3.73 (2H, s, SCH2), 4.51 (1H, m, H-4), 7.2 (10H, m, 2×Ph--H)
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CCCCCCC.C(=O)(O)[O-].[K+].[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]>O>[CH2:38]([S:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:8]([O:10][CH3:11])=[O:9])=[CH:24][CH:25]=1)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCC(Oc1ccc(N)cc1)C(=O)OC
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCC(Oc1ccc(NS(=O)(=O)CCCC)cc1)C(=O)OC

Procedure:
A heel was created batchwise by charging 142.2 g (0.41 moles) of methyl 2-[4-aminophenoxy]tetradecanoate (the amine), 267.7 g of heptane, 45.7 g (0.46 moles) of potassium bicarbonate, and 119.7 g of deionized water. The two-phase mixture was stirred with high agitation (800-900 rpm) and heated to 55° C-60° C. at which point 71.4 g of butanesulfonyl chloride was added over approximately 1 hour. After stirring for one hour, the composition of the assay of the product in the upper organic phase was 98.9%. At this point, continuous feeds into the reactor system, which consists of two reactors and a processing tank, were started to provide six hours of residence time in the two reactors. The feed rates were: 1.46 g/min (2.63 mmoles/min) of the amine solution (63 wt % in heptane), 0.45 g/min (2.87 mmoles/min) of the butanesulfonyl chloride, and 1.42 g/min (2.87 mmoles/min) of a 20 wt % potassium bicarbonate solution.
Reaction SMILES: [N:1]([CH:4]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)=[C:2]=[O:3].[NH3:33]>C(Cl)Cl>[NH2:33][C:2]([NH:1][CH:4]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH:21]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:5]1[CH:6]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)=[O:3]
Reactant: N
Reactant: CC1CCCC(OC(N=C=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: ClCCl
Product: CC1CCCC(OC(NC(N)=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 56 mg (0.12 mmole) of α-isocyanato-3-(SR)-(3,5-Bis(trifluoromethyl)-benzyloxy)-2-(SR)-phenyl-1-(SR)-methylcyclohexane in 1 mL of methylene chloride was treated with 3 mL of ammonia-saturated methylene chloride at room temperature. After 1 hr, the solution was concentrated in vacuo and the residue purified by flash chromatography on 16 g of silica eluting with 400 mL of 100:2 methylene chloride: methanol to provide 54 mg (93%) of a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([C@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH2:35]([O:42]C(Cl)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([C:1](=[NH:2])[NH:3][C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[CH:12]=2)[CH:8]=[C:9]1[CH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])[CH3:14]
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)NC(=O)c3ccccc3)cc2n1CC

Procedure:
60 mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-1-ethylindol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate obtained in Example 60 was reacted with 24 μl of benzylchloroformate according to the same procedure as Example 154 to obtain 64 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[N:22]([CH2:24][PH:25](=[O:29])[O:26]CC)[CH3:23])([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[N:22]([CH2:24][PH:25](=[O:26])[OH:29])[CH3:23])([O-:3])=[O:2]
Reactant: CCO[PH](=O)CN(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Product: CN(C[PH](=O)O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
8.0 g (0.017 mole) of ethyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-P-methylaminomethylphosphinate are refluxed for 14 hours in 50 ml of 20% hydrochloric acid. The precipitated crystalline product is isolated and dried at 80° C. in vacuo, affording 7 g (96.8% of theory) of the title compound with a melting point of 153°-154.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH:13]2[CH2:15][CH2:14]2)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH:13]2[CH2:15][CH2:14]2)[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](c1ccc(Cl)cc1)C1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC[C@H](c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a stirred solution of methyl (2S)-(4-chlorophenyl)(cyclopropyl)ethanoate (7.72 g, 34.4 mmol) in methylene chloride (300 ml) at −78° C. under nitrogen is added diisobutyl aluminum hydride (86 ml of a 1.0 M solution in methylene chloride, 86.0 mmol). The reaction mixture is allowed to warm to room temperature and stirred for an additional hour. The reaction is quenched by the addition of saturated aqueous ammonium chloride and then filtered. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (15:85) to afford the title compound as a colorless liquid (5.45 g, 80%) which is characterized by 1HNMR, 13CNMR and mass spectral analyses.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([O:5]C)=[O:4].[OH-].[Na+].Cl>CO>[F:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(F)c1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(F)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution containing methyl 2-fluoro-2-(quinolin-6-yl)acetate (0.49 g, 2.2 mmol) in methanol (3.0 ml) was added sodium hydroxide (5 M, 1.0 ml, 5.0 mmol). The mixture was stirred at rt for 48 h and then neutralized with 5 N HCl (1.0 mL). The solution was allowed to sit overnight during which time a precipitate formed. The solution was filtered and the filtercake washed with cold water then dried under vacuum to afford the title compound as a tan solid. MS (ESI, pos. ion) m/z: 206 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])=[N:6][C:7]=1[C:8]([NH:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])=[N:6][C:7]=1[C:8]([NH:10][CH2:11][CH3:12])=[O:9]
Reactant: CCNC(=O)c1nc(-c2cccc(C(=O)OC)c2)cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Temperature: 92.5 °C
Yield: 97.1 %

Procedure:
Methyl 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.6 mmol) was suspended in a 20 mL of 1:1 MeOH-5% aqueous sodium hydroxide and heated at 90-95° C. for 4 hours. The homogeneous reaction mixture was cooled to room temperature, concentrated to half the initial volume, cooled in an ice-bath, and acidified to pH of 4 with concentrated HCl. A white solid precipitated and was collected, washed with water and dried in vacuo to give 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoic acid (445 mg, 97% yield). The pyrazine acid (40 mg, 0.14 mmol) was dissolved in DMF (1 mL), and then 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour benzylamine (30 mg, 0.27 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution then brine and dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-ethyl-6-(3-{[(phenylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (a tan color solid, 22 mg, 42% yield): 1H NMR (400 MHz, DMSO-d6): 9.14 (s, 1H), 8.88 (s, 1H), 8.87-8.85 (b, 1H), 8.51 (s, 1H), 8.37-8.34 (d, 1H), 7.87-7.85 (d, 1H), 7.63-7.59 (b, 1H), 7.58-7.54 (t, 1), 7.34-7.23 (m, 4H), 4.53-4.52 (d, 2H), 3.38-3.29 (m, 2H), 1.171.14 (t, 3H); MS (EI) for C21H21N5O2: 376 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([C:12]2[CH:13]=[C:14]([CH:40]=[CH:41][CH:42]=2)[CH2:15][N:16]2[C:20](=[O:21])[C:19]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:17]2)=[O:11])[CH2:3][CH2:2]1.Cl.[O:44]1CCOCC1>>[O:21]=[C:20]1[C:19]2([CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[N:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:17][N:16]1[CH2:15][C:14]1[CH:13]=[C:12]([CH:42]=[CH:41][CH:40]=1)[C:10]([O:9][CH2:8][C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:44])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCCN3CCOCC3)c1)CN2c1ccccc1
Reactant: C1COCCO1
Agent: Cl
Product: O=C(OCC(=O)N1CCOCC1)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((2-morpholinoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.22 g, 0.38 mmol) was added 4M solution of HCl in dioxane (4 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-morpholino-2-oxoethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [CH:1]([C:3]1[CH:39]=[CH:38][C:6]([C:7]([N:9]([CH2:24][C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[CH:28][N:29]=2)[CH2:10][C:11]2[N:12](COCC[Si](C)(C)C)[CH:13]=[CH:14][N:15]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2]>FC(F)(F)C(O)=O.ClCCl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:10][C:11]2[NH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[CH:38][CH:39]=1)=[O:2]
Reactant: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To the compound 40 (1.7 g), a 50% trifluoroacetic acid-dichloromethane solution (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and an aqueous 5N sodium hydroxide solution (15 mL) was added to the residue. The aqueous layer was extracted three times with 50 mL of dichloromethane. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was concentrated to obtain the title compound (compound B) (922 mg) having the following physical properties.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13]Br>C(OCC)C>[Br:13][CH:5]1[CH2:6][CH2:7][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]1=[O:8]
Reactant: BrBr
Reactant: O=C1CCCOc2ccccc21
Solvent: CCOCC
Product: O=C1c2ccccc2OCCC1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b]oxepin-5-one (3.10 g, 12.8 mmol) in diethyl ether at 0° C., bromine (625 μl, 12.2 mmol) was added and stirred for 2.5 hours, gradually raising the temperature to room temperature. Purification on silica and triturating using diethyl ether and hexanes gave 4-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([NH:18][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Clc1nccc2[nH]cnc12
Solvent: O
Product: c1ccc(CNc2nccc3[nH]cnc23)cc1

Procedure:
A mixture of 4-chloro-1H-imidazo-[4,5-c]-pyridine (2.0 g, 13 mmole), benzylamine (5 ml) and a few drops of water was heated at reflux for 4 days. The reaction mixture was poured onto ice and water and the cold mixture was extracted twice with diethylether. The ether was removed in vacuo and the residual oil was triturated twice with hexane. The oil was suspended in water and the aqueous phase was neutralised with glacial acetic acid. The aqueous phase was taken to dryness in vacuo and resuspended in water (15 ml). It was applied to a column of Dowex 50 (H+) (10 g). The column was washed with water until the ultra violet absorbance of the eluant had fallen to zero. The column packing was removed from the column and heated with several portions of concentrated ammonium hydroxide solution (400 ml). The basic solution was filtered in vacuo, cooled and neutralized with glacial acetic acid. The yellow solid was collected and dried in vacuo at 40° C. Yield of 4-benzylamino-1H-imidazo-[ 4,5-c]-pyridine 0.94 g, m.p. 60°-64° C., 31.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:12]=1.S(Cl)([Cl:32])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([Cl:32])=[O:16])[N:12]=1
Reactant: COc1ccc(CNc2nc(CCC(=O)O)nc3sc4c(c23)CCCC4)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(CCC(=O)Cl)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro [1]benzothieno-[2,3-d]pyrimidine-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionyl chloride is obtained. This is transferred to aqueous ammonia, the mixture is stirred for one hour and, after customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionamide is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:24][C@H:25]2[O:27][CH2:26]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:24][C@@H:25]2[CH2:26][O:27]2)=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OC[C@@H]2CO2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Methyl-pyridin-3-ol (0.218 g, 2.0 mmol) was placed in a flask with DMF (10 mL) and NaH (60% dispersion in oil, 77 mg, 2.0 mmol) and stirred for 30 min. at room temperature. (S)-glycidyl 3-nitrobenzene sulfonate (0.52 g, 2.0 mmol) was then added to the reaction mixture, which was then stirred at room temperature for 14 hours. The reaction was quenched with NaHCO3 (saturated) and then extracted three times with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to yield crude product which was purified by silica gel chromatography (60% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])=[C:3]([CH3:5])[CH3:4]>CCOC(C)=O.[Pd]>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)=C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)C(C)C)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 69.12A (0.050 g, 0.2 mmol) in EtOAc (3 mL) at 23° C. was added palladium on carbon (0.02 g, 0.2 mmol). The reaction was placed under an atmosphere of hydrogen and stirred for four hours. The reaction was then filtered and concentrated in vacuo. The purity of 69.12B was deemed sufficient such that it was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[CH:41][C:40]=1[Cl:53])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[CH:41][C:40]=1[Cl:53])[CH3:35]
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)ccc1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (2-chloro-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.