Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([Cl:34])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 20 h
Yield: 72 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886 mg, 5.0 mmol) in CCl4(20 ml) was added triphenylphosphine(1.574 g, 6.0 mmol) at rt. After 20 h stirring at reflux temperature, the solvent was evaporated. Saturated NaHCO3 aqueous solution and water was added to the residue, and the mixture was extracted with AcOEt. The extract was brine, dried(Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 100 g, CH2Cl2/MeOH: 50/1-45/1) to give 706 mg(72%) of pale yellow oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH2:8][CH2:9][CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCCc1nc(I)c(I)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-diiodo-2-propyl-1H-imidazole (15.000 g; 41.443 mmol) in anhydrous DMF (260 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (1.989 g; 49.732 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (10.216 g; 45.587 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting dark-orange homogeneous mixture was further heated at 100° C. for 1 h30. The reaction mixture was cooled to rt, and water (300 ml) was added slowly. This mixture was extracted with ether (3×200 ml). The combined organic layers were washed with brine (2×100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The crude was purified by FC (heptane/EA=1/1) to give the pure product [2-(4,5-diiodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was further dried under HV (8.690 g; 42%). LC-MS: tR=0.88 min.; [M+H]+=505.77 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrC(C)C(Br)=[O:48]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:48])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: CC(Br)C(=O)Br
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 987 mg of trans-6-amino-3 -chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part B) in 50 mL of dry ether was added 0.350 mL of dry pyridine and 1.66 g of α-bromopropionyl bromide. The cooling bath was removed and then after 30 min at ambient temperature, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 50 mL of dry DMF, 2.35 g of lithium iodide and 2.3 g of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 3 days. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product. The title compound was obtained by crystallization from ethyl acetate/hexanes, and recrystallization from ethyl acetate afforded 650 mg of pure title compound: mp 171-172°; HRMS: Calcd. for C16H168NO2F3Cl (M+H)+: 346.082166. Found: 346.080681: mp 147-147.5°; HRMS: Calcd. for C17H18NO2F3Cl (M+H)+: 360.097816. Found: 360.097869
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.COCCOC.[OH-].[Na+]>O>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([O:3][CH2:2][C:1]#[N:4])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: N#CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)OCC#N)cc1
Reaction time: 6.5 h

Procedure:
Method of preparation: 8.1 g (0.1 mole of glycolonitrile (70% aqueous solution) is added to a cooled (15° -20° C.) mixture of 9.5 g (0.05 mole) of p-toluenesulfonyl chloride in 20 ml. of 1,2-dimethoxyethane and 50 ml. distilled water. A solution of 2.1 g (0.05 mole) of NaOH in 50 ml. distilled water is added slowly with stirring at 20°-25° C. over a period of 6.5 hours, maintaining the pH of the reaction mixture at about 8. The insoluble material is filtered off, washed with cold water, and dried at 40° C. under vacuum to yield 6.8 g (64% conversion) of the product, a light brown solid, m.p. 48°-50.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:25]([C:27]5[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=5)=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added methyl 4-formylbenzoate (143 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered, and after washing with water and ethyl acetate, drying yield the title compound (239 mg, 67% yield) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19]C[CH2:17][CH2:16]3)[N:13]([C:21]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:22])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[Cl:41]C1C=C(C(N2CCNC(CC)(CC)C2)=O)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:21]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:41])[CH:29]=4)[N:24]=3)=[O:22])[C:14]([CH2:16][CH3:17])([CH2:20][CH3:19])[CH2:15]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)CN(C(=O)c2cccc(Cl)c2)CCN1
Reactant: O=C(c1cccc(Cl)c1)N1CCN(C(=O)c2ncn(-c3ccccc3)n2)C2(CCCCC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC)CN(C(=O)c2cccc(Cl)c2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
By using the same synthesis strategy as for (3-chloro-phenyl)-[1-(1-phenyl-1H-[1,2,4]-triazole-3-carbonyl)-1,4-diaza-spiro[5.5]undec-4-yl]-methanone the following compounds were prepared from (3-chloro-phenyl)-(3,3-diethyl-piperazin-1-yl)-methanone trifluoroacetate as amine and the respective carboxylic acid:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.CC1(C)O[C:26](=[O:28])[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[CH:30]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]1[CH:37]=[CH:38][N:39]=[C:35]1[C:31]1[CH:30]=[C:29]([C:24]2[CH2:25][C:26](=[O:28])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(-c3ncco3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ncco3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (137 mg) and 2,2-dimethyl-6-(3-oxazol-2-yl-phenyl)-[1,3]dioxin-4-one (Example L5) (271 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (83 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:33][C:29]5[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (20 ml), and potassium carbonate (400 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 3-picolylchloride hydrochloride (180 mg) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (100 ml), and the precipitated crystals were recovered by filtration. The resulting crude crystals were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (200 mg, 52%).
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C[O-].[Na+]>C1(C)C(C)=CC=CC=1.CO>[C:11]([CH2:12][C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Methylbenzoate (136.0 grams; 1.0 mol), acetophenone (30.0 grams; 0.25 mol), sodium methoxide (17.3 grams; 0.3 mol) and xylene (300 ml) were placed into a four-necked, round bottom, one liter flask equipped with stirrer, nitrogen addition adapter, thermometer and Oldershaw column connected with distillation head and a trap. The mixture was heated with stirring to 135°-140° C. and maintained there for 6 hours while under a blanket of nitrogen. At 110°-120° C. methanol started to evolve and the reaction mixture became semi-solid. After two hours of heating the contents of the flask somewhat liquified. Towards the end of the reaction, nearly 25 ml of liquid consisting of methanol and xylene had been collected in the trap. The reaction mixture was cooled to room temperature and acidified with hydrochloric acid (500 ml of 6N). Stirring was continued for about 30 minutes until all the solid was dissolved. The xylene layer was separated and washed twice with water, then twice with aqueous sodium carbonate and then twice again with water. The xylene layer was removed by evaporation from the dibenzoylmethane (53.1 grams; 95% yield). Analysis by GLC showed the product to be 95% pure. This product after recrystallized from methanol had a melting point of 77°-78° C. The distillate (347.0 grams) containing xylene, methylbenzoate and water was subjected to azeotropic distillation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@@:11]2([CH2:26][OH:27])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28](OC([C@@H]1C[C@@]2(COC)[C@H](C2)N1C(OC(C)(C)C)=O)=O)C.[OH-].[Na+].O[Li].O>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@@:11]2([CH2:26][O:27][CH3:28])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@]2(COC)C[C@@H]2N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: [Li]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC[C@@]12C[C@@H]1N(C(=O)OC(C)(C)C)[C@H](C(=O)NCc1cccc(Cl)c1F)C2

Procedure:
were obtained using the same protocols as described in Scheme B28 steps D and E for the preparation of (1R,3S,5S) and (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester starting from (1R,3S,5S) and (1S,3S,5R)-5-methoxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester. NaOH was replaced by LiOH.H2O in step D. The diastereoisomers were separated by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-methoxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester as a colorless oil: TLC, Rf (c-hexane/EtOAc 1:1)=0.50; MS (UPLC/MS): 413.3/415.2 [M+H]+, 457.3/459.3 [M+HCOO]−; tR (HPLC conditions a): 3.74 min and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-methoxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester as a colorless oil: TLC, Rf (c-hexane/EtOAc 1:1)=0.30; MS (UPLC/MS): 413.2/415.3 [M+H]+, 457.3/459.3 [M+HCOO]−; tR (HPLC conditions a): 3.57 min.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2cccc(C)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c1
Yield: 94 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(3-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 2 & 3, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 94% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl.[C:15]([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:15][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 4-(4-aminophenyl)-butyric acid (5 g, 27.90 mmol) in MeOH (100 mL) at room temperature was added HCl conc. (37% 15 mL). The resulting mixture was stirred overnight at 50° C. then treated with a saturated aqueous solution NaHCO3 and Na2CO3 solid until pH 9. The solvent was evaporated under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The crude material was purified by flash chromatography using CH2Cl2/MeOH as solvent mixture yielding 40 (4.93 g, 91%) as orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]=[CH2:15])[CH:3]=1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[OH-].[Na+]>O1CCCC1>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[CH:14]=[CH2:15])[CH2:9][CH2:10]2)=[O:22])=[CH:19][CH:18]=1
Reactant: C=Cc1cc(C)ccc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1cc(C)ccc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 4-bromo-3-chlorotoluene (2.1 g), Boc-piperazine (1.9 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg), sodium tert-butoxide (1.4 g) and toluene (20 mL) was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.1 g). To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (1 g), palladium acetate (74 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (271 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(4-methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g). 4-(4-Methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g) was dissolve in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N aqueous sodium hydroxide solution (8 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give 1-(4-methyl-2-vinylphenyl)piperazine (606 mg). 1-(4-Methyl-2-vinylphenyl)piperazine (606 mg) was dissolved in tetrahydrofuran (8 mL), 4-iodobenzoyl chloride (1.1 g) and 1N aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1 g).
Reaction SMILES: CC[O-].[Na+].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][CH:13](Br)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[F:12][CH:13]([S:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(F)Br
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)Sc1ccccc1
Yield: 89.6 %

Procedure:
To 150 ml of tetrahydrofuran (THF) were added 6.5 g (0.1 mole) of pulverized EtONa and 11.1 g (0.1 mole) of thiophenol and the mixture was refluxed for 10 minutes. Thereto was added 18.5 g (0.1 mole) of ethyl fluorobromoacetate and the mixture was refluxed for one hour with stirring. THF was removed by an evaporator and the precipitated NaBr was filtered. The organic layer was washed with water, dried and distilled to obtain 19.2 g (90%) of ethyl fluoro(phenylthio)acetate.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([N:24]2[CH:28]=[C:27]([C:29](=[O:31])[NH2:30])[C:26]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:25]2)([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]1)=[O:14])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[C:29]([C:27]1[C:26]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:25][N:24]([C:18]2([CH2:21][C:22]#[N:23])[CH2:17][CH2:16][N:15]([C:13]([O:12][CH:10]([CH3:11])[CH2:9][OH:8])=[O:14])[CH2:20][CH2:19]2)[CH:28]=1)(=[O:31])[NH2:30]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CO)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example 30-51) (86 mg, 0.15 mmol) in THF (1.0 mL) was added a solution of TBAF.3H2O (316 mg, 1.00 mmol) in THF (1.0 mL). The resulting mixture was allowed to stir at ambient temperature for 3 hours. The mixture was then diluted with DCM, washed with water, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by MPLC on silica gel (using a gradient elution of 0-20% MeOH/DCM) to afford the title compound, Example #31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH2:18][CH2:19][CH3:20])[C:15]([CH3:17])=[N:16][C:12]=4[CH:11]=3)=[N:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)(Cl)Cl>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH2:18][CH2:19][CH3:20])[C:15]([CH3:17])=[N:16][C:12]=4[CH:11]=3)=[N:7][C:6]=2[CH:23]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCn1c(C)nc2cc(-c3nc4cc(N)ccc4o3)ccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCn1c(C)nc2cc(-c3nc4cc(NC(C)=O)ccc4o3)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.4 %

Procedure:
To a solution of 5-(5-aminobenzoxazol-2-yl)-2-methyl-1-n-propylbenzimidazole (see Working Example 82-4) (200 mg, 0.653 mmol) in chloroform (5 mL) was added triethylamine (132 mg, 1.31 mmol) and acetic anhydride (100 mg, 0.979 mmol), and this was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated, the precipitated crystals were filtered, and after washing with water were dried to yield the title compound (176 mg, 77% yield) as pale yellow crystals.
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1.ClC(OCC)=O.O[N:55]1[C:59](=[O:60])[CH2:58][CH2:57][C:56]1=[O:61]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([O:47][N:55]3[C:59](=[O:60])[CH2:58][CH2:57][C:56]3=[O:61])=[O:46])=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:33]3[C:28]([N:27]=[C:26]4[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)O)cc2)cc1
Agent: Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
1.41 ml of triethylamine are added to 3.1 g of (4) in 50 ml of tetrahydrofuran, the mixture is cooled to -20° C., and 0.474 ml of ethyl chloroformate is added. After stirring for 20 min, 575 mg of N-hydroxysuccinimide are added, and the mixture is stirred at -20° C. for 3 hours and left to reach room temperature overnight while stirring. The precipitate is filtered off with suction, the filtrate is concentrated, the residue is taken up in dichloromethane or ethyl acetate, and the resulting solution is washed with water, NaHCO3 solution and water and dried over MgSO4. The organic phase is concentrated, and the residue is recrystallized from toluene.