Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:15])([F:14])[C:7]1[S:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1>>[Cl:3][CH2:12][C:10]1[S:11][C:7]([C:6]([F:15])([F:14])[F:5])=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)s1
Product: FC(F)(F)c1ccc(CCl)s1
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Thionyl chloride (4.89 g) was added to [5-(trifluoromethyl)thiophen-2-yl]methanol (500 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (289 mg).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:19])=O>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:19])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc(Cn2cncc2CCl)cc1

Procedure:
A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole (1.00 g, 4.70 mmol), in thionyl chloride (5 mL), was stirred at 70° C. for 16 hours. The solvent was evaporated in vacuo and the resulting solid suspended in CH2Cl2, collected by filtration and dried in vacuo. The material was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccn1C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)n1C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.5 g. (0.03 mole) of p-nitrobenzoyl chloride in 60 ml. methylene chloride is added to a suspension of 3.9 g. (0.03 mole) aluminum chloride in 20 ml. methylene chloride. The resulting suspension is added dropwise to a chilled (-15°C.) solution of ethyl 1-methylpyrrole-2-acetate in 50 ml. methylene chloride. The solution is stirred for 15 minutes at -10°C. and at room temperature for 15 minutes. The reaction mixture is poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo. A solid, ethyl 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetate, crystallizes from the remaining oily residue which is isolated by recrystallization from methanol, m.p. 103°-106°C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].CN(C)C(N(C)C)=N>O1CCCC1.CN(C)C=O>[O:26]=[C:21]1[N:22]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:23](=[O:25])[CH2:24][O:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)COC2=O)CC1

Procedure:
A suspension of 13.60 g (46.36 mmol) of 1,1-dimethylethyl 4-{[(methylsulphonyl)oxy]methyl}piperidine-1-carboxylate, prepared in step 2.1., 9.37 g (92.72 mmol) of 1,3-oxazolidine-2,4-dione and 16.02 g (139.08 mmol) of 1,1,3,3-tetramethylguanidine in a mixture of 180 ml of tetrahydrofuran and 30 ml of dimethylformamide is heated at reflux for 24 hours. It is allowed to return to ambient temperature and is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 then 95/5 mixture of dichloromethane and methanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][CH:10]([CH3:18])[C:11](=O)[CH2:12][C:13](OC)=[O:14].[OH-].[Na+]>>[Cl:9][CH:10]([C:11]1[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:13](=[O:14])[CH:12]=1)[CH3:18]
Reactant: Cc1cccc(N)n1
Reactant: COC(=O)CC(=O)C(C)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc2nc(C(C)Cl)cc(=O)n12
Temperature: 110 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a manually stirred polyphosphoric acid (30 g, 200 mmol) in a 200 mL beaker was added 6-methyl-2-pyridinamine (Aldrich, 4.7 g, 43 mmol), followed by methyl 4-chloro-3-oxopentanoate (8.584 g, 52.15 mmol). The mixture was heated with stirring at 110° C. for 5 h. After being cooled, the dark slurry was transferred on to 100 g of ice. The pH of the mixture was adjusted to 6-7 with 10% sodium hydroxide. The mixture was extracted with methylene chloride. The combined organic layers were washed with water, brine, dried over magnesium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0-10% methanol in methylene chloride, to yield the desired product (3.16 g, 32.7%). LCMS calculated for C11H12ClN2O (M+H)+: m/z=223.1. Found: 223.2.
Reaction SMILES: [BrH:1].Br.CC(O)=O.C1(C)C=CC(S([N:16]2[CH2:29][CH2:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:23][C:22]3[N:50]=[C:18]([CH:19]=[CH:20][CH:21]=3)[CH2:17]2)(=O)=O)=CC=1>CC(O)=O>[BrH:1].[C:18]12[CH:19]=[CH:20][CH:21]=[C:22]([N:50]=1)[CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:16][CH2:17]2
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)Cc3cccc(n3)CN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1cc2nc(c1)CNCCNCCNC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A solution of HBr and AcOH was prepared by mixing 48% HBr and glacial AcOH in a 64:35 ratio. To 112 mL of the HBr/AcOH mixture was added 5.5 g (8.2 mmol) of 3,6,9-tris(p-tolylsulfonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (prepared by the procedure of Example B) and the reaction mixture was heated at mild reflux with constant stirring for 72 hrs. The reaction mixture was then cooled to room temperature and concentrated to approximately 1/10 of the original volume. The remaining solution was stirred vigorously and 15-20 mL of diethyl ether was added. A off-white solid formed which was filtered, washed with diethyl ether, and dried in vacuo. The dry tetrahydrobromide salt was then dissolved in 10 mL of water, adjusted to pH 9.5 with NaOH (50% w/w) and continuously extracted with chloroform for 4 hrs. After drying over anhydrous sodium sulfate, the chloroform was evaporated to give a light-tan oil which gradually crystallized upon standing at room temperature to yield 1.2 g (71%) of the title product, mp 86°-88° C. and further characterized by:
Reaction SMILES: FF.[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[N:20]=[C:21](\Cl)/[C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:21]([C:22]([F:23])([F:24])[F:25])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:4]2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)/C(Cl)=N/c1ccc(Cl)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: FF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
The synthetic intermediate imine (Z)—N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride (a pale yellow oil) was prepared as described in Huang et al., J. Fluorine Chem., 74:279-282 (1995) and used without distillation. To ethyl isocyanoacetate (0.467 g, 4.13 mmol) in dry THF (50 mL) was added NaH (170 mg, 4.13 mmol, 60% dispersed in oil) at 0° C. and after 5 minutes, (Z)—N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride (1.0 g, 4.13 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was purified using an 80 g SiO2 column and a 10-100% EtOAc/hexanes gradient. Obtained 900 mg (68% yield) of ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate as a pale yellow solid. This compound matched the 1H NMR found in the J. Fluorine Chem. reference.
Reaction SMILES: O=[C:2]([CH3:22])[CH2:3][N:4]([C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].C[O-].[Na+]>C(O)C>[CH3:22][C:2]1[CH2:3][N:4]([C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13](=[O:21])[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)(C)N(CC(C)=O)C(=O)Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)N1CC(C)=C(c2ccccc2)C1=O
Yield: 23.7 %

Procedure:
325.5 g (1.07 mol) of ethyl 2-[N-(2-oxopropyl)phenylacetylamino]isobutyrate was dissolved in 1.5 l of ethanol, and 77 g (1.28 mol) of 90% sodium methylate powder was added thereto. The mixture was refluxed under heating for 30 minutes. Ethanol was distilled off, and the residue was poured into ice water. Precipitated crystals were collected by filtration. The crystals were thoroughly washed with hexane and dried to obtain 73 g (yield: 24%) of the desired product having a melting point of from 64 to 66° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1>>[CH3:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:19][C:18]=13)=[CH:29][CH:28]=2
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccccc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from phenyl boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.02 (d, 1H), 7.67 (d, 2H), 7.54 (s, 1H), 7.30 (m, 5H), 6.94 (d, 1H), 6.54 (d, 1H), 6.09 (s, 1H), 2.39 (s, 3H); RP18-HPLC RT: 6.21 minutes; API MS 356 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4]([C:7]([O:9]CC)=O)=[N:5][N:6]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4]([C:7](=[O:9])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:5][N:6]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)c1nnc(C)n1-c1ccccc1C
Agent: N
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1c(C)nnc1C(=O)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 10C (1.0 g, 4.1 mmol) in toluene cooled by an ice bath, benzylmagnesium chloride (2M in THF) (3.0 mL, 6.0 mmol) was added dropwise. After one hour, ammonia chloride solution was added to the mixture and extracted with ethyl acetate (50 mL twice). The organic layer was dried with Na2SO4, filtered and concentrated and used without further purification. MS (m/z) 292 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: COc1ccc(CC2CCCN2Cc2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC2CCCN2)cc1OC

Procedure:
Hydrogenate 11.7 g of 1-benzyl-2-(3,4-dimethoxybenzyl)pyrrolidine in ethanol with 6.5 g of palladium/activated charcoal (10% strength)/hydrogen. Free the product from solvent and catalyst, and then distil it under a high vacuum. Purify via the picrate to obtain a yield of 3.2 g (38.5% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24].C(N(CC)CC)C.[C:32]1([S:38]([N:41]=[C:42]=[O:43])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.C(Cl)Cl>[CH3:23][C:22]1[C:15]2[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH2:3][CH2:2][NH:1][C:42]([NH:41][S:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)(=[O:40])=[O:39])=[O:43])[C:5]3=[O:24])=[CH:18][S:17][C:16]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCN)c4ccccc43)c12
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc2scc(Cn3c(=O)n(CCNC(=O)NS(=O)(=O)c4ccccc4)c4ccccc43)c12
Reaction time: 2 h
Yield: 76.4 %

Procedure:
1-(2-Amino-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (28 mg, 0.083 mmol) is added into DCM (1.0 mL) at room temperature and triethylamine (0.014 mL, 0.10 mmol) is added. Then Benzenesulfonyl isocyanate (0.014 mL, 0.10 mmol) is added into the above reaction mixture. After stirring for 2 hr, another 0.014 mL of Benzenesulfonyl isocyanate is added and the mixture is further stirred for 30 min. Then 1.0 mL of 1.0M HCl is added along with 5 mL of water. The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried (Na2SO4) and concentrated to give crude product. Purification by preparative TLC affords 33 mg (76%) of the title compound. LCMS (ESMS): m/z 521.17 (M+H+).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:18][C:2]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1
Reactant: CCC1Oc2ccc(C(=O)C(C)Br)cc2NC1=O
Reactant: Nc1ccccn1
Product: CCC1Oc2ccc(-c3nc4ccccn4c3C)cc2NC1=O
Yield: 47.7 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.07 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.28 g) and 2-aminopyridine (2.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(=O)(O)[O-].[Na+].CCOC(C)=O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 36 h
Yield: 18.5 %

Procedure:
To a solution of 3-(2-methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester (2.1 g, 7.2 mmol) in methanol (50 mL) was added sodium borohydride (1.08 g, 28.8 mmol). After stirring for 36 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried (Na2SO4) and concentrated. To a solution of this material in ethanol (50 mL) was added 10% Pd/C. This reaction was then placed on a Parr hydrogenation apparatus with 60 psi of hydrogen gas. After 72 h, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (370 mg, 19%). MS (ESI): mass calcd. for C16H23NO3, 277.2; m/z found, 222.2 [M-t-Bu]+. 1H NMR (CDCl3): 7.23-7.10 (m, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.92-6.77 (m, 2H), 3.96 (t, J=8.0 Hz, 2H), 3.81 (s, 3H), 3.65-3.63 (m, 2H), 2.94-2.78 (m, 5H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:30])[NH:9][CH:10]([C:23](=[O:29])[NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:11][S:12][CH2:13][C:14]([C:16]([O:18][CH2:19][CH2:20]CC)=[O:17])=O)[C:3]([OH:5])=[O:4].Cl.[NH2:32][OH:33]>>[NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:30])[NH:9][CH:10]([C:23](=[O:29])[NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:11][S:12][CH2:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:32][OH:33])[C:3]([OH:5])=[O:4]
Reactant: NO
Reactant: CCCCOC(=O)C(=O)CSCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O
Agent: Cl
Product: CCOC(=O)C(CSCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)=NO

Procedure:
Similarly, by following the procedure of Example 30A and substituting 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid with 2-amino-4-[2-(2-butoxycarbonyl-2-oxo-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid and hydroxylamine HCl with another substituted hydroxylamine there are obtained the following compounds:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([O:10][C:11]([F:14])([F:13])[F:12])=[C:2]([B:20]([OH:25])[OH:21])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(OC(F)(F)F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)c(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of 2-Bromo-4-methoxy-1-trifluoromethoxy-benzene (Preparation 59, 19.0 g, 73.9 mmol) in anhydrous tetrahydrofuran (400 ml) was added n-butyl lithium (2.5M solution in hexanes, 44.2 ml, 110.9 mmol) while maintaining the temperature below −70° C. under an atmosphere of nitrogen. The resulting solution was stirred at −70° C. for 1 hour. Tri-isopropyl borate (20.9 g, 110.9 mmol) was added and the mixture stirred at −70° C. for an additional 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (400 ml). The resulting mixture was acidified to pH˜5 by addition of hydrochloric acid (1N aqueous solution). The layers were separated and the organic layer was washed with water (200 ml) then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo. Residue was purified by recrystallization from ethyl acetate:petroleum ether (2 ml:50 ml) to afford the title compound as a white solid (7.5 g, 43%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)#[N:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:41]([C:40]3[CH:44]=[CH:45][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)=[O:42])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccc(C#N)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 4-cyano-benzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H36N3O2Cl2 [(M+H)+] 624.2179, observed 624.2177.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[N:29]=[C:28]([NH:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]4)[CH:27]=[N:26][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[NH:21]1[CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:24]4[N:29]=[C:28]([NH:30][C@H:31]5[CH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][CH2:36]5)[CH:27]=[N:26][CH:25]=4)=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)[CH:23]=[N:22]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cncc(N[C@H]3CC[C@H](O)CC3)n2)c2cc(-c3cn[nH]c3)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O[C@H]1CC[C@H](Nc2cncc(-c3c[nH]c4ncc(-c5cn[nH]c5)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of trans-4-({6-[1-(phenylsulfonyl)-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl)amino}cyclohexanol (0.63 g, 0.12 mmol) in MeOH (1.3 mL) was added potassium carbonate (0.051 g, (0.37 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with MeOH (10 mL) and CH2Cl2 (10 mL), silica gel was added and concentrated to a crude residue. The residue was purified by silica gel chromatography (MeOH/CH2Cl2 gradient) to afford trans-4-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl)amino}cyclohexanol as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 12.95 (s, 1H); 11.99 (s, 1H); 8.75 (s, 1H); 8.53 (s, 1H); 8.19 (s, 1H); 8.14 (d, 1H); 7.92 (s, 1H); 7.64 (s, 1H); 6.79 (d, 1H); 4.49 (d, 1H); 3.79 (br s, 1H); 3.43 (br s, 1H); 1.83 (br s, 2H); 1.31 (br s, 2H); 1.26 (q, 4H). LRMS (ESI) calculated for C20H21N7O [M+H]+, 376.2; found 376.1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:20][C:21]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH2:22][CH:23]=[O:24].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][P:4]([C:9]([F:11])([F:10])[CH:23]([OH:24])[CH2:22][C:21]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH3:20])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: COc1ccc(F)cc1C(C)(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of the difluoromethylphosphonic acid diethyl ester (1.35 g) in THF (5.0 mL) cooled in a dry ice/acetone bath was added LDA (5.0 mL, 1.5M in cyclohexane) dropwise over 5.0 minutes. After 10.0 minutes, a solution of 3-methyl-3-(2-methoxy-5-fluorophenyl)butyraldehyde (0.94 g) in THF (5.0 mL) was added dropwise. After an additional 20.0 minutes, acetic acid (1 mL) was added and the mixture was warmed to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated in vacuo. Fractionation of the residue over silica gel (eluent: methylene chloride-ethyl acetate (1:4)) gave the desired [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]phosphonic acid diethyl ester (1.15 g, 40%) as an oil that crystallized on treatment with hexanes.