Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.CC(O)=O.Br>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:16]=2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 90 °C
Yield: 75.6 %

Procedure:
To a mixture of (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 2.60 mmol, Preparation K, Step A) and AcOH (7.44 mL, 130 mmol) was added HBr (4.76 mL, 33 wt % in acetic acid, 26 mmol) at ambient temperature. The reaction mixture was heated at 90° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc, washed with water, saturated NaHCO3, and brine, dried with MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 2-3% MeOH/DCM to yield the title product (0.73 g, 76%). MS (apci) m/z=372.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:29][CH2:30][CH2:31][S:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)=[O:11])[CH2:29][CH2:30][CH2:31][S:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1ccc(SCCCBr)cc1
Reactant: Cc1ccc(C(=O)Cc2cc(F)cc(F)c2)cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SCCCC(C(=O)c2ccc(C)c(C)c2)c2cc(F)cc(F)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A sample of 2-(3,5-difluorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1450736-61-4] (5.0 g, 19.2 mmole) was dissolved in THF and cooled to −78° C. Lithium diisopropyl amide (10.6 mL, 1.1 eq.) was added dropwise and the resulting mixture was stirred for 30 minutes. A solution of methyl 4-[(3-bromopropyl)thio]benzoate [CAS 134520-57-3] (6.1 g, 1.1 eq) in THF was then added dropwise and the reaction mixture was allowed to stir overnight. It was then refluxed at 90° C. overnight. The reaction mixture was cooled to room temperature, then to 0° C. after which it was quenched with 1M HCl to pH 2. The resulting mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with saturated NaCl, dried with MgSO4, filtered, concentrated and purified by MPLC to give 4.28 g (48%) of Intermediate
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=1)=[O:18]>>[CH:26]([C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:31]=[C:30]([CH3:32])[CH:29]=2)[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: Cc1cc(Br)cc(C(=O)Nc2cccc(C(C)C)c2)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C)cc(C(=O)Nc3cccc(C(C)C)c3)c1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 3-bromo-N-(3-isopropylphenyl)-5-methylbenzamide were converted to the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[OH:20])(=[O:9])=[O:8].[H][H]>[Pd]>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:20])(=[O:9])=[O:8]
Reactant: [H][H]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 91.4 %

Procedure:
N-(3- methylthiopropyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (300 mg, 0.88 mmol) was reduced with hydrogen and 10% Pd/C (150 mg) to form the desired product (250 mg, 91%). 1H NMR (MeOD-d4): δ 6.84 (d, 1H), 6.77 (d, 1H), 2.93 (t, 2H), 2.40 (t, 2H), 1.89 (s, 3H), 1.63 (m, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cc1cccnc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromo-3-methylpyridine
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[O:23]1[CH2:26][C:25](=O)[CH2:24]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[CH:25]1[CH2:26][O:23][CH2:24]1)=[O:7])#[N:3]
Reactant: O=C1COC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C1COC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was reductively aminated with oxetane-3-one (prepared according to G. Wuitschik et al., Angewandte Chemie, International Edition (2006), 45(46), 7736) in analogy to experiment L3 to give to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-oxetan-3-yl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless foam. MS: 384.1 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 120 °C
Yield: 46.7 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.667 mmol) and tert-butyl (4-aminophenyl)carbamate (0.278 g, 1.344 mmol) in DMF (2 ml) was heated in a microwave reactor at 120° C. for 30 mins. EtOAc was added, and the mixture was washed with brine and evaporated. The residue was triturated in MeOH, the solvent was decanted and the residue was purified by silica gel column chromatography using 15-65% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.147 g, 47%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 9.18 (s, 1H), 9.16 (s, 1H), 7.22 (dt, 1H), 7.18 (dt, 2H), 7.08-7.00 (m, 4H), 6.64 (d, 2H), 1.65 (s, 9H), 1.44 (s, 9H); 13C NMR (d6-DMSO): δ 160.3, 153.0, 136.8, 132.3, 131.9, 129.6, 129.3, 128.6, 125.9, 123.2, 117.9, 109.2, 79.8, 61.4, 28.8, 27.9; Mass Spectrum: M−H+ 470.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17])C.[OH-].[Na+].Cl>C(O)C>[CH3:16][C:8]1[N:9]=[C:4]([CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]2[CH2:24][C@@H:23]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:20]2)=[O:17])[O:3][N:7]=1
Reactant: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1noc(CCn2c(C(=O)N(CC(C)C)[C@H]3C[C@@H](C(=O)N4CCOCC4)CN(C(=O)OC(C)(C)C)C3)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 144.6 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (260 mg) in ethanol (5 ml) was added 2M aqueous sodium hydroxide solution (1.06 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue, N-hydroxy acetamidine (47 mg), 1H-benzotriazol-1-ol (79 mg) and N,N-diisopropylethylamine (217 μl) were dissolved in DMF (5 ml), WSC.HCl (121 mg) was added and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in toluene (15 ml), and the mixture was refluxed under heating for 15 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give the object product (191 mg).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:26][NH2:27])=[O:25].O>CN1CCCC1=O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:26][N:27]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[OH:1])=[O:25]
Reactant: NNC(=O)c1ccccn1
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(C(=NNC(=O)c2ccccn2)c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
47.0 g of 2-hydroxy-4-methoxybenzophenone and 27.7 g of picolinic acid hydrazide are stirred in 150 ml of N-methylpyrrolidone for 18 hours at 140° C. After the reaction mixture has cooled to room temperature, the brownish yellow solution is treated with 200 ml of water. The precipitate produced is isolated by filtration and washed with isopropanol and then with water. After the product has been dried under vacuum at 50°-60° C., 57.4 g of 2-hydroxy-4-methoxybenzophenone picolinoylhydrazone are obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[C:22]#[CH:23]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]23[CH2:17][CH:16]([CH2:18]2)[C:15](=[O:19])[N:14]([CH2:23][C:22]#[CH:21])[C:13]3=[O:20])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: C#CCBr
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 0.97 ml of propargyl bromide dissolved in 10 ml of N,N-dimethylformamide is then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the product is obtained having a melting point of 166°-168°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.[H-].[Na+].Cl>C1COCC1>[Cl:11][C:12]1[N:13]=[C:14]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[CH:15]=[N:16][CH:17]=1
Reactant: N#Cc1cccc(CO)c1
Reactant: Clc1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2cncc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxymethyl-benzonitrile (2.0 g, 15.0 mmol) and 2,6-dichloro-pyrazine (2.24 g, 15.0 mmol) in THF (150 mL) was added 60% NaH in mineral oil (0.9 g, 22.5 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was poured into 1N HCl (100 mL) and extracted with Ethyl Acetate (1×250 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness. The crude material was chromatographed over Silica Gel (40 g) eluting with hexanes (1000 mL) followed by ethyl acetate (500 mL) to obtain 3.53 g of the desired pure product (I-3a) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:25]3[NH:19][C:20](=[O:21])[NH:22][C:23]3=[O:24])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 24.43 g (100 moles) of 3-phenylmethoxy-4-methoxybenzaldehyde (Berichte 67, 1214/1934/), 10.01 g. (100 mmoles) of hydantoin, 38 ml of anhydrous acetic acid and 19.5 g of anhydrous sodium acetate is heated to 140° C. with shaking and the solution obtained is refluxed at 158°-162° C. for 2.5 hours, then cooled and poured into 250 ml of ice-water. The gum obtained becomes crystalline after 30 minutes. The crystals are filtered, washed successively with water, ethanol and ether and dried to give 14.75 g (45.5%) of the title compound, m.p. 249°-251° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>ClCCl.CN(C)C1C=CN=CC=1>[Si:15]([O:12][CH:3]([C:2]([F:1])([F:13])[F:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(CCc1ccccn1)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CCc1ccccn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h
Yield: 89.3 %

Procedure:
A solution of 700 mg (3.4 mmol) of 1,1,1-trifluoro-4-pyridin-2-ylbutan-2-ol in 10 mL of dichloromethane was treated with 616 mg (4.1 mmol, 1.2 eq.) of tert-butyldimethylsilyl chloride, 697 mg (10.2 mmol, 3.0 eq.) of imidazole and 415 ng (3.4 mmol) of 4-dimethylaminopyridine at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 36 hours. Then the mixture was concentrated and the residue was purified by flash chromatography to give 970 mg (89%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=O)[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([Cl:22])=[O:18])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccncc3)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2[nH]c(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-pyridyl)-1H-benzimidazole-4-carboxylic acid (155 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.056 ml) and N,N-dimethylformamide (2 drops) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride. To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (76.8 mg) and triethylamine (65 mg) in dichloromethane (5 mL) was added 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride in dichloromethane (2 ml) under ice bath cooling and stirred at ambient temperature for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49). To the purified product was added water and 1N hydrochloric acid (0.51 ml). The solution was lyophilized to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1OC)c1ccccc1
Yield: 63.9 %

Procedure:
A mixture of 0.50 g (2.65 mmol) of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde, 0.668 g (2.92 mmol) of methyl 2-bromophenylacetate and K2CO3 (0.73 g, 5.3 mmol) in acetone (8 mL) was refluxed for 14 h. The mixture was cooled, filtered and evaporated in vacuo, and the residue was purified by flash chromatography on a silica gel column using 5% ethylacetate in hexane to afford 0.570 g (64%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:41])[CH2:10][N:11]2[C:15]3=[N:16][C:17]([C:25]4[S:26][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[S:38]([CH3:40])=O)=[CH:28][N:29]=4)=[C:18]([O:21]C(=O)C)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12]2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9](=[O:41])[CH2:10][N:11]2[C:15]3=[N:16][C:17]([C:25]4[S:26][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[S:38][CH3:40])=[CH:28][N:29]=4)=[C:18]([OH:21])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12]2)[CH2:5]1
Reactant: CC(=O)Oc1c(-c2ncc(Cc3ccc(F)cc3S(C)=O)s2)nc2n(CC(=O)N3CC(C)OC(C)C3)ccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CSc1cc(F)ccc1Cc1cnc(-c2nc3n(CC(=O)N4CC(C)OC(C)C4)ccn3c(=O)c2O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of the product of example 171 (38 mg, 0.06 mmol) in MeOH (5 ml) was added K2CO3 (20 mg, 0.14 mmol) and then the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with dichloromethane. The organic layers were dried and concentrated. The resulting solids were collected and washed with cold MeOH (2-3 ml) to give the title compound (15 mg, yield 42%).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:54]([NH:58]C2C=CC(OC)=CC=2)[CH:55]([F:57])[F:56])=[C:33]([CH:53]=1)[CH2:34][NH:35][C:36](=[O:52])[C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:51])[C@@H:43]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[OH:44]>O.CC#N>[CH:45]1([C@@H:43]([OH:44])[C:42]([N:38]2[CH2:39][CH2:40][CH2:41][C@H:37]2[C:36]([NH:35][CH2:34][C:33]2[CH:53]=[C:29]([Cl:28])[CH:30]=[CH:31][C:32]=2[CH:54]([NH2:58])[CH:55]([F:57])[F:56])=[O:52])=[O:51])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)C2CCCCC2)C(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: NC(c1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1)C(F)F
Temperature: 25 °C

Procedure:
A solution of CAN (0.0647 g, 0.12 mmol) in water (0.4 mL) was added to a stirred solution of N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (0.0332 g, 0.06 mmol) in CH3CN (1.5 mL) at 0° C. and the solution was warmed to ambient temperature. After 4 h the solution was partitioned between EtOAc and 10% aqueous NH4OH. The resulting two phase suspension was filtered and the EtOAc layer was washed with 10% sodium sulfite solution and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica (eluting with 1-10% of 10% ammonium hydroxide in methanol/chloroform gradient) to give the title compound as a gum: LC-MS m/z=458.4.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 105 °C

Procedure:
A mixture of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (97 mg, 0.25 mmol) and acetic anhydride (0.24 mL, 2.5 mmol) was heated in a 105° C. oil bath for 8 h. The solvent was evaporated and the solid that formed was recrystallized from EtOAc/hexanes, and dried under vacuum to give the title compound. MS (ESI, pos. ion) m/z: 431 (M+1). Mp: 219.0–220.5° C. Anal. Calcd for C20H13F3N4O2S0.75 H2O: C, 54.11; H, 3.29; N, 12.62; S, 7.22. Found: C, 54.12; H, 3.07; N, 12.61; S, 7.30.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][C:13](=[O:15])[O:12][N:11]=1)=[O:3].O[CH2:17][CH2:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22].N1C=CC=CC=1>O1CCOCC1>[C:20]([O:19][CH2:18][CH2:17][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][C:13](=[O:15])[O:12][N:11]=1)=[O:3])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: O=C(Cl)OCCCCCc1noc(=O)o1
Reactant: C=C(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCC(=O)OCCCCCc1noc(=O)o1
Yield: 95.7 %

Procedure:
In accordance with the procedure of Example 1, 35.34g (0.15 moles) 5-(chloroformyloxypentyl)-1,3,4-dioxazol-2-one is reacted with 21.47g (0.165 moles) hydroxyethylmethacrylate in 75 ml 1,4-dioxane by adding 11.86g (0.15 moles) pyridine in 65 ml 1,4-dioxane over a 1 hour period at 19-21° C. After work-up, 47.30g of a slightly brown liquid is obtained which is analyzed by IR and NMR spectroscopy to be 5-[(methacryloyloxyethyl) formyloxypentyl]-1,3,4-dioxazol-2-one (yield 95.7%), having the following formula: ##STR16##