Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C(OC([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([OH:23])[CH2:19][C:20]([NH2:22])=[O:21])=O)C1C=CC=CC=1>[C].[Pd].C(O)(=O)C>[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([OH:23])[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: NC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCCCC[C@H](O)CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
Into a mixture of 10 ml of 90% aqueous methanol and 0.01 ml of acetic acid was dissolved 350 mg (1.19 mmoles) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanamide. After adding 50 mg of 5% palladium-carbon, the mixture was stirred under a hydrogen stream at room temperature for 3 hours. After removal of the catalyst by filtration, the filtrate was evaporated to dryness, dissolved again in a small volume of water and passed through a column (12 mm inner diameter) containing 30 ml of Dowex® 50W-X4 (H-type). The column was washed with 90 ml of water and eluted with 0.5M aqueous ammonia (3 ml in fraction size). The fraction Nos. 28 to 34 were combined and evaporated to dryness to yield 201 mg (96% yield) of (S)-7-amino-3-hydroxyheptanamide; [α]D22 -2° (c 2, water).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][CH:14]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19][C:20]([OH:22])=[O:21])=[CH:27][CH:28]=1
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CC(=O)O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
TFA (15 mL) was added dropwise to a solution of 4-tert-butyl 1-methyl 2-(4-chlorobenzyl)succinate (1.91 g, 6.1 mmol) in DCM (30 mL) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 5 hours. The reaction was then concentrated to dryness to give 3-(4-chlorobenzyl)-4-methoxy-4-oxobutanoic acid as a syrup (1.55 g, 95%), which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][C:35]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)ccc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c8) the title compound is obtained as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Br[CH:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:6][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([OH:19])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: NC(=S)c1cccc(Cl)c1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccc(Cl)c2)nc1O
Temperature: 60 °C
Yield: 72.6 %

Procedure:
340 mg of 3-chlorothiobenzamide was dissolved in 10 ml of ethanol, 570 mg of diethyl bromomalonate was added to the solution, and the mixture was heated at 60° C. for 2 hours. After the reaction mixture was cooled, and the resulting crystal was collected by filtration and recrystallized from ethanol to give 408 mg of ethyl 2-(3-chlorophenyl)-4-hydroxy-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process to give 306 mg of 2-(3-chlorophenyl)-4-hydroxy-5-thiazolecarboxylic acid (yield: 60%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].N1C=CC=CC=1.[C:15]1([NH:21][OH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>C(Cl)Cl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([N:21]([OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: ONc1ccccc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Under an argon atmosphere a stirred solution of 10.0 grams (0.065 mole) of 3-chloro-2,2-dimethylpropionyl chloride (prepared in the manner of Example 1, Step B) in 70 ml of methylene chloride was cooled to -70° and 6.1 grams (0.075 mole) of pyridine was added dropwise. A solution of 7.0 grams (0.065 mole) of N-phenylhydroxylamine in 30 ml of methylene chloride was then added dropwise over a 20-minute period. During the addition the reaction mixture temperature rose to -55°. Upon completion of addition the reaction mixture was stirred at -70° to -55° for 30 minutes, then was allowed to warm to ambient temperature where it was stirred for two hours. The reaction mixture was diluted with 100 ml of methylene chloride and washed with 100 ml of water, 100 ml of an aqueous 10% hydrochloric acid solution, and finally with 100 ml of water. The organic layer was dried by standing over magnesium sulfate for 16 hours. The darkened mixture was filtered and the filtrate concentrated under reduced pressure to give a black residue. The residue was slurried with 15 ml of hexane and the insolubles collected by filtration. The insoluble material was recrystallized from hexane/ethyl acetate to give 3.7 grams of 3-chloro-N-hydroxy-N-phenyl-2,2-dimethylpropanamide; mp 120°-121°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+].C(O)C>[Cl-].[Na+].O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[N:20]/[OH:19])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)cc(OCc2ccccc2)c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(/C=N/O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 3-(benzyloxy)-5-methylbenzaldehyde (948 mg), hydroxyl ammonium chloride (320 mg), sodium bicarbonate (837 mg), and ethanol (10 mL) was stirred overnight at room temperature. To the reaction mixture, water and brine were added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (804 mg).
Reaction SMILES: Br.[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH2:24]([Cl:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C(O)(C)(C)C>[ClH:31].[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4]
Reactant: ClCc1ccccc1
Reactant: CCCN1CCCC(c2cccc(O)c2)C1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCN1CCCC(c2cccc(OCc3ccccc3)c2)C1
Product: Cl
Yield: 52.6 %

Procedure:
A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (1.0 g. 0.0033 mol), potassium t-butoxide (1.0 g, 0.009 mol) and benzylchloride (1.0 g, 0.009 mol) in t-butanol (25 ml) was refluxed for 1 h. Water was added and the mixture extracted with ether. The organic phase was dried with Na2SO4 and evaporated to dryness giving a pale yellow oily residue. The residue was chromatographed through a silica gel column with methanol as eluant. The pertinent fractions were collected and evaporated to dryness. The oily residue was dissolved in ether and HCl-saturated ether was added, giving white crystals. Evaporation and treatment of the residue with acetone gave 0.60 g (52%) of the desired product as white crystals, mp. 171° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=482.1, tR (minutes, Method G)=2.76
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[C:9](=O)[CH2:8][N:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.CCN(C(C)C)C(C)C.Cl[CH2:45][C:46]1[N:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)[O:48][N:47]=1>O1CCOCC1.C(OCC)(=O)C>[Cl:57][C:53]1[CH:52]=[C:51]([C:49]2[O:48][N:47]=[C:46]([CH2:45][S:22][C:9]3[N:10]([CH3:11])[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:7][CH:8]=3)[N:50]=2)[CH:56]=[CH:55][CH:54]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: CN1C(=O)CN=C1c1ccco1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1c(SCc2noc(-c3cccc(Cl)c3)n2)cnc1-c1ccco1
Yield: 11.6 %

Procedure:
2-Furan-2-yl-3-methyl-3,5-dihydro-imidazol-4-one (described in Takeuchi, H., Hagiwara, S., Eguchi, S., Tetrahedron (1989) 6375-6386) (50 mg, 0.30 mmol) was dissolved in dioxane (3 ml) and Lawesson reagent (136 mg, 0.34 mmol) was added. The reaction mixture was heated to reflux over night and then allowed to room temperature at which time DIPEA (212 ml, 1.22 mmol) and 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (140 mg, 0.61 mmol) was added. The resulting mixture was heated to reflux for 5 h and then kept at room temperature over night. Ethyl acetate was added and the reaction mixture was washed with water followed by brine. The organic phase was dried over MgSO4 and evaporated. The title compound (13 mg, 11%) was obtained by flash chromatography using 1% methanol in chloroform. 1H NMR (CD3OD) d (ppm): 7.96 (m, 1 H), 7.90 (m, 1H), 7.60 (dd, 1H), 7.57 (ddd, 1H), 7.46 (t, 1H), 7.09 (s, 1H), 6.86 (dd, 1H), 6.52 (dd, 1H), 3.95 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]=[C:11]([O:15][CH3:16])[NH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[NH3:18]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:17])[N:10]=[C:11]([O:15][CH3:16])[NH:12][C:13]2=[O:14])=[CH:6][CH:7]=1.[NH4+:18]
Reactant: N
Agent: COc1nc(=O)n(-c2ccc(Cl)cc2)c(=O)[nH]1
Solvent: CO
Product: [NH4+]
Reaction time: 0.5 h

Procedure:
To a mixture of 10 parts of 3-(p-chlorophenyl)-6-methoxy-s-triazine-2,4(1H,3H)-dione and 100 parts of methanol is added 1 part of ammonia gas at 20°C. The solution is stirred for 30 minutes and then evaporated under vacuum to give 10.6 parts of ammonium 3-(p-chlorophenyl)-6-methoxy-s-triazine-2,4(1H,3H)-dione.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[S:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][N:28]([S:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:41])=[O:40])[CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Reactant: COC(=O)CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nc(C(C)C)no5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (Compound 43E, 95 mg, 0.223 mmol) and triethylamine (0.08 mL, 0.56 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 3-(chlorosulfonyl)propanoate (62.5 mg, 0.335 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 60% EtOAc) to afford methyl 3-(4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propanoate (75 mg, 0.13 mmol, 58% yield) as an off white solid. LCMS (m/z)=576 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:14][CH2:13][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: N#Cc1c(Cl)cccc1-n1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1c(Cl)cccc1-n1cccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A solution of 1-(3′chloro-2′-cyanophenyl)pyrrole (10 g) in diethyl ether solution was added dropwise to a solution of 1M lithium aluminium hydride in ether solution (100 ml) under nitrogen gas. After addition was complete, the reaction mixture was refluxed for 2 h. and then allowed to stir at room temperature overnight (18 h). The mixture was subsequently quenched with water (4 ml), 2N NaOH (8 ml) and water (16 ml). Stirring was continued for a further 1 h after addition. The crystalline salts were filtered and the filtrate dried over anhydrous magnesium sulphate. After filtering, the ether fitrate was evaporated in vacuo to give the title compound (9.4 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:8]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC=O
Reactant: Nc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture was poured into 300 mL of 0.67M NaOH(aq.), and extracted with ethyl acetate (3×50 mL). The combined organic layers were back extracted with brine (1×50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting with 3:1 ethyl acetate: hexanes to give 1.18 g (79%) of a colorless solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33](Cl)[C:34](OCC)=[O:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:40])(=[O:3])[CH3:2].[NH2:41][C:42](N)=[S:43].S1(CCCC1)(=O)=[O:46]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]3[S:43][C:42](=[O:46])[NH:41][C:34]3=[O:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:40])(=[O:3])[CH3:2]
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3cc(OC(C)=O)c(C(C)(C)CC(C)(C)C)cc3O2)cc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)CC2=O

Procedure:
The procedure described in Example 2 was repeated, but using 7.3 g of ethyl 3-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy]phenyl}-2-chloropropionate (prepared as described in Preparation 25), 1.3 g of thiourea and 8 ml of sulfolane, to give the title compound as a slightly yellow powder, softening at 80° -88° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13].CC(C)=O>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:12][NH:13]2
Reactant: NN
Reactant: N#Cc1c(F)cccc1F
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1n[nH]c2cccc(F)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 140.3 %

Procedure:
To a solution of 2,6-difluorobenzonitrile (3 g, 21.6 mmol) in anhydrous ethanol (50 mL) was added hydrazine hydrate (4.18 mL, 86 mmol). The reaction was heated at 90° C. under nitrogen for 4 hours. Reaction mixture was cooled to room temperature, treated with acetone (20 mL) and left to stand for 18 hours. The mixture was evaporated in-vacuo to yield an orange/brown solid which was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid (4.58 g), which was absorbed onto Florisil (60-100 mesh), applied to a 100 g silica SPE cartridge and purified on a Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 48-57 were combined and the solvent was evaporated in-vacuo to yield the title compound as a brown solid (3.08 g, 94%). LCMS (System B) RT=1.38 min, ES+ve m/z 152 (M+H)+.
Reaction SMILES: C[C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH2:13](N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22].O>O1CCCC1>[C:20]([O:12][CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][C:9]1([CH3:13])[CH2:10]3)[CH2:11]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CCN(CC)CC
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)OC1C2CC3CC(C2)CC1(C)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
In 300 ml of tetrahydrofuran, 30 g of 2-methyl-2-adamantanol, 36 g of triethylamine and 4 g of N,N-dimethylaminopyridine were dissolved, and to the solution was dropwise added 29 g of methacrylic chloride under cooling with ice over a period of 30 minutes. The temperature of the solution was raised to room temperature and reacted as it was overnight. To the reaction solution was added 500 ml of distilled water under cooling with ice and then extracted with ethyl acetate. The organic layer was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 17 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[N:23]=[C:24]([CH3:30])[N:25](C(C)(C)C)[C:4]=2[C:3]=1[CH3:31].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[N:23]=[C:24]([CH3:30])[NH:25][C:4]=2[C:3]=1[CH3:31]
Reactant: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(C(C)(C)C)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c2[nH]1

Procedure:
The material from Example 32 was diluted with toluene then combined with phosphorous oxychloride and heated at reflux overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with water, basified with ammonium hydroxide then extracted several times with methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 10-40% ethyl acetate in hexane to provide the desired product.
Reaction SMILES: [O:1]=[C:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[O:1]=[C:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][C:5]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17])=[O:7]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)N1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CCCN1C(=O)CCC(=O)N1CCC[C@H]1CO
Reaction time: 3 h

Procedure:
A solution of 4-oxo-4-(2-oxo-1-pyrrolidinyl)butyric acid (5.02 g), L-prolinol (2.74 g) and HOBt (3.72 g) in DMF (50 ml) was cooled to -25° C. and DCC (5.64 g) was added thereto. After 3 hours' stirring at a temperature of -25°-0° C., the mixture was stirred at room temperature for 15 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was dissolved in chloroform and washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in sequence. The organic layer was dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 3.41 g of N-[(4-oxo-4-(2-oxo-1-pyrrolidinyl)butanoyl]-L-prolinol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]2[CH2:37][O:36][B:35]([OH:38])[C:34]=2[CH:39]=1.ClC1C=C(C2(C(F)(F)F)ON=C(C3C=CC(C(NC4C=CC5COB(O)C=5C=4)=O)=C(C)C=3)C2)C=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]5[CH2:37][O:36][B:35]([OH:38])[C:34]=5[CH:39]=4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCc1ccc2c(c1)B(O)OC2
Agent: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc2c(c1)B(O)OC2
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2

Procedure:
The title compound was prepared from 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid and 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol by the same method as described for 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-methylbenzamide. It was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1 H), 8.94 (m, 1 H), 7.37-7.82 (m, 9 H), 4.95 (s, 2 H), 4.49 (m, 2 H), 4.34 (m, 2 H), 2.37 (s, 3 H) ppm; MS: m/z=563 (M+1, ESI+).