Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Br:20][C:21]1[C:22](Cl)=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][CH:10]([O:12][C:22]2[C:21]([Br:20])=[CH:26][N:25]=[C:24]([Cl:27])[N:23]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)ncc2Br)C1
Yield: 94.7 %

Procedure:
To a solution of (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester (2.5 g, 13.3 mmol) in THF (40 mL) were added Cs2CO3 (8.6 g, 26.6 mmol) and 5-bromo-2,4-dichloro-pyrimidine (3 g, 13.3 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was filtered and concentrated, diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel to give the product (4.75 g, 12.6 mmol, yield: 95%). ESI-MS (M+1): 378 calc. for C13H17BrClN3O3 377.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4].[C:21]([C:25]1[C:29]([CH:30]=[O:31])=[CH:28][NH:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]([C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[S:10][C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[C:7]=2[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4])[N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Reactant: CC(C)(C)c1n[nH]cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)cc1C=O
Temperature: 70 °C
Yield: 82.4 %

Procedure:
2-(2-Bromoacetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.66 g, 4.60 mmol), 3-tert-butyl-1H-pyrazole-4-carbaldehyde (1.75 g, 11.49 mmol) and potassium carbonate (2.54 g, 18.38 mmol) were mixed with DMF (20 mL) and heated at 70° C. for 2 h. On cooling, the reaction was partitioned between EtOAc and water. The organics were washed with brine, dried over MgSO4 and concentrated directly onto silica for chromatographic purification (0-100% EtOAc/heptane). Concentration in vacuo yielded a white solid (1.64 g, 3.79 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]([C:9]1[CH:24]=[CH:23][C:12]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:11]=2[CH:10]=1)=O)([CH3:5])[CH2:3][OH:4].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:5])[CH2:3][O:4][C:7]([C:9]2[CH:24]=[CH:23][C:12]3[O:13][CH2:14][C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[C:17](=[O:18])[C:11]=3[CH:10]=2)=[N:6]1
Reactant: CC(C)(CO)NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc3c(c2)C(=O)c2ccccc2CO3)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
In this process, 8.0 g of N-(1,1-dimethyl-2-hydroxyethyl)-11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxamide is suspended in 100 ml of methylene chloride. To the suspension is added 3.6 g of thionyl chloride under a nitrogen atmosphere and ice-cooling and the mixture is stirred at room temperature for one hour. To the mixture is added 300 ml of methylene chloride, and the mixture is washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=2:1 ). The resultant crude product is recrystallized from hexane to obtain 6.3 g of the desired product as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([O:21]CC)=[O:20].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1c1ccc(OC)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@@H]2CCCC[C@H]2C(=O)O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
To a stirred solution of 1.22 g (3.8 mmol) of trans-ethyl 2-(2,3,4-trimethoxyphenyl)cyclohexane-1-carboxylate in 20 mL of THF and 10 mL of methanol was added 10 mL of 10% aqueous NaOH. The mixture was stirred at room temperature for 18 h and heated at reflux for 18 h. After cooling, the bulk of the organic solvents was removed in vacuo and the residue was diluted with 100 mL of 5% aqueous NaOH and washed with 100 mL of ether. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted with two 100 mL portions of ether. These ether extracts were combined, dried over MgSO4 and the solvent removed in vacuo to leave 0.88 g of trans-2-(2,3,4-trimethoxyphenyl)cyclohexane-1-carboxylic acid as an oil. 1H NMR (CDCl3) -- 1.3-2.2 (m, 8H), 2.65 (m, 1H), 3.1 (m, 1H), 3.8 (s, 9H), 6.6 (d, 1H), 6.8 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]2=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]2=[N:17][OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C1CCC(=O)C(c2cccc(Br)c2)N1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(c2cccc(Br)c2)N1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-piperidine-2,5-dione (38.2 g) and hydroxylamine hydrochloride (19.8 g) in pyridine (300 ml) was stirred at room temperature under nitrogen. After 4 h the mixture was evaporated in vacuo. The crude mixture was partitioned between chloroform (200 ml) and water (200 ml) then was basified by the addition of 8% sodium bicarbonate solution (~300 ml). The mixture was extracted with chloroform (300 ml×2). The combined organic extracts were washed with saturated brine and evaporated in vacuo. Trituration with ether gave the title compound as a pale yellow solid (34.9 g). T.l.c. (Ethyl acetate) Rf 0.44, 0.28, E/Z mixture.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][CH2:11][CH2:12]O)[CH:4]=1>O>[CH3:1][NH:2][CH2:12][CH2:11][C:10]#[C:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: OCCC#Cc1cccnc1
Solvent: O
Product: CNCCC#Cc1cccnc1
Reaction time: 3 h
Yield: 546.1 %

Procedure:
An aqueous methylamine solution (5 mL, 40%, 58.7 mmole) was mixed with XII (200 mg, 0.08 mmole) and stirred for 3 hr. in a sealed tube at 45° C. After the reaction was complete, water (10 mL) was added to the cooled reaction mixture, and the reaction mixture was extracted with chloroform (10×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on a silica gel column using methanol:chloroform (1:9) and then with a chloroform: methanol mixture containing 1% triethylamine as eluent. About 70 mg of XIII was obtained as a slightly yellow syrup, which was distilled at 110°-112° C., 0.04 mm Hg. XIII was converted to its mono fumarate salt form, which exhibits a melting point of 103°-104° C.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:49](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:49])[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1
Reaction time: 2.5 h

Procedure:
Analogously to Example 40g, 40 ml of 4M HCl in dioxane are added to 1.9 g (3 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 3 ml of DMF. After 2.5 hours, the mixture is worked up. The title compound is obtained: TLC: Rf=0.55 (methylene chloride/methanol: 9/1); HPLC20-100: tRet=8.74; FAB MS (M+H)+=534.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[NH:10][C:9]=3[C:8](=S)[NH:7][C:6]2=[O:18])[CH2:3][CH2:2]1>C(N)CC>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[NH:10][C:9]=3[C:8]([NH:5][CH2:4][CH2:1][CH3:2])=[N:7][C:6]2=[O:18])[CH2:3][CH2:2]1
Reactant: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2CC1CC1
Solvent: CCCN
Product: CCCNc1nc(=O)n(CC2CC2)c2nc(C(C)C)[nH]c12
Reaction time: 10 h

Procedure:
5.29 g of 3-cyclopropylmethyl-8-isopropyl-6-thioxanthine and 50 ml of propylamine were heated in a 450 ml reactor to 150° C. After 10 hours, the solution was evaporated to dryness, the residue dissolved in 200 ml of methanol, treated with 0.26 g of charcoal, filtered and concentrated. The crystals were collected, washed and dried to give the title compound (4.81 c) as off-white crystals mp 208-10° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=4)=[O:35])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methylphenyl isocyanate (74 mg, 0.56 mmoles), the title compound was isolated as a white solid. Yield; 65 mg (33%) (M+H)=476.4
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[CH3:14][NH:15][CH3:16]>C1(C)C=CC=CC=1.C(OCC)C.C1COCC1>[CH3:14][N:15](/[CH:12]=[C:9]1\[C:10](=[O:11])[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH2:7][CH2:8]\1)[CH3:16]
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1nc2c(s1)C(=O)/C(=C\N(C)C)CC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 87.9 %

Procedure:
To a stirred solution of 2-methyl-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carbaldehyde (5 g, 25.6 mmol) in toluene (50 mL) and diethylether (25 mL) was added dimethylamine (15 mL, 35 mmol) as a solution in THF. The reaction was stirred for at room temperature for 40 hours. The reaction was then concentrated under reduced pressure to give a brown residue, which was triturated with hexane to give the desired product (5.0 g, 87%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.35 (s, 1H), 3.10 (s, 6H), 2.98 (t, J=6.2 Hz, 2H), 2.82 (t, J=6.2 Hz, 2H), 2.65 (s, 3H); LCMS [M+H]: 223.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:12][S-:13].[Na+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5]
Reactant: C[S-]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
[step 1] Commercially available 3-chloro-2-nitroaniline (3.0 g, 17 mmol) was dissolved in DMF (87 mL), sodium thiomethoxide (1.54 g, 21 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with water, and the mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give 3-(methylthio)-2-nitroaniline (2.5 g, 78%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: O=Cc1ccccc1F
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1cccs1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of thiophene-2-thiol (1.5 mL), potassium carbonate (8.0 g) and N,N-dimethylformamide was treated dropwise with 2-fluorobenzaldehyde (1.7 mL), and the resulting mixture was stirred at room temperature for 42 hours. The mixture was treated with ice/water, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 9:1 by volume), followed by distillation at 50° C./11 mbar to afford the title compound as a red oil (1.9 g).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[C:1]([O:6][CH2:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCCCCCCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCCCCCCCCCCC
Reaction time: 6 h

Procedure:
Two hundred six grams of a reaction mix containing a 5:1 mole ratio of methyl methacrylate, 1-dodecanol, and 100 ppm phenothiazine as inhibitor were added to a 500 ml flask equipped with an agitatior, thermocouple, and a 10-tray Oldershaw fractional distillation column. Thirty grams of the heterogeneous zirconium vinylbenzyl acetylacetonate/styrene/divinylbenzene catalyst was added. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of methyl methacrylate and methanol was removed from the upper portion of the fractionating column. The reaction was continued in this manner for 6 hours while the temperature at the column was 64°-67° C. and the temperature in the pot was 101°-107° C. Gas liquid chromatography (GLC) analysis showed 30% conversion of 1-dodecanol with a selectivity to dodecyl methacrylate of 95%.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:7]=[CH:6][C:5]([O:14][CH3:15])=[C:4]2[C:9]=1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3]2
Reactant: COc1ccc(OC)c2c1CCC(O)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(OC)c2c1CCC(=O)C2
Temperature: 25 °C
Reaction time: 7 h
Yield: 38.4 %

Procedure:
The tetrahydronaphthalene (2.1 g; 10.1 mmol) was dissolved in 20 ml of methylene chloride. The resulting solution was added to a solution of 3.27 g (15.2 mmol) of pyridinium chlorochromate in 60 ml of methylene chloride. The mixture was stirred for seven hours at room temperature and then was filtered through a bed of Celite. The filtrate was evaporated in vacuo to a dark, viscous residue. The residue was dissolved in methylene chloride and placed on a flash silica column. The column was eluted with methylene chloride, and the eluate was evaporated in vacuo to give 0.8 g (38.4%) of 5,8-dimethoxy-2-tetralone as a gold, crystalline solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[CH:60]=[O:61])[CH2:53][CH2:52]1>CN(C=O)C.O>[CH:60]([C:59]1[CH:62]=[CH:63][CH:64]=[CH:65][C:58]=1[O:57][CH:54]1[CH2:55][CH2:56][N:51]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:52][CH2:53]1)=[O:61]
Reactant: O=Cc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 43.4 %

Procedure:
DIPEA (360 mg, 2.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (190 mg, 0.8 mmol) in DMF (2.0 mL) followed by HOBt (160 mg, 1.2 mmol) and EDCI.HCl (230 mg, 1.2 mmol). After 2 minutes of stirring, 2-(piperidin-4-yloxy)-benzaldehyde hydrochloride (200 mg, 0.8 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 150 mg (44% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 433.18, 98.8%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 10.3 (s, 1H), 8.2 (m, 1H), 7.8 (m, 2H), 7.7 (m, 2H), 7.5 (m, 2H), 7.4 (m, 2H), 7.1 (m, 2H), 5.0 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(Br)cc1

Procedure:
To a solution of 1-(4-bromophenyl)ethanone (2.0 g, 10 mmol) and (S)-2-methylpropane-2-sulfinamide (1.2 g, 10 mmol) in THF (20 mL) was added Ti(OiPr)4 (5 mL). The reaction mixture was refluxed overnight. The mixture was quenched with sat. NH4Cl solution and diluted with EtOAc. The mixture was filtered through a pad of Celite and washed with EtOAc. The layers were separated and the organic layer was washed with brine, dried and concentrated to give the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:33])(=[O:32])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:6]1[CH3:34].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:35])=[O:2])[C:6]([CH3:34])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](=[O:33])(=[O:32])[NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)NCc2ccc(F)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)NCc2ccc(F)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of (5-fluoro-3-{2-[(4-fluorophenyl)methylsulfamoyl]benzyl}-2-methylindol-1-yl)acetic acid methyl ester (0.22 g) and tetrahydrofuran (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (3.0 mL), and the resulting mixture was stirred at 40° C. for 3 hours. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3.5:6.5 to 9:1 by volume) to afford the title compound as a white solid (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][C@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][C@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: O=S(=O)(OC[C@H]1CCCCO1)C(F)(F)F
Product: COc1cn(C(C[C@H]2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
333 mg (0.80 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.96 ml (0.96 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 426 mg (purity 70%, 1.20 mmol, 1.5 eq.) of (2R)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 85 mg (purity 94%, 19% of theory)
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[C:19]=1[F:31].CC(=O)OCC>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[C:19]=1[F:31]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Br)c(F)c(Br)c1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)c(F)c(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (34 mg, 0.14 mmol) in DMF (3 mL) was added 1,3-dibromo-2-fluoro-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (50 mg, 0.14 mmol) and TEA (15 mg, 0.14 mmol) at rt. The mixture was stirred at 25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography eluted with PE:EA (5:1) to give the final title compound 5-(5-(3,5-dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (50 mg; yield 59%) as solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.92-7.68 (m, 5H), 4.45-4.40 (q, J=22 Hz, 1H), 4.34-4.30 (q, J=22 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.9% at 220 nm and 98.4% at 254 nm; MS: m/z=552.0 (M+1, ESI+).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:9][C:10]([O:12]CC)=[O:11].Cl.[CH3:16][S:17]([C:20]1[CH:35]=[CH:34][C:23]([CH2:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)N)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[F:33][C:30]1[CH:29]=[C:28]2[C:27](=[CH:32][CH:31]=1)[N:25]([CH2:24][C:23]1[CH:34]=[CH:35][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:21][CH:22]=1)[C:2]1[CH:3]([CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2=1
Reactant: CCOC(=O)CC1CCCCCC1=O
Reactant: CS(=O)(=O)c1ccc(CN(N)c2ccc(F)cc2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(Cn2c3c(c4cc(F)ccc42)CCCCC3CC(=O)O)cc1

Procedure:
Following the procedure of Example 1, but using ethyl 2-oxo-cycloheptaneacetate and 1-(p-methylsulfonylbenzyl)-1-(p-fluorophenyl)hydrazine hydrochloride as starting materials, the title compound is obtained.