Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][CH:19]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:13][CH2:14][C:15]2[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:18][CH:19]=2)[CH:5]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCO)cc1OCc1coc(/C=C/c2ccccc2)n1
Product: COc1ccc(CCCOS(C)(=O)=O)cc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 94 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 94%. Recrystallization from ethyl acetate-hexane gave pale yellow needles, mp 112-113° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH:40]=O)[C:34](=[O:42])[CH:33]=[CH:32]2)([O-:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:35]4[C:36]5[C:31](=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:38][CH:37]=5)[CH:32]=[CH:33][C:34]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)ccc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc([N+](=O)[O-])ccc32)CC1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To 2 mL of a chloroform solution containing 0.32 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.21 g of (6-nitro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 20 μL of acetic acid were added, then, to the reaction mixture, 0.29 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.28 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:6][C:7](=[O:46])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:18]=[C:17]4[S:31]([N:34]3[CH2:39][CH2:38][N:37]4C(=O)[O:41][CH2:42][C@H:36]4[CH2:35]3)(=[O:33])=[O:32])[C:11]([CH3:44])=[C:10]([F:45])[CH:9]=2)[CH2:5][CH2:4]1.C(O)(=O)C>CO>[CH:3]1([NH:6][C:7](=[O:46])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:18]=[C:17]4[S:31]([N:34]3[CH2:39][CH2:38][NH:37][C@@H:36]([CH2:42][OH:41])[CH2:35]3)(=[O:33])=[O:32])[C:11]([CH3:44])=[C:10]([F:45])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCN4C(=O)OC[C@H]4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCN[C@@H](CO)C3)c2c1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 21.2 %

Procedure:
2 N aqueous NaOH solution (2 mL) was added to a solution of N-cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-4-{[(8aR)-3-oxotetrahydro[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl]sulfonyl}-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide (Example 49d, 0.291 g) in methanol (2 mL) and the mixture stirred at 90° C. for 45 min. The reaction was neutralised with acetic acid and the volatiles removed under reduced pressure before partitioning between water and DCM. The organic layer was separated and the aqueous extracted further (2×) and the combined organics dried (MgSO4), filtered and evaporated. The residue was purified by SCX (eluting with methanol to remove impurities, then flushing with methanolic ammonia to elute product). Further purification by preparative HPLC (Xbridge column using a 95-5% gradient of 0.3% aqueous ammonia in acetonitrile), solvent evaporation under reduced pressure and trituration with diethyl ether gave the title compound (0.059 g).
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:35])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37](C)([O-])[CH3:38].[K+].C(Br)C=C>C1COCC1>[C:1]([O:20][CH2:21][C@@H:22]([O:35][CH2:38][CH:37]=[CH2:36])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(COCC[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCO[C@@H](CCOCc1ccc(OC)cc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of Compound 5 (10 grams, 21.4 mmoles) in dry THF (250 ml), a solution of 1M of potassium t-butoxide (Aldrich) (27.8 ml, 27.8 mmoles) in THF was added, under argon atmosphere. The mixture was stirred at room temperature for 5 minutes and, thereafter, allyl bromide (Aldrich) (7.4 ml, 85.5 mmoles) was added. The mixture was stirred for 18 hours at 55° C. The solvent was thereafter evaporated to dryness and the residue was extracted with ethyl acetate (250 ml) and washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting yellowish oily residue was purified by silica gel chromatography, using 1:2 (v:v) ethyl acetate:hexane as eluent. 10.75 grams (99% yield) of Compound 6 were obtained as an oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[O:16][C@@H:15]2[C@@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1[OH:21]>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:21][C@@H:13]2[CH2:12][O:16][C@@H:15]3[C@@H:17]([O:20][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:18][O:19][C@H:14]23)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C

Procedure:
p-Toluenesulfonyl chloride (2722 g, 14.28 mol) was added to a solution of isosorbide (869 g, 5.95 mol) in pyridine (5000 mL) in portions with stirring at 0° C. After the reaction mixture was stirred at ambient temperature overnight, the mixture was poured into ice-water (5000 mL) with stirring, and extracted with DCM (4000 mL×3). The combined organic layers were washed successively with water (3000 mL×3), 1 N aqueous HCl (3000 mL×3, pH=6), and saturated aqueous NaHCO3 (3000 mL×2), and dried over anhydrous Na2SO4. After removal of the solvent via vacuum, ethanol (1000 mL) was added. The resulting precipitate was filtered, and washed with ethanol to give the desired product as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5](C(OCC)=O)[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10]CC)=[O:9])C.Cl>>[F:19][C:15]1[CH:14]=[C:13]([CH:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:7][C:8]([OH:10])=[O:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(c1cccc(F)c1)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: O=C(O)CC(CC(=O)O)c1cccc(F)c1
Temperature: 0 °C

Procedure:
2-Ethoxycarbonyl-3-(3-fluoro-phenyl)-pentanedioic acid diethyl ester (2-2) (6.90 g, 19.5 mmol) was treated with 6 N HCl (150 mL). The mixture was refluxed for 24 hr, poured into 200 mL ice-water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide 2-3 as a solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:26]([C:23]1([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:25][CH2:24]1)=[O:27])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(N)ccc2[nH]1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ccc4[nH]c(C(C)(C)C)cc4c3)CC2)cc1
Reaction time: 3 h

Procedure:
2-tert-Butyl-1H-indol-5-amine (19 mg, 0.10 mmol) and 1-(4-methoxyphenyl)-cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.00 mL) containing triethylamine (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 362.2, found 363.3 (M+1)+; Retention time 3.48 minutes.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)=[S:11])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:17][CH:18]=1)=[S:11])[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCNC(=S)Nc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=S)Nc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
The compound (93.8 mg) obtained in Example 35-2 was dissolved in anhydrous methanol (3.8 ml) and added with 1-methyl-2-imidazole carboxaldehyde (38.5 mg) and sodium cyanoborohydride (43.4 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 13.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (86.6 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:14]([OH:17])(=[O:16])=[O:15].CO>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:14]([OH:17])(=[O:16])=[O:15])=[C:7]([O:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(C(C)(C)C)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(C)(C)C)ccc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 131.1 %

Procedure:
To a cooled (0° C.) solution of 29 (6.19 g; 37.69 mmol) in anhydrous dichloromethane (160 mL) was added chlorosulfonic acid (3.0 mL; 45.22 mmol) dropwise. After addition as complete, the reaction was stirred at 0° C. for an additional 30 minutes, allowed to gradually warm to room temperature and further stirred overnight. The reaction mixture was concentrated under reduced pressure to about 500 mL and washed with aqueous hydrochloric acid (20 nm; 20N). The organic layer was separated and dried over magnesium sulfate which resulted in formation of a white precipitate. Methanol (200 mL) was added to dissolve the precipitate. The organic solution was filtered and concentrated under reduced pressure to yield the title compound as a purple solid (12.07 g).
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH2:12])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:14]1([C:20](OC)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:1]1([NH:9][C:10]2[S:11][C:14]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:20](=[O:21])[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCCC1
Reactant: COC(=O)C1(Br)CCCCC1
Product: O=C1N=C(NC2CCCCCCC2)SC12CCCCC2

Procedure:
Synthesis was performed from N-cyclooctylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([C:30]([O:32]C)=[O:31])=[CH:28][CH:29]=[C:24]3[N:23]=[C:22]2[CH3:34])=[C:18]([Cl:37])[CH:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=[C:24]3[N:23]=[C:22]2[CH3:34])=[C:18]([Cl:37])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3Cl)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(C(=O)O)nc2n1Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Methyl 3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (391 mg) was dissolved in 1,4-dioxane (4 ml). 1N Aqueous sodium hydroxide solution (3.7 ml) was added and the mixture was stirred at room temperature for 2 days and at 80° C. for 2 hr. To the reaction mixture was added 1N hydrochloric acid to adjust the pH to 4. Water (40 ml) was added and the precipitated crystals were collected by filtration to give 3-(4-(N-(tert-butoxycarbonyl)-amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (261 mg) as pale-yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[I-].[Na+].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CNS(=O)(=O)CCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-N-methylbutane-1-sulfonamide (Example 5; 180 mmol), and sodium iodide (198 mmol) in DMF (180 ml) was stirred for 10 min at room temperature. Sodium azide (397 mmol) was added and the reaction mixture was stirred overnight at 60° C. The mixture was filtered off The organic phase was extracted with AcOEt/water. The crude mixture was concentrated and was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].N1C=CN=C1>O1CCCC1>[C:7]1([C:5]2[N:6]=[C:2]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:3]([CH3:19])[C:4]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cn1c(Cl)nc(-c2ccccc2)c1-c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -20 °C

Procedure:
A solution of 2-chloro-4,5-diphenyl-1-methylimidazole (1.46 g, 5.4 mmol) from Step B in tetrahydrofuran (THF) (20 mL) under nitrogen was cooled to −70° C. in a dry ice/acetone bath. n-Butyl lithium (1.6 N in hexanes, 10.2 mL, 16.3 mmol) was added via syringe. The reaction was allowed to warm to −20° C. for 2 hr. In a separate round-bottomed flask, a solution of benzyl chloroformate (CBZ-Cl) (4.3 mL, 16.3 mmol) in THF (10 mL) was cooled to −20° C. The above imidazole reaction was added via a double-tipped needle to the solution of CBZ-Cl and after 20 min the reaction was allowed to warm to rt for 30 min. The reaction was then quenched into an aqueous sodium bicarbonate solution and was then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (5% methylene chloride and 15% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)C.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (3.68 g, 16.1 mmol, 1.00 equiv), {[2-(trifluoromethyl)phenyl]methyl}amine (2.57 mL, 18.3 mmol, 1.14 equiv), and DMAP (392 mg, 3.21 mmol, 0.200 equiv) in CH2Cl2 (100 mL) was added diisopropylethylamine (DIEA, 3.49 ml, 20.1 mmol, 1.25 equiv) and EDCI (3.11 g, 20.1 mmol, 1.25 equiv). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The solution was washed with H2O, sat NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was stirred in CH2Cl2 (60 mL) and TFA (60 mL) for 20 min at room temperature, and then the solvents were removed in vacuo. The residue was diluted with CH2Cl2, and the resulting solution was neutralized carefully with sat NaHCO3 (aq). Solid NaCl was used to saturate the aqueous layer, which was then extracted 3 times with ethyl acetate. The organic layers were combined, dried with Na2SO4, filtered and concentrated to afford 4.43 g (97% yield) of the desired product. MS (ES+): m/e 287.0 [M+H]+.
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.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])=[CH:20][C:19]=1[C:30]([F:33])([F:32])[F:31].Cl.CC(=O)OCC>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:26]([F:27])([F:28])[F:29])[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:20][C:19]=1[C:30]([F:31])([F:32])[F:33]
Reactant: C=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(F)c(C(F)(F)F)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (522 mg, 2.18 mmol) in DMF (5 mL) was successively added 1-fluoro-2-(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (563 mg, 2.18 mmol) and TEA (440 mg, 4.36 mmol) below −10° C. The mixture was stirred at rt overnight, poured into 1N HCl solution and extracted with EA (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-TLC eluted with PE:EA (1:1, 1% HOAc) and pre-HPLC to give the final title compound (200 mg, yield 20.0%) as white solid: 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.03-8.00 (m, 1H), 7.91-7.89 (d, J=12 Hz, 1H), 7.77-7.68 (m, 4H), 4.52-4.46 (d, J=18 Hz, 1 H), 4.36-4.30 (d, J=18 Hz, 1 H), 1.48 (s,6H). LC-MS: 462 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[CH2:9]([O:11][C:12](=[O:16])[C:13](Cl)=[O:14])[CH3:10].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:20]1[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=1)=[O:14])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(OC)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
Aluminum chloride (84.30 g, 632 mmol) was added to chloroform (300 ml) and chloroglyoxylic ethyl ester (60 g, 439 mmol) was added dropwise to the resulting suspension over 20 minutes at 0° C. The reaction mixture was stirred for 40 minutes at 5° C. At the same temperature, anisole (68.79 g, 636 mmol) was slowly added dropwise to the reaction solution and then stirred for 12 hours at 10° C. When the reaction is completed, the reaction solution was cooled and, after adding cooling water (100 ml), extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound as a yellow solid (TLC identification). The resulting compound was used in the next reaction without further purification.
Reaction SMILES: C[N:2]([C:4](/[C:6](/[Br:14])=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)[CH3:3].[CH2:15]([O:17][C:18]([C:20]1[C:21](N)=[N:22][NH:23]C=1)=[O:19])[CH3:16].Br>C(O)C.C(O)(=O)C>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[C:7]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:6]([Br:14])[CH:4]=[N:2][C:3]=12)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C(=O)/C(Br)=C/C1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(Br)cnc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a mixture of 1.69 g (6.50 mmol) of 2-bromo-1-cyclohexyl-3-dimethylamino-propenone and 1.01 g (6.50 mmol) of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester in 6 mL of ethanol was added 1.0 mL of 30% hydrogen bromide in acetic acid solution, and the resulting mixture was heated at reflux for 1 h. Then the reaction mixture was cooled to rt and concentrated to give a residue which was chromatographed on silica gel (gradient elution with dichloromethane to 25% ethyl acetate in dichloromethane) to give 620 mg (27% over 2 steps) of 6-bromo-7-cyclohexyl-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR (δ 8.70 (s, 1H), 8.49 (s, 1H), 4.44 (q, J=6.8 Hz, 2H), 2.70–2.57 (b, 1H), 1.98–1.90 (m, 2H), 1.87–1.78 (m, 2H), 1.78–1.69 (m, 2H), 1.59–1.42 (m, 4H), 1.43 (t, J=6.8 Hz, 3H)); LC-MS—calcd for C15H18BrN3O2 [M++H]+: 352.06, found: 352.0.