Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1.[N+](=[CH2:33])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:20]([O:22][CH3:33])=[O:21])[CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1
Reactant: C=[N+]=[N-]
Reactant: CN(C)CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Product: COC(=O)C(CCN(C)C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-3-(dimethylamino)propylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-3-(dimethylamino)propylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:19][Mg]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH3:19])[CH2:12][CH2:13]2)=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Reactant: C[Mg]Br
Product: CC(=O)C1CCN(C(=O)c2ccc(F)cc2)CC1

Procedure:
In a manner similar to that described in Preparation 4, 1-(4-fluorobenzoyl)piperidine-4-carboxylic acid is reacted with methylmagnesium bromide to afford the title compound.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1[C:15](=[O:16])[CH2:14][CH2:13]C1=O.N1C=CC=CC=1.C(O)C#C.CCN(CC)CC>C1COCC1>[C:2]1([C:1]2[CH:13]=[C:14]([CH2:15][OH:16])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1ccccc1
Agent: C#CCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1cc(-c2ccccc2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
(Z)-Benzaldehyde oxime (3.4 g, 28.2 mmol) was dissolved in anhydrous THF (50 mL) and cooled to 0° C. N-Chlorosuccinimide (5.63 g, 42.3 mmol) and pyridine (221 mg, 2.8 mmol) were added and the mixture was stirred at room temperature for 1 hour. Prop-2-yn-1-ol (1.89 g, 33.4 mmol) and NEt3 (286 mg, 2.8 mmol) were added and the mixture was heated at reflux for 2 hours. The reaction was cooled and quenched with water, extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was concentrated under vacuum to give a crude product, which was purified by column chromatography to afford (3-phenylisoxazol-5-yl)methanol as a white solid (1.8 g).
Reaction SMILES: Cl[CH2:2][S:3][CH2:4][CH2:5][O:6]C(=O)C.Cl[C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[NH:13][CH:14]=[N:15]2.C([N:22](CC)CC)C>CN(C)C=O>[OH:6][CH2:5][CH2:4][S:3][CH2:2][N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][CH:18]=[N:19][C:11]=2[NH2:22]
Reactant: CC(=O)OCCSCCl
Reactant: CCN(CC)CC
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CSCCO
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Following the procedure of Schaeffer, et al. J. Med. Chem., 14, 367 (1971), 2-acetoxyethyl chloromethyl sulfide (3.37 g) was added to a mixture of 6-chloropurine (3.09 g), triethylamine (2.23 g) and dimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 90 hours and the solvent then removed under reduced pressure. The residual oil was dissolved in chloroform (30 ml) and placed on a column of Florisil (200 g) in chloroform. Elution with chloroform resulted in the desired product in 2.1 liters of eluate (after discarding the initial 300 ml collected). The solvent was evaporated to give a residual oil. Ether-pet.ether was added and the mixture chilled to give 9-(2-acetoxyethylthiomethyl)-6-chloropurine (1.4 g, mp 82°-87° C.). Recrystallization from ether gave white prisms m.p. 89°-91° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].CN(C)[CH:26]=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH2:1][O:2][CH2:3][CH2:4][O:27][CH3:26])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CN(C)C=O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1cc(O)ccc1C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C

Procedure:
13.39 g of N-tert-butoxycarbonyltyrosine methyl ester was dissolved in 65 ml of tetrahydrofuran and 65 ml of dimethylformamide, and to the solution was added 1.9 g of 60% sodium hydride with stirring in an ice bath. After removing from the ice bath, the mixture was stirred at a room temperature for 30 minutes, and after addition of 5.4 g of methoxyethoxymethyl chloride with ice cooling, stirred for 15 hours allowing to warm to a room temperature. The reaction mixture was poured on ice, saturated with sodium chloride and extracted twice with 800 ml of chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (4:1) to obtain 13.85 g of the title compound in a colorless amorphous form.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:12][CH:13]([CH2:18][OH:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][C:6]=2[S:5][C:4]=1[NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])#[N:2].C(N(C(C)C)CC)(C)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([N:12]([CH:13]([CH2:18][OH:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])[CH2:11][C:6]=2[S:5][C:4]=1[NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])#[N:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NC(CO)C(C)(C)C)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(N(C(=O)C1CCCCC1)C(CO)C(C)(C)C)C2
Reaction time: 16 h

Procedure:
To a solution of the intermediate isolated in Step A in 5.0 mL of dichloromethane was added 0.175 mL (1.00 mmol) of di-isopropylethylamine and 0.041 mL (0.280 mmol) of cyclohexanecarbonyl chloride. After stirring 16 h at ambient temperate, the reaction mixture was concentrated in vacuo, and purified by preparative reversed phase HPLC, affording the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].C([Mg]Br)C.[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](Cl)=[O:23]>[Cl-].[Zn+2].[Cl-]>[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[NH:9][CH:8]=1)=[O:23]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)C(C(=O)c2c[nH]c3cc(C#N)ccc23)C1(C)C
Yield: 48.6 %

Procedure:
A mixture of 6-cyanoindole (Lancaster, 1.0 g, 7.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 8.4 mL, 8.4 mmol), zinc chloride (1.0 M solution in Et2O, 8.4 mL, 8.4 mmol) and the product of Example 1A (11 mmol) was processed as described in Example 1B to provide the title compound (0.91 g, 3.4 mmol, 49% yield). MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[CH3:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12]>[Ni]>[C:2](=[O:3])([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][CH2:6][CH3:5])[NH2:1]
Reactant: NC(N)=O
Reactant: CCCCOCCO
Agent: [Ni]
Product: CCCCOCCOC(N)=O
Temperature: 135 °C
Yield: 98 %

Procedure:
60 parts of urea are mixed with 177 parts of butylglycol and 3 parts of a cation exchanger which is commercially available under the registered name Lewatit CA 9259 and, having been treated in accordance with Example (1 a), contains nickel, in a stirred apparatus. The mixture is heated to 135° C., whilst stirring. It is then heated for 10 hours at 140° C. After cooling, the mixture is filtered and the excess butylglycol is distilled from the filtrate under reduced pressure. 158 parts of n-butoxyethyl carbamate (corresponding to 98% of theory, based on urea) are obtained. On distillation of the end product in a high vacuum, a residue of only 0.9% by weight is left. The pure butoxyethyl carbamate has a boiling point 118°-120° C. at 0.2 mm Hg.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([F:15])=[CH:8][N:7]=1>C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([F:15])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1C1OCCO1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cnc1C1OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-5-fluoro-3-nitropyridine (10 g, 46.69 mmol) in ethanol (140 mL) was added Pd/C (1 g) under nitrogen atmosphere. The reaction mixture was stirred for overnight under hydrogen atmosphere at 25° C. The reaction mixture was filtered through Celite™ and washed with EtOH. The filtrate was concentrated in vacuo and residue was purified by column chromatography on silica gel using 0-40% EtOAc in hexane to give 2-(1,3-dioxolan-2-yl)-5-fluoropyridin-3-amine: LC-MS (ESI) m/z 185.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)=[CH:11][C:10]=2[P:25](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)=[CH:11][C:10]=2[P:25](=[O:38])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:39][CH:40]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Oc3ccc([N+](=O)[O-])cc3)c(P(=O)(c3ccccc3)c3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccc(Oc3ccc(N)cc3)c(P(=O)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 250 mL Parr hydrogenation flask were charged [2,5-bis(4-nitrophenoxy) phenyl]diphenylphosphine oxide (5.4 g, 0.0098 mol) and 1,4-dioxane (100 mL). The solution was warmed to effect dissolution with subsequent cooling to room temperature upon which 10% Pd/C (0.59 g) was added. The mixture was degassed prior to the introduction of hydrogen gas. The mixture was agitated under a hydrogen atmosphere for ˜24 hours at room temperature. After degassing the solution, the Pd/C was removed by filtration and the solution added to stirred water to afford an off-white solid. The crude solid was collected via filtration, washed with water, and dried at room temperature to afford 4.1 g (76% crude yield). Recrystallization from aqueous ethanol afforded [2,5-bis(4-aminophenoxy)phenyl]diphenylphosphine oxide as a tan solid (3.2 g, 80% recovery), m.p. 205-208° C. Anal. Calcd. for C30H25N2O3P: C, 73.16%; H, 5.12%; N, 5.69%; P, 6.29%. Found: C, 72.87%; H, 5.08%; N, 5.78%; P, 5.64%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[N+:9]([C:4]1[CH:3]=[C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])[CH:7]=[CH:6][C:5]=1[OH:8])([O-:11])=[O:10]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Yield: 40.1 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 4-amino-2-nitrophenol (1.00 g, 6.49 mmole), DMF (30 ml), TEA (0.5 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.30 g, 7.78 mmole), 1.00 g (40.0% yield) of 2-nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol was obtained as a reddish solid.:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Br:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:11][CH2:10][CH2:9][Br:8])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)Cl
Reactant: OCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)OCCBr
Temperature: 0 °C
Reaction time: 19.5 h

Procedure:
4-Pentenoyl chloride (2.8 mL, 25.4 mmol) was dissolved in anhydrous methylene chloride (50 mL) and cooled to 0° C. under nitrogen. 2-Bromoethanol (2.0 mL, 28.2 mmol) and triethylamine (3.8 mL, 27.3 mmol) was added to the reaction solution resulting in a thick yellow slurry. The reaction solution was stirred for 19.5 h while slowly warming to 22° C. The reaction mixture was diluted to 100 mL with methylene chloride and extracted with 75 mL of each of the following: water, sat. ammonium chloride, and sat. sodium bicarbonate. The organic phase was dried (MgSO4), filtered and condensed in vacuo to yield a yellow oil (5.2 g cu. 100%) which was used as is for the next step. 1H NMR δ 5.90-5.65 (m, I H), 5.15-4.90 (m, 2H), 4.39 (t, 2H, J=6.0), 3.48 (t, 2H, J=6.0), 2.50-2.30 (m, 4H).
Reaction SMILES: [NH4+].[C:2]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6]([O-:8])=[O:7])#[N:3]>Cl>[C:2]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6]([OH:8])=[O:7])#[N:3]
Reactant: CCC(C#N)CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: CCC(C#N)CC(=O)O
Temperature: -20 °C
Yield: 96 %

Procedure:
A 300-mL portion of the filtrate described above, containing 1.26 M 3-cyanopentanoic acid ammonium salt, was adjusted to pH 2.5 with ca. 60 mL of 6 N HCl, then saturated with sodium chloride and extracted with 4×200 mL of ethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and the solvent removed by rotary evaporation at reduced pressure at 28° C. The resulting slightly-yellow viscous oil was stirred under high vacuum (50 millitorr) to remove residual solvent at 28° C., then cooled to -20° C. for 2-3 h to produce 3-cyanopentanoic acid as a crystalline white solid (45.9 g, 96% yield); m.p. 33.0-34.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:34]3[O:35][CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[F:43])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]=C(C)O[N:26]=3)=[CH:21][CH:20]=2)=[N:12]1)=[O:5])[CH3:2].O.C(O)(=O)C>CO.[Fe]>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:29])=[CH:23][CH:24]=2)[C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:34]3[O:35][CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[F:43])=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 62.5 °C
Reaction time: 40 h
Yield: 45.5 %

Procedure:
To a solution of 68 mg of 5-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester in 6 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 68 mg of iron powder, and the mixture was stirred at 62.5° C. for 40 hours under a nitrogen atmosphere. After cooling, the reaction mixture was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid). The title compound (16.0 mg) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.CCN(C(C)C)C(C)C>CCO>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)=[N:3][C:2]=1[F:1]
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(F)c(F)cc2[N+](=O)[O-])n[nH]1
Reaction time: 8 h

Procedure:
To a solution of 2,3,6-trifluoro-5-nitropyridine (Intermediate 40, 1.0 g) in EtOH (20 ml) at 0° C., was added 5-methyl-1H-pyrazol-3-amine (550 mg) and DIPEA (2 ml). The resulting mixture was stirred at this temperature overnight. The title compound was collected via filtration (780 mg). LCMS: 377 [M+1].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33](CO)=[C:32]([Cl:36])[CH:31]=[N:30][CH:29]=1>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33]([CH2:32][Cl:36])=[C:20]([Cl:24])[CH:31]=[N:30][CH:29]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)c1cncc(Cl)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cncc(Cl)c1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Polymer bound triphenylphosphine (3 mmol/g, 234 mg, 0.702 mmol) and CCl4 (400 μL) were added to a stirred solution of 5-chloro-4-hydroxymethyl-nicotinic acid methyl ester (14.2 mg, 0.070 mmol) in DCM (4 mL). After stirring for 2 h at room temperature, the reaction mixture was filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 220.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.1 g), 5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.3 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.2 g), melting point: 126–127° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
250 g (1.32 mol) of 4-bromo-2-fluoroaniline was dissolved in 500 mL of pyridine, 178 mL (1.45 mol) of pivaloyl chloride was added dropwise under ice-cooling and the mixture was stirred for 10 minutes. The reaction solution was poured into 1.5 L of ice water and the precipitated crystals were collected by filtration. The crystals were washed with 1N hydrochloric acid and water and dried by heating at 40° to 60° C. under reduced pressure to give 350 g of 4-bromo-2-fluoro-N-pivaloylaniline (yield: 97%).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C@@H:7]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])C.Cl>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C@H:7]([CH2:6][OH:5])[C@H:8]([CH3:13])[C:9]([F:10])([F:11])[F:12])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)[C@H](C)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]([C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 12 h
Yield: 79.9 %

Procedure:
A solution of lithium borohydride (2.0 M in THF, 0.23 mL) was added to a solution of (2S,3S)-2-(4-chloro-benzenesulfonylamino)-4,4,4-trifluoro-3-methyl-butyric acid ethyl ester (86 mg, 0.23 mmol) in THF (5 mL) and stirred for 12 h. Careful addition of 2N HCl (aq) was performed until pH<2. Organic solvent was removed in vacuo. The aqueous layer was extracted with EtOAc (2×20 mL) and organic layers were combined and washed with brine. The organic layer was dried over Na2SO4 and solvent removed in vacuo. The crude solid was purified by flash chromatography (20% EtOAc/hexanes) to provide a white solid (61 mg) in 80% yield. Mass Spectrum (−ESI): 330.0 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]3[C:15]=2[CH2:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:18]1([C:9]2[NH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]=2[CH2:11][CH:12]([CH3:17])[CH:13]([CH3:16])[CH2:14]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1=C(C)Cc2c(-c3ccccc3)[nH]c(-c3ccccc3)c2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1Cc2c(-c3ccccc3)[nH]c(-c3ccccc3)c2CC1C

Procedure:
1 g of the product obtained in Example 6, 1.2 g of ammonium format and 0.2 g of 10% Pd/C in 70 ml of ethanol are heated at reflux for 3 hours, then filtered and concentrated. The expected product is isolated by chromatography on silica gel (eluant: cyclohexane/ethyl acetate: 90/10).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[N:3]=[N:2]1.[CH3:11][O:12][C:13]1[C:14](=O)[C:15](=[O:19])[C:16]=1[O:17]C>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:14]3[C:15](=[O:19])[C:16](=[O:17])[C:13]=3[O:12][CH3:11])[C:4]=2[NH:3][N:2]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1cccc2[nH]nnc12
Solvent: CO
Product: COc1c(Nc2cccc3nn[nH]c23)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
A mixture of 2.045 g (15.2 mmol, 1 eq) of 1H-1,2,3-benzotriazol-4-amine and 1.80 g (12.7 mmol, 1 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 30 ml of methanol was stirred at ambient temperature for 2 days. The reaction medium (set solid) was filtered. 2.04 g of a mixture of 3-(3H-benzotriazol-4-ylamino)-4-methoxycyclobut-3-ene-1,2-dione and 3,4-bis(3H-benzotriazol-4-ylamino)cyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. Mixture of products (29% correct product). Yield=19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)[OH:14])[CH:7]=[CH:6]2.Cl>C(O)=O>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[OH:14])[N:16]=[CH:17]1
Reactant: COc1ccc2cc(C(O)(c3cccnc3)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: O=CO
Product: COc1ccc2cc(C(O)(c3cccnc3)c3c[nH]cn3)ccc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
(6-Methoxynaphthalen-2-yl)-(pyridin-3-yl)-(1-trityl-1H-imidazol-4-yl)methanol (0.80 g) was dissolved in 90% solution of formic acid (3 ml), and the solution was stirred at 50° C. for 30 min. To the solution was added 1 N-hydrochloric acid, and precipitate was filtered off. The filtrate was washed with ether, and neutralized with potassium carbonate. The filtrate was extracted with chloroform and concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform:methanol=5:1). Recrystallization from THF gave the titled compound (0.36 g) as a colorless powder.