Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:10]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[NH:11][C:12](=[O:26])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:14]=2[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42]>C1COCC1>[CH:1]1([C:7]([C:9]2[CH:10]([C:27]3[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=3)[N:11]([CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[C:12](=[O:26])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[C:14]=2[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1=C(C(=O)C2CCCCC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)C2CCCCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Example 21 (780 mg, 1.67 mmol) in THF (25 ml) is added sodium hydride (60% dispersion in mineral oil; 653 mg, 2.53 mmol). The mixture is stirred for 1 hour at room temperature, then 2-bromo-N,N-diethylethanamine (653 mg, 2.53 mmol) is added, and the solution is stirred overnight (16 h) at room temperature. The reaction mixture is quenched with methanol (10 ml), concentrated, and the crude product is purified by preparative HPLC.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[C:16]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=2[S:18][CH:19]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:24][C:22]1[CH:21]=[CH:20][C:17]2[S:18][CH:19]=[C:15]([CH2:14][N:38]3[CH2:39][CH2:40][N:36]([C:28]4[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=4)[C:37]3=[O:41])[C:16]=2[CH:23]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)nc1C
Yield: 65 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(bromomethyl)-5-chlorobenzo[b]thiophene to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 65% yield: MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:22])[CH:17]([NH2:21])[C:18]([OH:20])=[O:19]>>[NH4+:3].[C:18]([CH:17]([NH:21][C:2]1[C:11]([C:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:16][NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NCC(N)C(=O)O
Product: O=C([O-])c1cc2cc(Cl)ccc2nc1NC(CNc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O
Product: [NH4+]
Yield: 23 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-2,3-diaminopropionic acid to provide the title compound in 23% yield as yellow needles (recrystallization from MeOH/water/NH4OH).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][C:35]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cc(C(F)(F)F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.50 mg, 33.7% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.67 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H), 7.30-7.10 (m, 6H), 7.14 (d, 1H, J=7.4 Hz), 6.97 (apparent d, 1H, J=7.7 Hz), 5.37 (apparent dd, 1H, J=5.0, 8.5 Hz), 3.4 (m, 2H), 2.8 (m, 2H), 2.6 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.4 Hz), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.1 Hz, overlapped); ESMS m/e: 542.6 (M+), 543.54 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:36])([C:32]([F:35])([F:34])[F:33])[C:3]([F:31])([F:30])[C:4]([F:29])([F:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.[BrH:37].S(=O)(=O)(O)O>>[Br:37][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:29])([F:28])[C:3]([F:31])([F:30])[C:2]([F:36])([F:1])[C:32]([F:35])([F:34])[F:33]
Reactant: Br
Reactant: OCCCCCCCCCCCCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCCCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 1.00 g of 22-(nonafluorobutyl)-1-docosanol and 30 mL of 48 weight percent hydrobromic acid was slowly added 3 mL of concentrated sulfuric acid, and the reaction mixture was heated at 100° C. for 24 hr. The mixture was cooled to room temperature, and the solid product was collected by filtration and dissolved in hexanes. The filtrate was extracted once with hexanes, and the combined hexanes solutions were washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. Filtration and concentration yielded 1.03 g of 1-bromo-22-(nonafluorobutyl)docosane as an off-white solid, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:9])=O)[C:3]=1[CH3:10].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]#[N:9])[C:3]=1[CH3:10]
Reactant: Cc1c(C(N)=O)n[nH]c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C#N)n[nH]c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-iodo-4-methyl-1H-pyrazole-3-carboxamide (compound 258.2, 800 mg, 3.19 mmol) in dichloromethane (10 mL). The solution was cooled to 0° C., then trifluoroacetic anhydride (1.32 mL, 9.5 mmol) and triethylamine (3.16 mL, 22.7 mmol) were each added carefully drop-wise. The mixture was stirred for 2 h at 0° C., then the pH was carefully adjusted to 7-8 with aqueous sodium bicarbonate (10%). The aqueous phase was extracted with ethyl acetate (2×40 mL) and the combined organic layers were washed with 2×10 mL of brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a white solid (280 mg, 38%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:13]S(O)(=O)=O.OO>CO>[OH:13][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-Benzodioxan-6-carboxaldehyde (5.20 g) was dissolved in MeOH (60 mL) containing conc. H2SO4 (0.6 mL). At 0° C. an aqueous solution of 30% H2O2 (4.7 mL) was added to the mixture over 5 minutes. The mixture was warmed to room temperature, stirred an additional 18 h and evaporated. The residue was taken up with H2O and extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 3:1) to give 6-hydroxy-1,4-benzodioxan (3.85 g). ESMS: m/z 153 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:10]=1)=[O:9]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
The starting material is prepared as follows: The mixture of 68 g of 5-chloro-2 -methylbenzoic acid and 170 ml of thionyl chloride is refluxed for 1 hour, evaporated under reduced pressure and the residual acid chloride dried in a high vacuum. It is taken up in 500 ml of benzene and the solution added dropwise to the suspension of 100 g of anhydrous aluminum chloride and 600 ml of benzene while stirring and cooling with an ice bath. Thereupon the bath is removed and the mixture stirred at room temperature for 16 hours. It is combined with some ice, followed by 340 ml of 2N hydrochloride acid and the mixture stirred for a half hour. It is diluted with diethyl ether, the organic layer separated and washed with 5% sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated under reduced pressure, to yield the 5-chloro-2methylbenzophenone showing in the I.R, spectrum a strong band at 1660 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (81 mg, 0.27 mmol) in N,N-dimethylformamide (5 mL) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (112 mg, 0.29 mmol), N,N-diisopropylethylamine (0.14 mL. 0.80 mmol), and 2-aminothiazole (40 mg, 0.40 mmol). The reaction was stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate to 60/40 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazol-2-yl-propionamide (35 mg, 34%) as a light yellow oil: EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+) 384.0466, found 384.0468.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[C:14]1C=CC(F)=C(F)C=1>>[CH3:14][C:4]([C:3]1[C:2]([Cl:1])=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=1)=[O:6]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Fc1ccc(Cl)cc1F
Product: CC(=O)c1cc(F)c(F)cc1Cl
Yield: 82 %

Procedure:
According to the process disclosed in EP-A2-303,291, 2-chloro-4,5-difluorobenzoic acid is prepared by acylating 1-chloro-3,4-difluorobenzene to give 2-chloro-4,5-difluoroacetophenone with a yield of 82% of theory and then oxidizing with sodium hypochlorite to 2-chloro-4,5-difluorobenzoic acid in a yield of 85.1% of theory. The total yield of this process thus only amounts to about 70% of theory, relative to the 1-chloro-3,4-difluorobenzene as the starting material. It is further a disadvantage of this process that, according to the illustrative example, the acylation must be carried out at a temperature of 120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: BrCCCCCCBr
Product: COc1ccc(C2=NN(CCCCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 1,6-dibromohexane as described for compound 58. Purified by chromatography [ethyl acetate/petroleum ether (60-80° C.), 1:2]. Crystallized from petroleum ether (60-80° C.). M.p. 74-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[O:20][C:16]=2[CH3:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1cc2ccccc2o1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1oc2ccccc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10.1 g 4-chloro-3-sulfamoylbenzoyl chloride and 5.8 g 2-methylbenzo[b]furan in the presence of 11.4 g aluminum chloride. After evaporation of the extraction agent, the residue is stirred with di-isopropyl ether, and the solids are filtered off. Colorless crystals, m.p. 183° C. (from methanol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].COC([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])=O.[CH3:18][C:19](C)=[O:20].COC1C=C(C=CC=1OC)C(N1CCN(CC(Cl)=O)CC1)=O>O.CC(C)=O>[C:19]([NH:13][C:12]1[CH:11]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:20])[CH3:18]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)=O
Agent: COc1ccc(C(=O)N2CCN(CC(=O)Cl)CC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccccc1
Reaction time: 3 h

Procedure:
8.28 Grams of potassium carbonate was dissolved in 50 ml of water-acetone (1:2), and to this solution was added 15.1 g of o-methoxycarbonylaniline. Under ice-cooled condition, an acetone solution of 34.4 g of [4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetylchloride was added dropwise thereto. After completion of the addition, the reaction was carried out at a room temperature for 3 hours, then acetone was removed by distillation. The residue obtained was extracted with chloroform, then the extract was washed with water, dried and chloroform was removed by distillation. The residue obtained was crystallized by adding ethyl acetate, and the crystals were collected by filtration. Recrystallized from ethanol to obtain 29 g o-methoxycarbonyl-α-[4-3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]1>>[OH:24][CH2:23][C:19]1([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:22][CH2:21][CH2:20]1
Reactant: NC1(CO)CCC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: O=C(NC1(CO)CCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-amino-cyclobutanemethanol (CAN 180205-34-9, 66.02 mg, 0.64 mmol) as starting materials, and isolated (50 mg, 36.86%) as off white solid; LC-MS (UV peak area, ESI) 97.56%, 318.4 (M+H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([C:15]2[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:19]1[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 105.8 %

Procedure:
Benzyl bromide (696 mg, 4.01 mmol) was added to ethyl 5-phenyl-1H-pyrazole-3-carboxylate (880 mg, 4.1 mmol) and potassium carbonate (562 mg, 4.01) in DMF (8 mL). The reaction was stirred for several h and then diluted with water. The mixture was washed several times with ethyl acetate and the combine extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified on ISCO using 0-100% ethyl acetate/hexane gradient to give ethyl 1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate (1.3 g, quantitative). MS (ESI) m/z: Calculated for C19H18N2O2: 306.14. found: 307.1 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:28][O:29][NH2:30].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=[C:6]([C:1](=[N:30][O:29][CH3:28])[CH2:2][CH2:3][CH3:4])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCCC(=O)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NOC)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12

Procedure:
1-(5-Butyryl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea, which may be produced as in Example 108 (46.0 mg, 0.13 mmol) and O-methylhydroxylamine HCl (18.0 mg, 0.22 mmol) in ethanol (1.0 mL) were charged with sodium acetate trihydrate (55.0 mg, 0.41 mmol). After 24 h the reaction was concentrated then taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organic was concentrated and the resulting oil chromatographed (0-10% isopropanol/CH2Cl2) to afford 1-ethyl-3-[5-(1-methoxyimino-butyl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-urea. MS (APCI+): m/z 382.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13](=[O:14])[NH:21][NH:22]2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1F
Solvent: O
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(OCc3ccccc3)ccc12
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Methyl 4-(benzyloxy)-2-fluorobenzoate (52.4 mg) which can be prepared according to the method described in Reference example 30, etc. was dissolved in n-butanol (1 mL; manufactured by Kanto Chemical Co., Inc.), added with hydrazine monohydrate (96 μL; manufactured by Sigma-Aldrich Co.), and stirred in a sealed tube under microwave for 1 hour at 160° C. Precipitates from the reaction solution were filtered and washed with n-butanol to obtain the title compound (39.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].[N:12](OCCC(C)C)=O.Cl.C(N)(=O)C>CCCCO.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[N:12][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)CCON=O
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Agent: CC(N)=O
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2nnsc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
To a solution of 2-Amino-5-nitrobenzenethiol (5b) (6.0 g, 35.3 mmol) in n-BuOH (30 mL), cooled to 0° C., a solution of Isoamyl nitrite (5.0 mL, 37.1 mmol) in n-BuOH (30 mL) was added followed by conc. HCl (5.0 ml). The reaction mixture was warmed to room temperature and stirred for 5 h. To the resulting reaction mixture Acetamide (0.4 ml) was added and stirred for another 30 min at room temperature. After completion of reaction (by TLC), the reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine solution (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography to afford 6-Nitrobenzo[d][1,2,3]thiadiazole (5c) (3.5 g, 54%) as a yellow solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=O)[CH2:31][C:32]1[O:36][CH:35]=[N:34][CH:33]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[O:36][CH:35]=[N:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cnco1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cnco3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 10 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and oxazol-5-yl-acetic acid methyl ester with heating for 5 days to afford the title compound as tan solid (13 mg, 10%). LC/MS (Method B) 3.84 min, [M+1]+ 476.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH2:21])[CH2:17][CH2:18][CH2:19][NH2:20]>>[CH:2]1[C:11]2[C:6](=[C:7]([S:12]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][NH2:21])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Product: NCCCCNS(=O)(=O)c1cccc2cnccc12
Yield: 61.9 %

Procedure:
According to the method of Reference Example 2, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (18.8 g) and 1,4-butylenediamine (25 g) to obtain the title compound (12.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:20][O:19][N:18]([CH3:17])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)c1cnccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a 500 ml round bottom flask, pyrazine-2-carboxylic acid (58 g, 467.37 mmol) was suspended in dry CH2Cl2 (250 ml): oxalyl chloride (50.1 ml, 560.85 mmol) was added along with a few drops of DMF, and the mixture was stirred at room temperature for 12 hours. N,O-Dimethylhydroxylamine hydrochloride (54.7 g, 560.85 mmol) was added, and the resultant mixture was cooled down to 5° C. Triethylamine (195 ml, 1402.12 mmol) was added via a dropping funnel, and the reaction mixture was stirred at room temperature for 30 minutes before being filtered. The filter cake was washed with EtOAc, and the combined filtrate was washed with saturated sodium bicarbonate and brine, concentrated to an oil and dried under high vacuum to give the desired product (72 g).