Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[O:11][C:10](=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10](=[O:19])[O:11]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-fluorophenyl)-7-methyl-2H-chromen-2-one (24.0, 94.3 mmol), NBS (18.5 g, 103.8 mmol) and benzoyl peroxide (1.14 g, 4.72 mmol) in 470 mL of CCl4 was brought to reflux. The solution was left overnight at reflux and then filtered hot. Once cooled to rt the solvent was removed, the compound was dissolved in CH2Cl2 and a purification was done with a small pad of silica gel using hexane-EtOAc (8/2) to (1/1). The solvent was removed and the solid triturated with hexane-EtOAc and filtered to give the title compound. The remaining solvent was removed to give additional compound contaminated with some starting material and dibromo compound. 1H NMR (400 MHz, acetone-d6): δ 7.67 (2H, m), 7.55 (1H, s), 7.50 (1H, d), 7.40 (3H, m), 6.40 (1H, s) and 4.75 (2H, s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[O:26]=[C:27]1[N:36]([CH:37]([CH3:41])[C:38]([OH:40])=O)[CH:35]=[CH:34][C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]1=2.[F:42][C:43]1[C:44]([NH:55][NH2:56])=[N:45][CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH3:54])[CH:53]=2)[CH:48]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:42][C:43]1[C:44]([NH:55][NH:56][C:38](=[O:40])[CH:37]([N:36]2[CH:35]=[CH:34][C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]2=[O:26])[CH3:41])=[N:45][CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH3:54])[CH:53]=2)[CH:48]=1
Reactant: CC(C(=O)O)n1ccc2ncccc2c1=O
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NNc1ncc(-c2cnn(C)c2)cc1F)n1ccc2ncccc2c1=O
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
HATU (1053 mg, 2.7 mmol), 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (470 mg, 1.8 mmol) and 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (421 mg, 2 mmol) (step 1 of General Method K) were taken up in 6 mL of acetonitrile. DIPEA (967 μl, 5.5 mmol) was added and the reaction was stirred for 30 minutes, until reaction was complete. The crude material was concentrated and then purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH4OH) to yield N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (500 mg, 67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:53])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([NH2:38]=[O:53])=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)[NH2+][O-])(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (1.0 mmol) and dichloromethane (10 mL). Cool to 0° C. Add portionwise, m-chloroperbenzoic acid (1.0 mmol). After the addition is complete, warm to ambient temperature. After 18 hours, extract the reaction mixture with water. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Purify the residue by chromatography to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (806 mg) in tetrahydrofuran (25 ml) was added triethylamine (1.80 ml). This was cooled in an ice bath under a nitrogen atmosphere, and methanesulfonyl chloride (0.499 ml) was added dropwise, followed by stirring at the same temperature for 30 min. The reaction mixture was partitioned after addition of ethyl acetate (100 ml) and water (70 ml). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a colorless oil (1.05 g, 92.0%).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([N:43]2CCNCC2)=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:9]([N:11]2[CH2:12][CH2:13][N:43]([C:40]3[CH:41]=[CH:42][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=3)[CH2:15][CH2:14]2)=[O:10])[C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: N#Cc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 92.6 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and 1-(4-nitrophenyl)piperazine (183 mg). This was purified by silica gel column chromatography to give the title compound (358 mg) as a white powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCBr
Product: CCOC(=O)CCCCCCCCCBr
Reaction time: 3.5 h
Yield: 98.6 %

Procedure:
To this end, the 180.5 g of 10-bromodecanoic acid from Step II was added to the 11 reactor (described above) along with 645 g of absolute ethanol. The mixture was heated and stirred for about 3.5 h. GC analysis confirmed that reaction was completed when 10-bromodecanoic acid could not be detected. Next, excess ethanol and residual water were removed through evaporation leaving 197.8 g of 94.9% pure ethyl 10-bromodecanoate residue. 150 g MTBE was added to the ethyl 10-bromodecanoate residue which then was washed repeatedly with 10% sodium carbonate solution followed by water. The mixture was phase separated to obtain 340.7 g of a mixture of ethyl 10-bromodecanoate and MTBE. According to GC analysis the yield from Steps II and III was 89.7%.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].Br[CH2:10][C:11]#[N:12].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:11]([CH2:10][C:2]([CH3:1])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])#[N:12]
Reactant: CCC(C)C(=O)OC
Reactant: N#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C)(CC#N)C(=O)OC
Yield: 60.8 %

Procedure:
The reaction of methyl 2-methylbutyrate (13.34 g, 115 mmol) with bromoacetonitrile (16.56 g, 138 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (12.78 g, 126.5 mmol) with butyllithium in hexanes (2.5M, 50.6 mL, 126.5 mmol)) in THF (175 mL), as described above in the preparation of Example 1, gave 16.57 g of the crude product as a dark colored liquid. The crude product was vacuum distilled to give the nitrile (10.85 g, 61%) as a colorless liquid: bp 83°-85° C. (10 mmHg).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C(O)C.[OH-].[K+]>O>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccs1
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1C=C[NH+](C)C1C=Cc1cccs1

Procedure:
A mixture of 5.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2ml of 2-thiophenecarboxaldehyde, 20 ml of absolute ethanol and 1 g of potassium hydroxide is refluxed for 25 minutes. Water is added to the cooled mixture and the resulting solid is filtered off. Recrystallization from ethanol yields 3.8 g of the title compound, melting point 309°-311° C.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:32])=[O:31])[C:20]1=[O:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:31])=[O:32])[C:20]1=[O:39]
Reactant: CC(C)(C)[Si](OC1CCN(c2ccccc2S(=O)(=O)Nc2nccs2)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(O)CCN1c1ccccc1S(=O)(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (5.5 gm, 9.53 mmol) in THF (40 mL) under N2, was added a solution of tetrabutyl ammonium fluoride in THF (1 M, 40 mL, 38.12 mmol). Upon completion of addition, the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with CH2Cl2 (2×50 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (2.6 gm, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.0; tR=0.54 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)[OH:18]
Reactant: O=Cc1ccncc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1ccncc1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol is treated with 4-pyridinecarbox-aldehyde (2.20 ml, 23.0 mmol), then treated with aqueous NaOH (2.5 ml, 50%) at 0° C., stirred for 1 hr at 0° C., warmed to room temperature, stirred for 3 hr. and diluted with water. The resultant mixture is filtered. The filtercake is dried under vacuum to afford the title product as a light yellow solid, 5.2 g (93%) mp 171-173° C., identified by mass spectral and NMR analyses.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(CC2C=CC=CC=2)C=1)CCCCCCCCCCC.C([Li])CCC.[C:54](=[O:56])=[O:55].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:54]([OH:56])=[O:55])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C=O
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Agent: CCCCCCCCCCCCc1cc(Cc2ccccc2)no1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Temperature: -78 °C

Procedure:
To a cold (-78° C.), stirred suspension of 3-dodecyl-5-(phenylmethyl)isoxazole and 5-dodecyl-3-(phenylmethyl)isoxazole (1.64 g, 0.00500 mol) in dry tetrahydrofuran (150 mL) was added dropwise over 3 minutes a 2.06M solution (5.0 mL, 0.010 mol) of n-butyl lithium in hexanes, and the mixture was stirred for 80 minutes under nitrogen. The resulting orange solution was poured into freshly crushed dry ice (~300 g), the mixture was covered with parafilm with a small hole to allow CO2 (g) to escape, and allowed to warm to room temperature over 3 hours. The residue was partitioned between ether and 0.1M HCl. The organic layer was washed (saturated NaCl), dried (MgSO4), and rotoevaporated to a yellow oil. The oil was dissolved in petroleum ether (50 mL). A solid crystallized. It was filtered off and dried in vacuo to give a white solid containing the title compound and 5-dodecyl-α-phenyl-3-isoxazole acetic acid; yield 1.70 g (91%); mp 88°-97° C.
Reaction SMILES: C[C:2]1([C:14]([O-:16])=O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:14]([CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:16])[NH2:18]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)[O-])C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)C1
Temperature: 25 °C

Procedure:
A solution of 1-tert-butyl 3-methylpyrrolidine-1,3-dicarboxylate (1.00 equiv.) and hydrazine (excess of 50% aq. solution) in ethanol (0.2 M final conc.) is heated to reflux. After the reaction is deemed complete, the reaction mixture is cooled to rt and partially concentrated. The resulting mixture is diluted with EtOAc, and the resulting organics are washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-13a.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-:26]>C1COCC1.O>[C:18]([O:17][C:15]([NH:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:11][C:12]([CH3:24])([CH3:23])[C:13]([OH:26])=[O:22])=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution (S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-3,3-dimethyl-2-oxopyrrolidine-1-carboxylate (2.7 g, 7.56 mmol) in THF (27 mL) and water (3 mL) was added LiOH (1 N, 15.2 mL, 15.2 mmol). The reaction mixture was stirred at RT overnight and concentrated. The residue was dissolved in water (20 mL), acidified with 10% citric acid to pH 6-7, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoic acid (2.6 g, 91.7%), which was used without further purification. LRMS (M-Boc+H+) m/z 276.2.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(C(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 15 h

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 2.24 g, 6.63 mmol), 2-bromo-4-trifluoromethylaniline (3.18 g, 13.25 mmol), p-toluenesulfonic acid monohydrate (1.35 g, 7.09 mmol) and xylene (5.0 mL) was stirred at 130° C. for 15 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give crude ethyl 4-[2-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate. The crude material (MS Calcd.: 573; Found: 574 (M+H)) was subjected for the next step without further purification. To a solution of the crude material in tetrahydrofuran (15.0 mL) was added lithium borohydride (193.0 mg, 8.86 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr and warmed to 60° C. and stirred for 19 hr. The reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless powder (110.4 mg, 0.207 mmol, 3.1% (2 steps)).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30].C(Cl)(Cl)Cl>CCOCC.CN(C)C1C=CN=CC=1>[CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][O:21][C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C=NCCCCBr
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C=C(COCCCCCCCCCCCCCCCC)COC(=O)NCCCCBr
Temperature: 22 °C
Reaction time: 22 h

Procedure:
3-Hexadecyloxy-2-methylenepropane-1-ol (from Preparation 1) (2.0 g) was dissolved in ether (40 ml). 4-Dimethylaminopyridine (0.16 g) and 4-bromobutyl isocyanate (1.6 g) were added, and the mixture was stirred for 22 hours at 22° C. Chloroform (40 ml) was added, and the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/chloroform 1:1 as eluent.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([CH:19]=1)[NH2:18].N1C=CC=CC=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C(#N)C>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([NH:18][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:19]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Cl)n2n1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Cl)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A stirred solution of 5-(3-chloro-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.025 g, 0.0867 mmol) in acetonitrile (1 mL) containing pyridine (0.261 mmol) is added trimethylacetylchloride (0.0867 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (0.030 g, 93%) as a white solid: LCMS (m/z)=373.4, 375.3 [M+H]+, tR=2.74 min. (compound same as Example 109)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2cc(N)cc(C)c2n1
Solvent: ClCCl
Product: COc1ccc2cc(NC(C)=O)cc(C)c2n1

Procedure:
A solution of acetic anhydride (0.55 cm3) in dichloromethane (20 cm3) was added dropwise to a stirred solution of 6-amino-2-methoxy-8-methylquinoline (1.0 g) in dichloromethane (30 cm3) at room temperature. After 1 hour the solution was diluted with dichloromethane (50 cm3), washed with saturated sodium carbonate solution (10 cm3), and dried (MgSO4). Evaporation of the solution in vacuo afforded a solid which was recrystallised from dichloromethane/hexane to give 6-acetamido-2-methoxy-8-methylquinoline, m.p. 193°-196° (1.143 g).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 88 %

Procedure:
As described for example 323 g, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (150 mg, 0.46 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (160 mg, 88%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to Example 1 by using 5-butyl-1,3,4-thiadiazole-2-thiol (260 mg, 1.49 mmol), NaH (60% dispersion in mineral oil, 66 mg, 1.65 mmol), and 3-chloropyrazine-2-carbonitrile (210 mg, 1.50 mmol) in DMF and benzene (4 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 3 hr.