Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:21])[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:21])[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)C(=O)Nc3ccccc3C2=O)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(c2ccc(O)cc2)C(=O)Nc2ccccc2C1=O
Yield: 49.5 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(4-methoxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (1.00 g, 3.55 mmol) and BBr3 (17.8 mL, 1.0 M solution in dichloromethane). After normal workup, the pure objective compound (0.47 g, 50%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.81 (s, 3H, CH3), 5.20 (br s, 1H, OH), 6.68 (d, J=8.9 Hz, 2H, ArH), 6.85-7.19 (m, 4H, ArH), 7.45-7.89 (m, 2H, ArH), 8.46 (br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[C:26]1([C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:32]([NH:34][C:35]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:36])(=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolveed in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 94%).
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.[CH3:28][O:29][C:30]([C@@H:32]1[CH2:36][CH2:35][C@H:34]([C:37](O)=[O:38])[CH2:33]1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][O:29][C:30]([C@@H:32]1[CH2:36][CH2:35][C@H:34]([C:37]([N:13]2[CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:15]=3)[CH2:9][C@@H:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:38])[CH2:33]1)=[O:31]
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)O)C1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](C(=O)N2CCN(c3ccc(OC)c(OC4CCCC4)c3)C[C@@H]2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (92 mg, 0.25 mmol) in CH2Cl2 (1 mL) at 0-5° C. was treated with a catalytic amount of DMAP and (1S,3R)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (47 mg, 0.28 mmol) followed by DCC (57 mg, 0.28 mmol). The reaction mixture was allowed to warm to room temperature and stir 1 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 30% then 50% EtOAc/hexanes as eluant to afford intermediate (1R,3S)-3-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid methyl ester as an oil (109 mg, 84%). LC/MS (Method B) 4.14 min, [M+1]+ 521. The intermediate (1R,3S)-3-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid methyl ester was then hydrolyzed with LiOH as described in Example 121, to afford the title compound as a colorless solid (85 mg, 80%) LC/MS (Method B) 3.68 min, [M+1]+ 507.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([S:7][C:8]2[CH:9]([CH3:22])[C@@H:10]3[CH:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[CH2:4][NH:3]1.[Na+].[CH3:24][C:25]1[O:29][C:28](=[O:30])[O:27][C:26]=1[CH2:31]Br>>[O:1]=[C:2]1[CH2:6][CH:5]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O:15][CH2:31][C:26]2[O:27][C:28](=[O:30])[O:29][C:25]=2[CH3:24])=[O:14])[CH2:4][NH:3]1
Reactant: Cc1oc(=O)oc1CBr
Reactant: CC1C(SC2CNC(=O)C2)=C(C(=O)[O-])N2C(=O)C([C@@H](C)O)[C@@H]12
Agent: [Na+]
Product: Cc1oc(=O)oc1COC(=O)C1=C(SC2CNC(=O)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.5 %

Procedure:
Following a procedure similar to that described in Example 39, but using 50 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate and 55 mg of 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide, 50 mg of the title compound were obtained as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][NH:10][CH3:11].O>C1COCC1>[F:1][C:2]1[N:3]=[C:4]([N:10]([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)n1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cccc(F)n1
Temperature: 150 °C

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at −60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>CCOC(C)=O>[N:35]([CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:36]=[N-:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(Cl)c2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(Cl)c2)C1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (15 g, 34 mmol) was dissolved into anhydrous DMF (150 mL), solid NaN3 (6.7 g, 102 mmol, 3 eq) was added and the reaction mixture was heated to 80° C. for overnight. The reaction mixture was cooled to rt and then was added with EtOAc (500 mL), the organic phase was washed with water (3×100 mL) and brine (2×80 mL), dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (13.3 g), which was used for next step without purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]#[C:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)CCC>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(C#Cc3ccccc3)c2c1
Yield: 92 %

Procedure:
This compound was prepared from 6b and tributyl(phenylethynyl)tin according to method J. Orange powder; Yield: 92%; mp 125-129° C.; 1H-NMR (300 MHz, DMSO-d6) δ 7.08 (dd, J=8.8, 8.8 Hz, 1H), 7.36 (dd, J=9.0, 2.6 Hz, 1H), 7.53 (m, 3H), 7.59 (d, J=2.6 Hz, 1H), 7.74 (m, 2H), 7.94 (d, J=9.1 Hz, 2H), 8.05 (dd, J=13.0, 1.8 Hz, 1H), 8.18 (s, 1H), 10.23 (s, 1H), 10.26 (s, 1H); 19F-NMR (300 MHz, DMSO-d6) δ −136.48 (dd, J=13.7, 9.2 Hz); MS (ESI) m/z 354 ([M−H]−), 356 ([M+H]+); Anal. Calcd for C23H14FNO2: C, 77.74; H, 3.97; N, 3.94. Found: C, 76.45; H, 3.88; N, 3.77.
Reaction SMILES: C([NH:8][CH:9]([CH2:23][CH3:24])[CH:10]([C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:15][N:16]=1)[OH:11])(OC(C)(C)C)=O.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:8][CH:9]([CH2:23][CH3:24])[C:10]([C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:15][N:16]=1)=[O:11]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(-c2ccncc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)C(=O)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
2-Bocamino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (334 mg, 1 mmol) and MeCl2 (5 ml) were mixed and TFA (0.5 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 350 mg of 2-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-one TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:22]=1)[O:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15](Cl)=[O:16].N.C(O)C.C[N:36](C)C=O>O>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:22]=1)[O:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15]([NH2:36])=[O:16]
Reactant: CN(C)C=O
Reactant: O=C(Cl)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: N
Solvent: O
Solvent: CCO
Product: NC(=O)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A mixture of {o-[5-(2,4-dichlorophenoxy)-2nitrophenoxy]phenoxy}acetyl chloride (1.11 g, 2.38 mmol), ammonia solution (5 mL of a 35% solution), ethanol (5 mL) and N,N-dimethylformamide (10 mL) is stirred for one hour, poured into water and extracted with an ether/ethyl acetate (1:1) solution. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow oil (1.0 g) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:24]I.S([O-])(O)=O.[Na+]>O1CCCC1.O>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([I:24])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: II
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccccc2)n1
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2)n1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-phenyl-1H-pyrazole (14.6 g) in tetrahydrofuran (80 ml) cooled to −78° C. was added n-butyllithium (1.6M solution in n-hexane, 24 ml) over 5 minutes, and then the mixture was stirred for 1 hour. To this mixture was added a solution of iodine (15.7 g) in tetrahydrofuran (30 ml) over 10 minutes, and the mixture was stirred for additional 1.5 hours. To this mixture were sequentially added water (5 ml) and a saturated aqueous solution of sodium hydrogen sulfite (30 ml), and then the mixture was warmed to 0° C., and additional water (150 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. A precipitated solid was collected by filtration, washed with water and a small amount of methanol, and dried under reduced pressure to give the titled compound (13.0 g).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1.CC1C=CC=CC=1>O>[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN2C(=O)c3ccccc3C2=O)C[C@H]1OC
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of 1.85 parts of 1,3-isobenzofurandione, 4.4 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 45 parts of methylbenzene was stirred for 3 hours at reflux temperature, using a water separator. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with a saturate solution of sodium carbonate and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.5 parts (42,4%) of cis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 208.2° C. (compound 88).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH3:20]>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:25]3[CH2:26][CH2:27][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:23][CH2:24]3)[C:6]=2[CH:17]=1
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.400 g, 1.15 mmol) and 4-propoxy-piperidine (79KS66) (0.332 g, 2.29 mmol) in MeCN (12 mL) were reacted according to GP10 shaking at 60° C. for 3 days and at 70° C. for 1 day. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50-1:20) to give the title compound (108LM30-27) (0.263 g, 63%). 1H NMR (CDCl3) δ 6.96 (dd, J=9.7 Hz, J=2.9 Hz, 1H), 6.91 (dd, J=8.9 Hz, J=4.9 Hz, 1H), 6.66 (dt, J=8.9 Hz, J=2.9 Hz, 1H), 4.56 (ABq, J=15.5 Hz, J=31.7 Hz, CH2), 3.95 (dd, J=13.5 Hz, J=8.1 Hz, 1H), 3.88 (dd, J=13.5 Hz, J=4.7 Hz, 1H), 3.38 (t, J=6.7 Hz, CH2), 3.32-3.23 (m, 1H), 2.79 (bs, 1H), 2.62 (bs, 1H), 2.26-2.12 (m, 3H), 2.19-1.95 (m, 2H), 1.94-1.84 (m, 2H), 1.66-1.53 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=952.8 Hz, 1H), 141.7 (d, J=9.2 Hz, 1H), 130.0 (d, J=42.4 Hz, 1H), 117.7 (d, J=38.4 Hz, 1H), 109.6 (d, J=93.2 Hz, 1H), 103.4 (d, J=114.4 Hz, 1H), 75.2, 69.8, 67.9, 63.7, 52.8, 52.0, 45.7, 31.8, 31.6, 29.5, 23.5, 17.1, 10.9; HPLC-MS (ammonium acetate) [M+H]+=365.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[NH:12])[CH3:11].C(=O)(O)[O-].[Na+].Br[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[N:12]=[C:10]1[CH3:11]
Reactant: CC(=N)Nc1c(Cl)cccc1Cl
Reactant: O=C(CBr)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)cn1-c1c(Cl)cccc1Cl
Temperature: 105 °C

Procedure:
A 500 mL flask was charged with 4.8 g (24 mmol) of N-(2,6-dichlorophenyl)acetamidine, sodium bicarbonate 4.03 g (48 mmol) and 250 mL anhydrous ethanol. 5 g (26.2 mmol) of 3-bromo-1,1,1-trifluoro-propan-2-one was added dropwise. After 1 h solid was filtered off and the filtrate was evaporated in vacuo to give a crude. A mixture of the crude and p-toluenesulfonic acid (668 mg, 3.5 mmol) in toluene was heated to 105° C. for 15 hours. The crude reaction mixture was washed into a separatory funnel with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give the crude product, which was then purified by column chromatography on silica eluting with EtOAc-Hexane (10:0 to 3:2) to afford 1-(2,6-dichloro-phenyl)-2-methyl-4-trifluoromethyl-1H-imidazole as a tan solid (0.9, 43%); 1H NMR (400 MHz, CDCl3): δ 7.52 (m, 2H), 7.43 (m, 1H), 7.19 (m, 1H), 2.2 (s, 3H); MS (ES): 295 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=3[CH:27]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[ClH:28]>CO.O1CCOCC1>[ClH:28].[O:19]1[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=3)=[CH:27][C:14]=2[CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 1,1-dimethylethyl 7-[2-(acetylamino)-1,3-thiazole-5-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.77 mmol) in a mixture of methanol (2 mL) and 4 N hydrogen chloride in dioxane (2 mL) was refluxed for 1 min. After cooling to room temperature the reaction mixture was concentrated, and azeotroped with methanol (3×) to give N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (221 mg, 88% yield) as a colorless solid. MS (EI) for C14H15N3O2S: 290 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[CH3:20][C:21]([S:24]([N:26]=[C:27]1[CH2:30][O:29][CH2:28]1)=[O:25])([CH3:23])[CH3:22]>C1COCC1>[C:21]([S:24]([NH:26][C:27]1([CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH2:30][O:29][CH2:28]1)=[O:25])([CH3:20])([CH3:22])[CH3:23]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CCOC(=O)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N,N-diisopropylamine (78 g, 770 mmol) was dissolved in anhydrous THF (200 mL) and cooled to −78° C. under nitrogen. Butyl lithium (2.5M solution in hexane, 297 mL, 743 mmol) was added drop-wise. The reaction was removed from the cooling bath for 30 minutes, then re-cooled to −78° C. A solution of ethyl propionate (72.8 g, 713 mmol) in anhydrous THF (200 mL) was added drop-wise and the reaction allowed to stir at room temperature for 1 hour. The reaction was cooled to −78° C. once again and a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Preparation 39, 50 g, 285 mmol) in anhydrous THF (200 mL) was added drop-wise. The reaction was stirred at between −40° C. and −60° C. for 4 hours before being quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (ethyl acetate elution) was not successful. The title compound was obtained as a yellow oil (40 g, 51% yield) and used without further purification.
Reaction SMILES: [C:1]([C:3]1([C:16]2[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>[Ni]>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:2][CH2:1][C:3]1([C:16]2[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COCOc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Product: COCOc1cccnc1C1(CNC(=O)c2ccc(Cl)cc2Cl)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 4-cyano-4-[3-(methoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate was reduced using Raney nickel and acylated using 2,4-dichlorobenzoyl chloride using the method exemplified in example 8-1 to afford the desired product: tert-butyl 4-{[(2,4-dichlorobenzoyl)amino]-methyl}-4-[3-(inethoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 8.18 (1 H, dd, J=1.3, 4.5 Hz), 7.50-7.46 (2 H, m), 7.33 (1 H, d, J=1.9 Hz), 7.25 (1 H, dd, J=8.3, 2.0), 7.15 (1 H, dd, J=4.6, 8.3 Hz), 6.70 (1 H, m), 5.25 (2 H, s), 4.01 (2 H, br s), 3.68-3.62 (2 H, m), 3.49 (3 H, s), 3.44-3.38 (2 H, m), 2.75-2.69 (2 H, m), 1.66-1.60 (1 H, m) 1.46 (9 H, s).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -25 °C
Reaction time: 0.58 h

Procedure:
Propionyl chloride (1.8 g) was added dropwise over a period of 15 minutes to a mixture of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (2.0 g) and triethylamine (2.4 g) in dimethylformamide (8 ml) at -30° C. under nitrogen. The reaction mixture was stirred for a further period of 35 minutes at -25° C. and was then poured into 2% hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer was washed with sodium chloride solution and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent to yield the required product as a yellow crystalline solid m.p. 84°-86° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1>>[CH2:10]([O:9][C:7](=[O:8])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)[CH3:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)c1cccs1
Product: CCOC(=O)C(=Nc1cccc(C(F)(F)F)c1)c1cccs1

Procedure:
Intermediate 7 was generated from ethyl thienylglyoxylate and 3-aminobenzo-trifluoride using general method G. The product was then purified on a column of silica gel (heptane/diisopropyl ether) and obtained in the form of a yellow oil.