Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21].Cl[C:32]([O:34][CH3:35])=[O:33]>O1CCCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([N:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(Cl)ccc2c1C(F)(F)F
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 0.42 h
Yield: 67 %

Procedure:
To a suspension of potassium hydride (0.9 g, 1.2 eq, 35% by weight dispersion in mineral oil) in dry tetrahydrofuran (20 mL) under argon at room temperature was added dropwise a solution of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (2.73 g, 6.53 mmol) in dry THF (30 mL). After stirring 25 minutes the reaction was cooled in an ice bath and a solution of methyl chloroformate (0.7 mL, 1.4 eq) in dry THF (18 mL) was added dropwise over a period of 20 minutes. After stirring 1 hour the reaction was quenched with saturated aqueous ammonium chloride and diluted with ether (300 mL). The ether layer was separated, and dried over magnesium sulfate. Silica gel was added and the ether was removed. The silica absorbate was flash chromatographed (4:1 petroleum ether:EtOAc) to give the title compound as a white solid (2.10 g, 67%). A small sample was further purified by trituration with petroleum ether, m.p. 117°-118° C.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].[C:11](#[N:14])[CH:12]=[CH2:13].N(C1C=NC=CC=1)N>>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:3]2[CH2:13][CH2:12][C:11]([NH2:14])=[N:4]2)[CH:6]=1
Reactant: C=CC#N
Reactant: NNc1cccnc1
Agent: Cl
Product: NC1=NN(c2cccnc2)CC1

Procedure:
In a typical reaction, 3-hydrazinopyridine.dihydrochloride and an anhydrous alcohol are introduced into a reaction vessel and the alkoxide base is gradually added. The mixture is stirred and the acrylonitrile is added. The mixture is stirred at about 60° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude 1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>C(OCC)(=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(CCO)n1
Reactant: BrCCCCCCBr
Solvent: CCOC(C)=O
Product: Cc1cccc(CCOCCCCCCBr)n1
Yield: 82.2 %

Procedure:
From 6-methyl-2-pyridineethanol (5 g) and 1,6-dibromohexane (26 g), stirring the reaction mixture under nitrogen for 18 h, and using ethyl acetate for extraction. FCC eluting with cyclohexane→cyclohexane-ethyl acetate (92:8) gave the title compound as a yellow oil (9 g), t.l.c. (System A 80:20:1) Rf 0.6.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1ccc2[nH]ncc2c1
Temperature: 90 °C

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (3.75 g, 0.029 mol) and 5-aminoindazole (4.0 g, 0.03 mol) in water (70 ml) was heated at 90° C. under argon for 1 h. The mixture was cooled, decanted the supernatant and residue was triturated with ethanol, cooled and filtered the solid. It was washed with cold ethanol, and dried. 1H NMR (CD3OD/400 MHz) δ 8.11 (s, 1H), 7.64 (m, 2H), 7.18 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2.0 Hz), 6.07 (m, 1H), 5.81 (d, 1H, J=2.8 Hz), and 1.94 (s, 3H); ES-HRMS m/z 242.0962 (M+H calcd for C13H12N3O2 requires 242.0924).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][O:17][C:18]([C:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(CC)CC)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:52].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]([C:20]3[C:32]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:52]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(OCCBr)c1cccc2c1Cc1ccccc1-2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCN1CCN(c2cccc(Cl)c2)CC1)c1cccc2c1Cc1ccccc1-2

Procedure:
To a stirred solution of 2-bromoethanol (3.3 g, 0.026 mol) in 50 mL of methylene chloride, fluorene-1-carboxylic acid chloride (6 g, 0.026 mol) and triethylamine (5 g, 0.05 mol) were added. The reaction mixture was stirred at room temperature overnight. The methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 7 g of the intermediate fluorene-1-carboxylic acid bromoethyl ester. The title compound was prepared by stirring 4-(3-chlorophenyl)piperazine (2.6 g, 0.011 mol), fluorene-1-carboxylic acid bromoethyl ester (3.5 g, 0.011 mol) and triethylamine (2.5 g, 0.025 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.68 in 30% methanol/ethylacetate system) was separated and converted to the dihydrochloride salt with ethanolic HCl (1.8 g, 31% yield), mp. 215°-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](/[N:8]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(Br)cc1
Product: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
A suspension of 4-bromobenzamide (9.50 g, 47.5 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (17.2 mL, 47.5 mmol) in a round bottom flask topped with a short path distillation head was placed in a preheated sand bath at 122° C. The reaction mixture was allowed to stir at this temperature for 1.5 hours, during which time the MeOH that was formed was collected from the distillation condenser. Upon cooling solids were formed and collected by vacuum filtration affording (E)-4-bromo-N-((dimethylamino)methylene)benzamide as a pale yellow solid (9.38 g, 77%) which was used directly in the next step without further purification. LCMS (APCI+) m/z 255, 257 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH2:4][CH2:3]1.[CH3:18][N:19]1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1=[O:25]>C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]2[CH:8]=[C:6]3[CH:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]3)[CH:21]3[C:20](=[O:25])[N:19]([CH3:18])[C:23](=[O:24])[CH:22]23)=[CH:15][CH:14]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: COc1ccc(C=CC2=CCCN(C)C2)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2C=C3CN(C)CCC3C3C(=O)N(C)C(=O)C23)cc1
Yield: 35.5 %

Procedure:
A solution of 15 g (0.065 moles) 1,2,3,6-tetrahydro-1-methyl-5-p-methoxystyrylpyridine (free base), 15 g N-methylmaleimide, 150 ml toluene and 20 mgs hydroquinone is refluxed under nitrogen overnight. The solution is allowed to cool and evaporate. Benzene is added and evaporated twice. Water is added, and the oil is extracted with benzene. The organic layers are evaporated. The residue crystallizes and filtration and washing with ether yields 7.85 g 3a,4,6,7,8,9,9a,9b-octahydro-4-(p-methoxyphenyl)-2,7-dimethyl-2H-pyrrolo[3,4-f]-isoquinoline-1,3-dione. Chromatography of the mother liquor on basic alumina (activity II) yields an additional 3.2 g (50%) cyrstals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[CH2:21](I)[CH3:22].[OH-].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][CH3:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC

Procedure:
In analogy to the procedure described for example 2 a], 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (PCT Int. Appl. (2003), WO 2004000785 A2) was reacted with ethyl iodide in the presence of potassium hydroxide to to give 2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13])([CH3:6])[CH3:5].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13])([CH3:6])[CH3:5])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C(=O)CBr)c1ccc(F)c(C#N)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(F)c(C#N)c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a stirred solution of 5-(4-bromo-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (10 g, 35.2 mmol) in DMF (100 mL) at 0° C. was added NaN3 (2.52 g, 38.7 mmol, 1.1 eq) portionwise. After stirring 2 h, the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with brine (100 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex/EtOAc=4:1) to give 5-(4-azido-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (6.6 g, 2 step overall yield 78%). 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (m, 1H), 7.50-7.46 (m, 1H), 7.25 (t, J=7.2 Hz, 1H), 3.8 (s, 2H), 1.55 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18](F)(F)F)[CH:13]=2)=[CH:10][CH:11]=1)=[O:5].[O:27]1C(C2C=C(B(O)O)C=CC=2)=[CH:30][N:29]=[CH:28]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:27][CH:28]=[N:29][CH:30]=3)[CH:13]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1ccc(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: OB(O)c1cccc(-c2cnco2)c1
Product: O=C(Nc1ccc(-c2cccc(-c3cnco3)c2)s1)c1c(F)cccc1F

Procedure:
Compound 121 was synthesized in an analogous fashion as described for Compound 117 except that 3-(oxazol-5-yl)-benzeneboronic acid was used instead of 3-trifluoromethylbenzeneboronic acid in the final step.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10]C1C2N=C(CCCC)N(CCN)C=2C2N=CC=CC=2N=1>>[CH:1]1([C:7]([NH2:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: NC(=O)C1CCCCC1

Procedure:
Using the general method of Example 92, cyclohexanecarbonyl chloride (94 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N12-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide as a white powder, m.p. 188-190° C. Analysis: Calculated for C22H30N6O: %C, 66.98; %H, 7.66; %N, 21.30. Found: %C, 66.72; %H, 7.57; %N, 21.48. HRMS (EI) calcd for C22H30N6O (M+) 394.2481 found 394.2475.
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([O:25][C:26]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CNCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCNCC1
Yield: 65.5 %

Procedure:
To 230 ml of dimethylformamide were added 25 g of homopiperazine and 5.4 g of sodium bicarbonate and then 25 ml of water followed by dropwise addition of 10 g of benzyloxycarbonyl chloride with stirring under ice cooling, and the mixture was stirred at a room temperature overnight. After evaporating off dimethylformamide under a reduced pressure, the reaction mixture was extracted three times with 100 ml of chloroform, and the extract was dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (9:1), to obtain 9 g of the title compound as a light yellow liquor liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: Fc1cccc(N2CCNCC2)n1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=109-111° C.
Reaction SMILES: [CH3:1][Mg+].[Br-].Cl[C:5]1[C:14]([F:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1.[OH-].[NH4+]>C1COCC1.CCOCC>[F:15][C:14]1[C:5]([CH3:1])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2
Reactant: C[Mg+]
Reactant: COc1ccc2cc(F)c(Cl)nc2c1
Agent: [Br-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2cc(F)c(C)nc2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51.2 %

Procedure:
To a suspension of Cu(I)Br (1.49 g, 10.4 mmol) in THF (30 mL) was added 3M MeMgBr (6.93 ml, 20.8 mmol) in ether at −78° C. After stirring at −78° C. for 5 minutes, 2-chloro-3-fluoro-7-methoxyquinoline (0.55 g, 2.60 mmol) in THF (10 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour, then allowed to warm to ambient temperature and stirred for 20 hours. Ammonium hydroxide (10 mL) was added slowly. The mixture was stirred at ambient temperature for 10 minutes, then passed through a pad of Celite® and washed with ether (50 mL). The filtrated was washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography 3:1 hexane/ethyl acetate to give 3-fluoro-7-methoxy-2-methylquinoline (0.255 g, 1.33 mmol, 51.3% yield) as a solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([CH2:36][N:37]([CH2:45]OC)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:45][N:37]([CH2:36][CH:33]1[CH2:34][CH2:35]1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(CC1CC1)C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
(R)-4-Benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (2.0 g, 6.06 mmol) was added to a flask in DCM (75 ml) followed by TiCl4 (1.38 g, 7.28 mmol) and DIEA (0.823 g, 6.37 mmol). The reaction was allowed to stir for about 15 to about 20 minutes at −78° C. at which point tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (1.57 g, 7.28 mmol) was added. The reaction allowed to stir for 5 minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction was then allowed to stir for 3 hours at room temperature. After the reaction was determined to be complete by HPLC, the reaction was cooled to 0° C. and quenched by the slow addition of aqueous NaHCO3 while stirring for 10 minutes. The organic layer was separated, and the aqueous layer was re-extracted (3×EtOAc). The combined organics were dried with MgSO4, filtered and concentrated. The crude residue was purified by column chromatography, eluting 6:1 to 2:1 hexane/EtOAc to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (2.70 g, 87%) as light brown oil. (LCMS (APCI+) [M−Boc+H]+ 412.9; Rt: 4.42 min)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH:19]([F:21])[F:20])[CH:3]=1.CN(C)C(=O)C.[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:20][CH:19]([F:21])[C:11]1[N:10]([C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]3)[CH:3]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: CC(C)(C)OC(=O)NN1CCC(CO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1nc(OCC2CCN(NC(=O)OC(C)(C)C)CC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a mixture of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (1 g) and N,N-dimethylacetamide (10 mL) were added tert-butyl 4-(hydroxymethyl)piperidine-1-carbamate (1 g) and cesium carbonate (3 g), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with hexane-ethyl acetate (1:1). The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (680 mg) as a white amorphous substance.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([OH:15])[CH:14]=1)[CH:10]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>C(O)(=O)C>[S:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:10]1[C:9]1[CH:12]=[C:13]([OH:15])[CH:14]=[C:7]([OH:6])[CH:8]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: Nc1ccccc1S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1cc(O)cc(-c2nc3ccccc3s2)c1
Yield: 48.8 %

Procedure:
An acetic acid (0.8 mL) and sodium acetate (196.6 mg, 2.40 mmol) were added to a suspension including 3,5-dihydroxybenzaldehyde (91.6 mg, 0.66 mmol) and 2-aminothiophenol (0.095 mL, 0.80 mmol, purity: 90%), and then, the reaction mixture was refluxed for 2 hours. The resultant precipitate was filtered, and the filtered product was washed with water and methylene chloride to obtain a gray solid Compound 21 (78.3 mg, 48.6%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].[OH-].[K+]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:17][C:16]([NH2:18])=[N:15][N:14]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(C(=O)O)cc12
Reactant: NNC(N)=S
Agent: [K+]
Agent: [OH-]
Product: Cc1n[nH]c2ccc(-c3nnc(N)s3)cc12
Temperature: 90 °C
Yield: 53 %

Procedure:
To a round bottom flash equipped with an overhead stir motor was added 80 g of polyphosphoric acid. The flask was heated to 90° C. and a finely ground mixture of 3-methyl-1H-indazole-5-carboxylic acid 4e (8.0 g, 45.5 mmol) and thiosemicarbazide (4.1 g (45.4 mmol) was slowly added over a period of 30 min. The resulting mixture was stirred for 24 hr. At this point 200 ml of ice water was added to the solution, and the pH of the resulting mixture was adjusted to 7.0 using solid KOH. A precipitate was formed in the process. The precipitate was isolated by filtration, washed sequentially with water and ether, and dried at reduced pressure, affording 5-(3-Methyl-1H-indazol-5-yl)-[1,3,4]thiadiazol-2-ylamine (4f) (5.50 g, 53% yield) as a tan colored solid. 1H 400 MHz NMR (d6 DMSO), 2.54 (3H, s), 3.17 (1H, s), 7.54 (1H, d, J=8.0 Hz), 7.83 (1H, t, J=8.0 Hz), 8.06 (1H, s). MS (API-ES) m/z (%): 232 (100%, M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=[C:2]2[CH:7]=1
Reactant: COc1ccnc(N)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2ccc(OC)cc2n1
Yield: 58.3 %

Procedure:
A mixture of 2-amino-4-methoxypyridine (1.0 g, 8.1 mmol) and ethyl 3-bromo-2-oxopropanoate (1.77 g, 9.1 mmol) in ethanol (10 mL) was refluxed for 6 h. After the reaction was concentrated, ethyl acetate (20 mL) was added to the residue. The mixture was basified by saturated aqueous sodium bicarbonate. The separated organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=1/1) to afford ethyl 7-methoxyimidazo[1,2-a]pyridine-2-carboxylate as a solid (1.04 g, 58%). 1H-NMR (DMSO-d6, 300 MHz): δ 8.37 (m, 2H), 6.91 (s, 1H), 6.70 (m, 1H), 4.25 (m, 2H), 3.81 (s, 3H), 1.28 (m, 3H) ppm; MS (ESI): 221.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](Cl)=[O:18]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=1[F:1])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1F
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1ccc(Cl)c(Br)c1

Procedure:
3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide was synthesized from 2-fluoro-3-(trifluromethyl)aniline and 3-bromo-4-chlorobenzoyl chloride according to the procedure described in Example 183. 3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide was obtained as a red-orange solid. MS (M−H+) 393.9; Calc'd for C14H7BrClF4NO: 395.