Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
4-Chlorobenzaldehyde (1x, 1.00 g, 7.1 mmol) and acetone (19, 0.26 ml, 3.5 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 3 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.75 g (70%) of yellow crystals: mp 187-189° C. [expected mp 191-193° C.]; 1H NMR: δ 7.00 (d, 2H, J=15.9 Hz), 7.37 (d, 4H, J=8.5 Hz), 7.52 (d, 4H, J=8.5 Hz), 7.66 (d, 2H, J=15.9 Hz); 13C NMR: δ 125.7, 129.2, 129.5, 133.2, 136.4, 141.9, 188.1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].[C-]#N.[Na+].CI>CO>[Br:1][C:2]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Br)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1ccc(N)c(Br)c1

Procedure:
A solution of 2-bromo-4-thiocyanoaniline (11.5 g., 0.05 mole) and sodium cyanide (1.23 g., 0.025 mole) in methanol (100 ml.) is stirred at room temperature overnight. Sodium cyanide (0.025 mole) is then added and the reaction heated at reflux 2 hours and then cooled (0°-5° C.). Methyl iodide is added and stirring continued. Thin layer chromatography shows one product spot. Product is recovered by extraction with methylene chloride, 8.4 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[CH:10]=[C:9]1[CH2:27]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[CH:10]=[C:9]1[CH2:27][N:33]1[C:29](=[O:39])[C:30]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:31]2[C:32]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)n1c(CO)cc2c(C(=O)OCc3ccccc3)cccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(CN2C(=O)c3ccccc3C2=O)cc2c(C(=O)OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonyl-2-hydroxymethylindole-4-carboxylate (465 mg), phthalimide (179 mg) and triphenylphosphine (640 mg) in tetrahydrofuran (15.0 ml) was added diethyl azodicarboxylate (425 mg) and the mixture was stirred at ambient temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was chromatographed on silica gel with n-hexane:ethyl acetate (6:1). The solid was triturated with methanol to give benzyl 1-tert-butoxycarbonyl-2-phthalimidomethylindole-4-carboxylate (440 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC1=NC(C)(C)CO1
Reactant: O=Cc1cccc(Cl)c1
Product: CC1(C)COC(C=Cc2cccc(Cl)c2)=N1

Procedure:
2-(2-m-Chlorophenylethenyl)-4,4-dimethyl-2-oxazoline (P-1895) was prepared by reacting m-chlorobenzaldehyde with 2,4,4-trimethyl-2-oxazoline.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc(Cl)cc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1F)c1ccccc1O

Procedure:
To a solution of salicylic acid (1.38 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 4-chloro-2-fluorobenzenamine (1.1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:60]1[C:65]([C:66]2[N:70]([CH2:71][CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[C:69]3[CH:78]=[C:79]([F:83])[C:80]([F:82])=[CH:81][C:68]=3[N:67]=2)=[CH:64][CH:63]=[CH:62][N:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:60]2[C:65]([C:66]3[N:70]([CH2:71][CH:72]4[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77]4)[C:69]4[CH:78]=[C:79]([F:83])[C:80]([F:82])=[CH:81][C:68]=4[N:67]=3)=[CH:64][CH:63]=[CH:62][N:61]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A solution of 4-hydroxymethyl-benzoic acid methyl ester (0.14 g, 0.84 mmol; CAS Reg. No. 6908-41-4), palladium (II) acetate (19 mg, 0.084 mmol; CAS Reg. No.) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (52 mg, 0.084 mmol; CAS Reg. No.) in dry toluene (10 ml) was stirred at 25° C. for 5 min. under argon atmosphere. To the resulting deep red solution was then added a solution of 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Ex. 1, intermediate a, 0.30 g, 0.84 mmol) in toluene (5 ml) and cesium carbonate (0.82 g, 2.52 mmol). The flask was purged with argon, and the reaction mixture was heated at 100° C. for 12 h. The solid was filtered, the filtrate concentrated in vacuo and the residue was purified by column chromatography over silica gel (15-20% ethyl acetate/n-hexane) to afford the title compound as brown sticky solid (60%). MS (Turbo Spray): m/z=492.3 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][Si](C)(C)C)=[CH:5][N:4]=[C:3]1[C:13]([OH:16])([CH3:15])[CH3:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:13]([OH:16])([CH3:14])[CH3:15])=[N:4][CH:5]=1)#[CH:8]
Reactant: Cn1c(C#C[Si](C)(C)C)cnc1C(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cnc(C(C)(C)O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To 2-(1-Methyl-5-trimethylsilanylethynyl-1H-imidazol-2-yl)-propan-2-ol (100 mg, 0.42 mmol) in 5 mL of THF was added IM TBAF in THF (1.3 mL, 1.3 mmol). The reaction was stirred at rt overnight, and then was diluted with 50 mL of water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine and dried with MgSO4, filtered, and concentrated to provide 58 mg of 2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])(O)=O.[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+].[O:26]=[C:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=2)[NH:28]1.[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:42]=1[CH2:43]Br>O.CC(C)=O>[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:42]=1[CH2:43][S:36]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:26])[CH2:35]2)(=[O:38])=[O:37]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Temperature: 30 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
Sodium monohydrogen phosphate dodecahydrate (142 g, 1.0 mol) and sodium sulfite (252 g, 2.0 mol) were dissolved in 2 L of water at room temperature, heated to 30° C., and added with 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 64b (232 g, 1.0 mol). Upon completion of the addition, the reaction mixture was stirred at 60° C. for 16 hours. A solution of 2,6-dichlorobenzyl bromide (240 g, 1.0 mol) in acetone (1.8 L) was added to the above solution, stirred at 60° C. for 1 hour, added with another acetone (200 ml) and stirred for another 2 hours. The reaction mixture was quenched with water (5 L), stirred at room temperature for 1 hour and filtered. The filter cake was washed with water (1 L) and acetone (1 L), and dried in vacuo to obtain the title compound 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (314 g, yield 88%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: Clc1ccc2c(ccn2Cc2ccccc2)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(ccn2Cc2ccccc2)n1
Temperature: 100 °C

Procedure:
A sealable vial was charged with 1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.25 g, 1.0 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (0.239 g, 1.03 mmol, Aldrich), tris(dibenzylideneacetone)dipalladium(0) (0.075 g, 0.082 mmol, Aldrich), 1,1′-bis(diphenylphosphino)ferrocene (0.0685 g, 0.124 mmol, Aldrich), cesium carbonate (0.336 g, 1.03 mmol), and toluene (2 mL). The mixture was degassed by a stream of nitrogen through the solution and the vial was then sealed and heated to 100° C. for 2 days. The crude reaction mixture was diluted with DCM, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded product (0.13 g, 29%).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[N:11][N:12]=2)[N:9]=1.[CH:22]([C:24]1[CH:25]=[CH:26][C:27]2N(C(CNC(=O)OC(C)(C)C)=NN=2)N=1)=O.Cl.NO.[OH-].[Na+]>C1COCC1>[CH:25]1([C:24]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]4[N:8]([C:10]([CH2:13][NH2:14])=[N:11][N:12]=4)[N:9]=3)[CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(/C=N/O)nn12
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1nnc2ccc(-c3cc(C4CC4)on3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
(E)-tert-butyl (6-((hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. Tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (400 mg, 1.44 mmol) and hydroxylamine hydrochloride (200 mg, 2.86 mmol) were combined in a flask with 25 mL of THF and 25 mL of 1 N NaOH solution. Stirred at rt for 1 h. Then added dichloromethane (50 mL) and extracted the aqueous layer 3 times with DCM (50 mL), dried over Na2SO4 and concentrated. Purified the oxime via MPLC (DCM/MeOH+1% NH4OH) to give title compound (200 mg, 47% yield) as a tan solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[N+]=[N-])[CH2:15][S:16][C@H:11]12)=[O:8].[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([NH2:17])[CH:15]([S:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[S:16][C@H:11]12)=[O:8]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: Sc1ccccc1
Solvent: ClCCCl
Product: NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1Sc1ccccc1

Procedure:
To a solution of 0.675 g. of p-nitrobenzyl 7β-(2-thienylacetamido)-3-azido-3-cephem-4-carboxylate in 33 ml. of 1,2-dichloroethane were added 5 equivalents (0.74 g.) of thiophenol and the solution was heated at the reflux temperature for 90 min. The reaction mixture was evaporated to dryness and the reaction product residue was chromatographed over 8 g. of silica (Merck, toluene) using 500 ml. of toluene vs. 500 ml. of 50% ethyl acetate:toluene. The early fractions (23-26) contained a mixture of starting material and the title compound. The middle fractions (31-36) contained 0.035 g. of the title compound while the later fractions (45-59) contained 0.236 g. of the 3-amino ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.CCN(C(C)C)C(C)C.[Cl-].[CH:23]1([O:29][C:30]([C:32]2[N:33]=[C:34]([CH:37]3[CH2:42][CH2:41][NH2+:40][CH2:39][CH2:38]3)[S:35][CH:36]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:40]1[CH2:39][CH2:38][CH:37]([C:34]2[S:35][CH:36]=[C:32]([C:30]([O:29][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:31])[N:33]=2)[CH2:42][CH2:41]1)=[O:12]
Reactant: O=C(O)Cc1cc(Br)ccc1Br
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cc3cc(Br)ccc3Br)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,5-Dibromophenyl)acetic acid (323 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (VII-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromotrispyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-{1-[(2,5-dibromophenyl)acetyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (250 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(Br)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
To a solution of 4-bromo-2-methoxyphenol (2.87 g, 14.13 mmol) in DMF (20 ml) was added ethyldiisopropylamine (6.15 ml, 35.32 mmol). The clear solution was stirred for 5 min. followed by addition of tert-butylchlorodimethylsilane (2.56 g, 16.95 mmol). The crude was purified via flash column chromatography (100% in hexane) to give (4-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane as a clear oil (4.45 g, 99%): 1HNMR (CDCl3) δ 6.95 (s, wide, 1H, Ar), 6.92 (d, J=2 Hz, 1H, Ar), 6.71 (d, J=7 Hz, 1H, Ar), 3.79 (s, 3H, OCH3), 0.98 (s, 9H, 3CH3), 0.13 (s, 6H, 2CH3). The product was carried over to the next step.
Reaction SMILES: C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.O.[C:17]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:22]=[CH:21][CH:20]=[C:19]([N:23](COCC[Si](C)(C)C)[C:24]2[O:28][C:27]([C:29]([N:31]([C:40]3[CH:41]=[N:42][C:43]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:44][CH:45]=3)COCC[Si](C)(C)C)=[O:30])=[N:26][N:25]=2)[CH:18]=1>C(Cl)Cl>[C:17]1([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]2[O:28][C:27]([C:29]([NH:31][C:40]3[CH:41]=[N:42][C:43]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:44][CH:45]=3)=[O:30])=[N:26][N:25]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCN(C(=O)c1nnc(N(COCC[Si](C)(C)C)c2cccc(-c3ccccc3)c2)o1)c1ccc(N2CCOCC2)nc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nnc(Nc2cccc(-c3ccccc3)c2)o1
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
Anisole (0.14 mL, 1.30 mmol) and a mixture of TFA:water (9:1) (3 mL) was added to (5-(biphenyl-3-yl{[2-(trimethylsilyl)ethoxy]methyl}amino)-N-(6-morpholin-4-ylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4-oxadiazole-2-carboxamide (Intermediate 49, 180 mg, 0.28 mmol). After 30 minutes the mixture was by diluted with DCM (40 mL) and washed with 1M aqueous NaHCO3 (20 mL). The DCM layer was separated and MeOH (5 mL) was added. The aqueous was again extracted with MeOH:DCM (1:9) (4×10 mL). DMF (5 mL) was added to the aqueous and the aqueous was extracted with MeOH:DCM (1:9) (2×10 mL). All organics were combined, dried, filtered and evaporated to give a solid which was triturated with hot Et2O (10 mL) and washed with Et2O (2×5 mL) then hexane (2×5 mL). Chromatography through silica using 0-100% DCM/EtOAc then 10% MeOH/DCM as eluent gave the title compound (30 mg, 24%) as a solid; 1H NMR δ 11.10 (1H, s), 10.98 (1H, s), 8.53 (1H, d), 7.99-0.93 (1H, m), 7.91 (1H, s), 77.67-7.61 (3H, m), 7.54-7.47 (3H, m), 7.41 (1H, t), 7.35 (1H, d), 6.88 (1H, d), 3.74-3.69), (4H, m), 3.45-3.40 (4H, m); MS m/e MH+ 443.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]=[C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[C:57]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)[CH:58]=2)[O:53][CH:52]=[CH:51]1>CN(C=O)C>[O:49]=[C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[C:57]([C:60]3[CH:61]=[C:62]([NH:66][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:63]=[CH:64][CH:65]=3)[CH:58]=2)[O:53][CH:52]=[CH:51]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3occc(=O)c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3occc(=O)c3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 25.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(4-oxo-4H-chromen-6-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 426 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:24])([F:23])[CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([C:16]([F:24])([F:23])[F:15])[CH2:18]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: FC(F)(F)C1CCCNC1
Product: Nc1nnc(N2CCCC(C(F)(F)F)C2)c(-c2ccccc2)n1
Yield: 7.8 %

Procedure:
5-Phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine (50 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethyl)piperidine (0.40 g, 2.58 mmol) according to the general procedure of Example 2.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br>C(Cl)Cl>[Br:15][C:8]1[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: CCc1ccccc1C=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 2-ethylbenzaldehyde (0.98 mL, 7.45 mmol) and AlCl3 (1.74 g, 13 mmol) in DCM (4.5 mL) at 0° C. is treated with a solution of Br2 (0.38 mL, 7.45 mmol) in DCM (4.5 mL) dropwise over 6 h then stirred 16 h at RT. After this time, the reaction mixture is poured over ice-water (50 mL), the layers separated and the aqueous layer extracted with DCM (3×50 mL). The organic phases are combined and washed with 2M HCl (100 mL), aqueous NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4 then the solvents removed in vacuo. Purification by column chromatography (gradient elution—100% heptane increasing to 10% EtOAc in heptane) gives the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:25])([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:25][C:11]1([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(Oc2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(Oc2ccccc2C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-methyl-4-(2-trifluoromethylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.025 g, 0.070 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at ambient temperature for 24 hours and then quenched with saturated aqueous solution of Na2CO3 (5 mL). The organic phase was washed with water (10 mL), saturated NaCl (10 mL), dried over MgSO4 and then concentrated in vacuo. The crude title compound was obtained and used without further purification.
Reaction SMILES: C([CH2:4][CH:5]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:17])[CH:11]=2)[C:6]1([CH3:19])[CH3:18])(O)=O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl-:37].[Li+]>C1C=CC=CC=1>[Cl:37][CH2:4][CH:5]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:17])[CH:11]=2)[C:6]1([CH3:19])[CH3:18]
Reactant: [Cl-]
Reactant: Cc1ccc2c(c1)C(C)(C)CC(CC(=O)O)C2(C)C
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)CC(CCl)C2(C)C
Reaction time: 6.5 h
Yield: 65.2 %

Procedure:
To a solution of 2-carboxymethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (30 g; 0.115 mol) in benzene (570 g), lead tetraacetate (66 g; 0.149 mol) and anhydrous lithium chloride (11.5 g; 0.271 mol) were added, and the temperature was elevated up to 80° C. After stirring for 6.5 hours, the reaction mixture was washed with water and dilute hydrochloric acid in order. After extraction of the unreacted carboxylic acid with 6% ammonia water, the benzene layer was dried over anhydrous sodium sulfate and concentrated to give 2-chloromethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (18.9 g; 0.075 mol). From the ammonia water layer, there was recovered the unreacted carboxylic acid (9.8 g).