Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:3]=12.[F:35][C:36]1[C:37]([CH2:42][OH:43])=[N:38][CH:39]=[CH:40][CH:41]=1>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[C:7]([C:7]2[CH:2]=[C:3]([CH:42]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][N:38]=3)[OH:43])[CH:4]=[N:5][CH:6]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:3]=12
Reactant: OCc1ncccc1F
Reactant: CC1(C)OB(c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccccc2F)c2c(Cl)c(-c3cncc(C(O)c4ncccc4F)c3)cnc21
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 176.1 %

Procedure:
A mixture of 4-chloro-3-(2-fluoro-phenyl)-5-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.2 mmol), 5-bromo-pyridin-3-yl)-(3-fluoro-pyridin-2-yl)-methanol (57 mg, 0.2 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (7 mg, 0.01 mmol) in THF/Acetonitrile/saturated NaHCO3 (5 ml/5 ml/5 ml) was stirred at 120° C. in the microwave for 20 minutes. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (2×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded {5-[4-chloro-3-(fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-pyridin-3-yl}-(3-fluoro-pyridin-2-yl)-methanol (102 mg, 88% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:19]1[CH:27]=[CH:26][C:22]2[CH2:23][CH2:24][O:25][C:21]=2[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=O)[CH3:16])[C:8]1=[O:18])[CH3:2].[NH2:29][C:30]1[C:35]([CH:36]=O)=[CH:34][CH:33]=[CH:32][N:31]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:19]1[CH:27]=[CH:26][C:22]2[CH2:23][CH2:24][O:25][C:21]=2[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:8]1=[O:18])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC(C)=O)C1=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 4-2 (540 mg, 1.4 mmol), 2-amino-3-formylpyridine (170 mg, 1.4 mmol; for prep. see JOC 1983, 48, 3401) and proline (161 mg, 1.4 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-3 as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[CH2:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=[O:37].ClC1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2]([CH3:1])=[O:37])=[CH:8][CH:7]=2)[N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[CH2:11]2)=[CH:31][CH:30]=1)#[N:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ccc(C(c2ccc(C#N)cc2)N2CC[C@@H](NC(=O)c3ccc(C#N)cc3)C2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C(c2ccc(C#N)cc2)N2CC[C@@H](NC(=O)c3ccc(C#N)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of (3R)-1-[(4-methylthiophenyl)(4-cyanophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (45.3 mg) in methylene chloride (2 mL) was added trifluoroacetic acid (31 μL) under ice-cooling and the mixture was stirred at room temperature or 30 minutes. Thereto was added m-chloroperbenzoic acid (23 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature for 4 hours. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution and the organic layer was extracted by a diatomaceous earth column (Chem Elut; VARIAN Inc.). The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=98:2→90:10). The resultant product was dissolved in t-buthanol and lyophilized to give (3R)-1-[(4-cyanophenyl)-(4-methylsulfinylphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (42.5 mg, yield: 91%) as a powder. MS(APCI) m/z: 469 [M+H]+
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>C1COCC1.C([Li])(CC)C.O>[C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:14]2[C:9](=[C:10]([B:26]([OH:31])[OH:27])[C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2c(B(O)O)c(F)ccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of 1-(tert-butyl-dimethyl-silanyl)-5-fluoro-1H-indole (30.0 g, 0.12 mol) in anhydrous THF (1000 mL) were added N,N,N′,N′-tetramethylethylenediamine (36.6 mL, 0.241 mol) and a solution of s-butyl lithium (1.4 M in cyclohexane, 172 mL, 0.241 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 2 h, then triisopropyl borate (37.5 mL, 162.7 mmol) was added dropwise. The resulting solution was stirred at −78° C. for 40 min, then allowed to warm to −20° C. An aqueous solution of HCl (2.4 M, 250 mL) was added and the resulting mixture was poured into H2O. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant yellow solid was then crystallised from DCM and cyclohexane to give the title compound as a white solid (25.0 g, 71%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[F:24]>CCOC(C)=O>[F:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of piperidine (5.88 g, 69 mmol) and Et3N (6.98 g, 69 mmol) in EtOAc (60 mL) was added 1,2-difluoro-4-nitrobenzene (10.00 g, 63 mmol) dropwise. The mixture was stirred at rt overnight. The resulting mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (14.00 g, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: BrCc1ccccc1Br
Product: N#Cc1ccc(N(Cc2ccccc2Br)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 2-bromobenzyl bromide
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[S:14]1(=[O:20])(=[O:19])[CH2:18][CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:15]2[CH2:16][CH2:17][CH2:18][S:14]2(=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S1(=O)CCCN1
Reactant: COC(=O)c1ccc(CBr)cc1Br
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1Br
Yield: 55.2 %

Procedure:
Using methyl 2-bromo-4-bromomethylbenzoate (500 mg) and isothiazolidine 1,1-dioxide (216 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (312 mg) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4]O.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: C[Si](C)(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1

Procedure:
Ex-36a) As depicted in Scheme 10, 2-Trimethylsilylethanol is treated with tosyl chloride in pyridine to give 2-trimethylsilyl-1-tosylethane.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:6][O:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1
Reactant: COC1CCC(C(=O)O)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(OC)CC1
Temperature: 25 °C

Procedure:
1.8 ml of concentrated sulphuric acid were added to a solution of 4.00 g (25.3 mmol) of 4-methoxycyclohexanecarboxylic acid in 32 ml of methanol, and the resulting reaction solution was heated under reflux overnight. The mixture was cooled to room temperature and the pH was adjusted to 7-8 using saturated aqueous sodium bicarbonate solution. The mixture was then extracted three times with 70 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product corresponded to the title compound. Yield: 4.30 g (99% of theory)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=3[F:23])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].ClC(Cl)C.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][C:16]=3[F:23])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)N
Reactant: CCCCNc1ccc2ncc(-c3ccc(C=O)cc3F)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCNc1ccc2ncc(-c3ccc(CNC(C)(C)C)cc3F)n2n1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A mixture of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3-fluoro-benzaldehyde (120 mg, 0.40 mmol) and dichloroethane (DCE, 4 mL) was treated with tert-butyl amine (0.050 mL, 0.50 mmol) and the resulting reaction mixture was maintained at RT for 20 min. The reaction was then treated with sodium triacetoxyborohydride (170 mg, 0.80 mmol) and the resulting mixture was maintained until LCMS indicated complete consumption of the aldehyde. The reaction was quenched with saturated aqueous sodium bicarbonate, the layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford butyl-{3-[4-(tert-butylamino-methyl)-2-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amine (98 mg, 67%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.21 (dd, J=12.3, 1.5 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=9.7 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.68 (d, J=9.7 Hz, 1H), 4.02 (s, 2H), 3.34 (t, J=7.2 Hz, 2H), 1.84 (s, 1H), 1.61-1.71 (m, 2H), 1.39-1.50 (m, 2H), 1.32 (s, 9H), 1.25-1.30 (m, 1H), 0.91-0.99 (m, 3H); LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H29FN5 370.2].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:10]([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:9][C:3]=1[CH:4]=[CH:5]C([O-])=O.[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:10]([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:9][C:3]=1[CH:4]=[CH2:5]
Reactant: COCCOCOc1cc(Cl)c(C=CC(=O)[O-])cc1OCOCCOC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: C=Cc1cc(OCOCCOC)c(OCOCCOC)cc1Cl
Yield: 34.2 %

Procedure:
Using the procedure of Stage C of Example 40, 60.8 g of the ester of Stage C and 293 ml of a molar solution of diisobutyl-aluminum hydride in hexane were reacted to obtain 18.5 g of the expected product.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:17][O-:18].[Na+]>CN(C)C=O.O>[CH3:17][O:18][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[N:7]3[CH2:13][CH2:12][CH2:11][C@H:8]3[CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(F)cc2OC[C@@H]2CCCN12
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC[C@@H]1CCCN1C2=O
Temperature: 110 °C

Procedure:
A solution of (S)-8-fluoro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]-benzoxazepine-5-one (0.5 g; 2.14 mmol), prepared as described in Example 5A, and sodium methoxide (0.244 g; 4.52 mmol) in dimethylformamide (2 mL) was heated at 110° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) to give the title product, m.p. 104-106° C.; EIMS: m/z=234 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:11]([I:16])=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1N
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)cc(I)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
A solution of methyl 2-amino-5-(trifluoromethyl)benzoate (0.59 g, 2.7 mmoles) in trifluoroacetic acid (5 ml) was treated with N-iodosuccinimide (0.68 g, 3.0 mmoles) and stirred at ambient temperature for 18 h. The mixture was evaporated to dryness and the residue treated with water (25 ml) and basified with potassium carbonate then extracted with dichloromethane (25 ml). The organic phase was then washed with 10% sodium metabisulphite solution (25 ml), separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 2 as a white solid (0.633 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]([F:41])([F:40])[CH:37]1[O:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:38][CH:37]([OH:39])[C:36]([F:41])([F:40])[F:35])[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:27])[F:28])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)NCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)NCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
100 mg (0.24 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[2-(trifluoromethyl)benzyl]-acetamide from Example 243A are placed with 119 mg (0.37 mmol) of caesium carbonate in 0.6 ml of DMSO and treated with 137 mg (1.22 mmol) of 1,1,1-trifluoro-2,3-epoxypropane. This is stirred for 3 hrs at 120° C. Next, 137 mg (1.22 mmol) of 1,1,1-trifluoro-2,3-epoxypropane are again added and the mixture stirred for a further hour at 120° C. The suspension is then cooled to RT, diluted with ethyl acetate and washed three times with saturated ammonium chloride solution. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 30.6 mg (24% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:19]Br)=[O:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:19][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH:8]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (501 mg) and 2-bromo-4-methylacetophenone (638 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one and three quarter hours, then cooled and the solid filtered off. The filtrate was evaporated, the residue was diluted with water (100 ml) and the product was extracted with ethyl acetate (3×50 ml). This was combined with the solid and crystallised from acetone: yield 306 mg, m.p. 214°-217° dec: λmaxEtOH 253 nm (ε 19760), 332 nm (ε 2620), λinf 232 nm (ε 11040).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([CH:10]=O)[CH2:7]1.[CH3:22][NH:23][C:24]1[CH2:28][S:27][C:26](=[O:29])[N:25]=1.CC(C)([O-])C.[K+].O>C(O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8](/[CH:10]=[C:28]2/[C:24]([NH:23][CH3:22])=[N:25][C:26](=[O:29])[S:27]/2)[CH2:7]1
Reactant: CNC1=NC(=O)SC1
Reactant: O=CC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CNC1=NC(=O)S/C1=C\C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Yield: 9.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azetidine-3-carbaldehyde (90 mg) and 4-(methylamino)-1,3-thiazol-2(5H)-one (38 mg) in ethanol (3 mL) was added potassium tert-butoxide (32 mg) at room temperature, and the mixture was stirred with heating under reflux for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: Nc1ccc(Br)cc1N
Reactant: O=CC=O
Solvent: CO
Product: Brc1ccc2nccnc2c1
Yield: 51 %

Procedure:
In a round bottom flask under nitrogen was combined 4-bromo-benzene-1,2-diamine (2.01 g, 10.7 mmol), methanol (50 mL), and glyoxal (40% by wt. 3.1 mL, 26.9 mmol) and the resulting solution stirred overnight. The reaction was then concentrated in vacuo and purified by flash column chromatography on silica gel using 5-10% ethyl acetate in dichloromethane as eluant to yield 1.14 g (50% yield) of 6-Bromo-quinoxaline as a yellow-orange solid. 1H NMR (DMSO-d6): 9.00 (d,2H,J=2.8 Hz), 8.36 (d,1H,J=2.2 Hz), 8.07 (d,1H,J=9.0 Hz), 8.02 (dd,1H,J=8.8,2.1 Hz). CHN for C8H5BrN2: calc. C 45.97, H 2.41, N 13.4; found C 45.99, H 2.09, N 13.09. LC/MS (Method A): r.t.=1.10 min., purity=99%, calculated mass=208, [M+H]+=209/211. HPLC (Method B): r.t.=7.4 min., purity=98.52% at 210-370 and 98.8% at 322 nm.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](N)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:27][C:28]1C=CC(C(N)=O)=C[CH:29]=1>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([O:27][CH2:28][CH3:29])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(N)=O)cc3)ccc21
Reactant: NC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzamide-Using 4-hydroxybenzamide, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.35 (6H, s), 1.37 (6H, s), 1.76 (4H, s), 7.32 (2H, d, J~8.6 Hz), 7.48 (1H, d, J~8.4 Hz), 7.89-7.98 (3H, m), 8.17 (1H, d, J~1.9 Hz).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][O:20][CH:21]([O:30][CH3:31])[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH3:32][N:33]1[C:37]([C:38]2[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=2)[CH2:41][CH2:42][O:43][CH2:44][CH2:45][C:46](O)=[O:47])=[N:36][N:35]=[N:34]1.C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C>[CH:24]1([N:23]([CH2:22][CH:21]([O:30][CH3:31])[O:20][CH3:19])[C:46](=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41][C:40]2[CH:49]=[CH:50][CH:51]=[C:38]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][N:36]=3)[CH:39]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1nnnc1-c1cccc(CCOCCC(=O)O)c1
Reactant: COC(CNC1CCCCC1)OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(CN(C(=O)CCOCCc1cccc(-c2nnnn2C)c1)C1CCCCC1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of T3P (0.52 mL) dissolved in THF (1.57M) was added in one portion to a stirred solution of N-(2,2-dimethoxyethyl)cyclohexanamine (0.09 mL), 3-(3-(1-methyl-1H-tetrazol-5-yl)phenethoxy)propanoic acid [Example 8, Step i)] (0.11 g) and triethylamine (0.69 mL) in acetonitrile (2 mL) at 25° C. The resulting solution was stirred at 25° C. for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane to afford the subtitled compound (0.10 g). 1H NMR (400 MHz, CD3OD) δ 7.68 (s, 1H), 7.65-7.60 (m, 1H), 7.54-7.48 (m, 2H), 4.52 and 4.37 (2×t, J=5.3 Hz, 1H), 4.18 and 4.18 (2×s, 3H), 4.05-3.95 and 3.68-3.61 (2×m, 1H), 3.76-3.67 (m, 4H), 3.35 and 3.33 (2×s, 6H), 3.25 (d, J=5.1 Hz, 2H), 2.96 and 2.95 (2×t, J=6.3 Hz, 2H), 2.66 and 2.64 (2×t, J=6.6 Hz, 2H), 1.82-1.04 (m, 10H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1>>[N:1]1[NH:2][N:3]=[C:15]([C:11]2[CH:10]=[C:9]([NH2:8])[CH:14]=[CH:13][CH:12]=2)[CH:16]=1
Reactant: C#Cc1cccc(N)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: Nc1cccc(-c2cn[nH]n2)c1
Temperature: 150 °C

Procedure:
The mixture of azidotrimethylsilane (137 μL, 1.03 mmol) and 3-amino-phenylacetylene (117 mg, 1.00 mmol) was heated in a sealed tube at 150° C. for 16 h. After that time, the mixture was cooled down and triturated by EtOAc/hexane (50%, 10 mL). The mother liquor was purified by TLC eluting with 7% MeOH/CH2Cl2. to give the title compound as brown oil. 1H NMR (CD3OD, 400 MHz): δ=6.61-6.64 (m, 1H), 7.01-7.09 (m, 3H), 7.94 (s, 1H). MS (ES+): m/z 161.20 (38) [MH+]. HPLC: tR=1.54 min (ZQ2000, polar—5 min).