Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CON(C)[C:18]([CH:20]1[CH2:22][CH:21]1[CH3:23])=[O:19]>CCCCCC>[CH3:9][C:4]1[CH:3]=[C:2]([C:18]([CH:20]2[CH2:22][CH:21]2[CH3:23])=[O:19])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: CON(C)C(=O)C1CC1C
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C)cc(C(=O)C2CC2C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-meta-xylene (5.7 mL in 120 mL of dry tetrahydrofuran) at −78° C. was added 30.6 mL of a 1.4M solution of n-butyllithium in hexane and the mixture stirred at low temperature. After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methyl-amide (5.0 g in 50 mL tetrahydrofuran) was added dropwise over 5 minutes and the mixture then allowed to warm slowly to room temperature. After 1 hour, the reaction was quenched by the addition of 20 mL 2N hydrochloric acid and 40 mL water. This was extracted with ethyl acetate washed with saturated sodium bicarbonate and brine then dried over sodium sulfate to give 6.95 g of the title compound (crude).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][NH2:33]>>[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][NH:33][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8](=[O:21])[NH:9]2)=[CH:14][CH:13]=1)=[O:20]
Reactant: CC1CCCCN1CCN
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Product: CC1CCCCN1CCNC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
15 mg (12%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 2-(2-methyl-piperidine-1-yl)-ethylamine (77 mL, 0.544 mmol).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])=[C:11](I)[CH:12]=2)[O:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:4].[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28](/[CH:29]=[CH:30]/[C:11]1[CH:12]=[C:13]2[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[C:6]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:7][C:8]2=[N:9][C:10]=1[N:15]([CH3:16])[S:17]([CH3:20])(=[O:19])=[O:18])#[N:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(/C=C/C#N)cc12
Yield: 70 %

Procedure:
2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (10 mg, 0.020 mmol), acrylonitrile (1.371 mg, 0.026 mmol), palladium(II) acetate (0.446 mg, 1.987 μmol) and triethylamine (2.77 μl, 0.020 mmol) in DMF (1 ml) were heated under microwave irradiation at 120° C. for 40 min. After LCMS showed predominant conversion to product, the reaction mixture was concentrated to dryness, taken up in DMF, filtered and purified by HPLC to afford the title compound (6 mg, 0.014 mmol, 70.5% yield). MS (ESI) m/z 429.3 (M+1). NMR (400 MHz, CD3CN) δ 8.51 (s, 1H), 8.06-8.03 (m, 2H), 7.94-7.89 (d, 1H, J=17 Hz), 7.34-7.30 (m, 2H), 6.91 (br s, 1H), 6.30-6.26 (d, 1H, J=17 Hz) (s, 1H), 3.31 (s, 3H), 3.12 (s, 3H), 2.91-2.89 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19]C1C=CC(F)=CC=1B(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:19])=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1cc(F)ccc1F
Product: O=C(O)c1csc(-c2cc(F)ccc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2,5-difluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[BH4-].[Na+].Cl>C(O)C.O>[CH3:31][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
In 200 mL of ethanol was dissolved 13.0 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one, followed by addition of 1.0 g of sodium borohydride under ice-cooling. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was neutralized with diluted hydrochloric acid under ice-cooling, diluted with water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to recover 12.1 g of a crude product. Purification of this crude product by silica gel chromatography gave 10.6 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3α-ol (yield: 81%) having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:33]([S:40][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Crude 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline was dissolved in 33 mL of dioxane, was treated with Pd2(dba)3 (0.376 g, 0.411 mmol), Xantphos (0.475 g, 0.821 mmol), and n,n-diisopropylethylamine (8.61 ml, 49.3 mmol), and was heated to 60° C. Benzyl mercaptan (1.943 ml, 16.43 mmol) was added, and the reaction mixture was allowed to stir for one hour at 60° C. The reaction mixture was concentrated and was purified by silica gel column chromatography (0 to 75% EtOAc/heptane) to yield 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline (4.616 g, 10.82 mmol, 65.9% yield) with minor impurities. m/z (ESI) 427.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](=[O:13])[CH2:11][OH:12])=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CO.[BH4-].[Na+].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:35][C:34]1[CH:36]=[CH:37][C:31]([S:28]([O:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:14]#[N:15])[CH:4]=[C:3]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[C:2]=2[Cl:1])(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CCC(=O)CO)c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
To a round bottom flask was added tert-butyl (2-chloro-5-cyano-3-(4-hydroxy-3-oxobutyl)phenyl)carbamate (500 mg, 1.476 mmol) and MeOH (1 mL). The solution was then cooled to 0° C. before NaBH4 (100 mg) was added. The reaction was then stirred at 0° C. for 30 min and then slowly warmed to room temperature, and stirred for additional 1 h. The reaction was then quenched with aq. NaHCO3, extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was then dissolved in DCM (10 mL). Pyridine (1 mL) was added. After the reaction was cooled to 0° C. Ts-Cl (310 mg, 1.623 mmol) was added, and the reaction was then allowed to warm to room temperature and stirred for 5 h. The reaction was then taken up with DCM, washed with brine, and concentrated in vacuo to give 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxybutyl 4-methylbenzenesulfonate (810 mg) as a yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[B:21]([OH:22])[OH:20]
Reactant: FC(F)(F)c1ccncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cnccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 15 %

Procedure:
n-Butyllithium (2.5 M in hexane, 2 mL) is added to a mixture of 3-bromo-4-(trifluoromethyl)pyridine (Matrix Scientific, 1 g, 0.022 mol) and triisopropylborate (1.25 mL) in anhydrous THF (9 mL) at −78° C. under nitrogen. The reaction mixture is stirred at −78° C. for 3.5 hr before warming gradually to room temperature. The reaction is quenched with water (9 mL). The organic solvent is removed under reduced pressure. The resulting aqueous phase is treated with NaOH (10 N) to obtain pH 10, washed with diethyl ether (1×8 mL), and aqueous phase is acidified to pH 5 using acetic acid. The solution is extracted with EtOAc (1×25 mL) and the organic layer is dried and evaporated to dryness to give the title compound (0.150 g, 15% yield). LCMS m/z=192.2 [M+H]+, tR=0.36 min.
Reaction SMILES: [N+:1]1([O-:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](OC2C=CC([N+]([O-])=O)=CC=2)=[O:8])[CH:2]=1.[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:22]1>CO>[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[O:31][CH2:32][CH2:33][CH2:34][NH:35][C:7]([C:3]2[CH:2]=[N+:1]([O-:19])[CH:6]=[CH:5][CH:4]=2)=[O:8])[CH2:22]1
Reactant: CC1CCCN(Cc2cccc(OCCCN)c2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc[n+]([O-])c1
Solvent: CO
Product: CC1CCCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To the active ester thus obtained there is added a solution of 3.8 g of 3-[3-(3-methylpiperidinomethyl)phenoxy]propylamine in 70 ml of methanol and the mixture is stirred 3 hours at 50° C. The solvent is evaporated, the residue is taken up with 30 ml of N hydrochloric acid and the acid solution is washed 3 times with 20 ml of ethyl acetate. The pH is adjusted to 7.8, then the solution is salted out with sodium chloride and extracted 6 times with 30 ml of ethyl acetate. The organic extracts are collected and dried over anhydrous sodium sulfate and the solvent in evaporated to dryness. The product is purified by chromatography on silica as described in Example 7. Thus, the N-[3-[3-(3-methylpiperidinomethyl)phenoxy]propyl]-3-pyridinecarboxamide 1-oxide is obtained, identical to the product of Example 8.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:15]([F:16])=[C:14]([C:17](O)=[O:18])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[CH3:22]>>[CH:1]1([NH:8][C:17](=[O:18])[C:14]2[C:13]([F:20])=[C:12]([F:21])[C:11]([CH3:22])=[C:10]([F:9])[C:15]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: NC1CCCCCC1
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCCC2)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using cycloheptylamine and 2,3,5,6-tetrafluoro-p-toluic acid (94%). 1H NMR (CDCl3) δ 1.53 (m, 6H), 1.57 (m, 4H), 2.03 (m, 2H) 2.28 (m, 3H), 4.17 (m, 1H), 5.85 (bs, 1H). MS (304.1, M+H) m. p. 164-165° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25]>CCOC(C)=O>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
To a solution of piperidin-4-ol (11.11 g, 0.11 mol) and Et3N (12.14 g, 0.12 mol) in EtOAc (500 mL) was added 1,2-difluoro-4-nitrobenzene (15.91 g, 0.10 mol). The mixture was stirred at rt for 24 h, and washed with water (200 mL×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as orange oil (19.35 g, 80%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:24][C:23]([Si:20]([CH3:22])([CH3:21])[O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1)([CH3:26])[CH3:25]
Reactant: O=C1N[C@H](CO)CN2CCC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2C(=O)N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.2 %

Procedure:
To a solution of (3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooled in an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was warmed to room temperature and stirred for 14 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). 1H NMR (400 Ah, CDCl3): 6.09-5.90 (m, 1H), 3.86-3.76 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10 (ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H), 2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (EI) for C14H28N2O2Si: 285 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][S:17]([N:20]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)(=[O:19])=[O:18]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:31]2[CH2:32][CH2:33][C:28]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[S:17]([CH3:16])(=[O:18])=[O:19])[CH2:29][CH2:30]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: CS(=O)(=O)N1Cc2ccccc2C12CCNCC2
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC3(CC2)c2ccccc2CN3S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 2-(methylsulfonyl)-2,3-dihydrospiro[isoindole-1,4′-piperidine] (13.2 mg, 0.050 mmol, 1.1 eq), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C24H25N3O4S: 451.1566, found 451.1567.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][CH3:16].[OH-].[Na+]>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:15][CH3:16])[N:7]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(-c2ccccc2)n1
Yield: 23 %

Procedure:
A mixture of 2,4-dichloro-6-phenyl-1,3,5-triazine (16.0 g, 70.8 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (80 mL) was cooled (0° C.), and a solution of NH2Me (8.00 g, 27.5% solution in H2O, 70.8 mmol, 1.00 equiv) was added. The pH of the reaction mixture was adjusted to 9-10 by treating with 1 N NaOH. The pH was maintained at 9-10 for 15 min (product formation monitored by LCMS). The mixture was diluted with water, and filtered to provide 12 g of crude product (filtered solid was washed with additional water). A portion of this material (8 g) was purified by HPLC to afford 3.6 g of the title compound. MS (ES+): m/e 221.1 [M+H]+.
Reaction SMILES: [CH:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[P:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10].C([Li])CCC.CCCCCC>CCOCC>[CH:9]([P:8]([C:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH:12]([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: [Li]C1C=CC=C1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1(P(C(C)C)C(C)C)C=CC=C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
50 ml of ether were placed in a round-bottomed flask containing 1.68 g (0.023 moles) of cyclopentadienyllithium. After cooling of the reaction flask to −20° C., 3.6 g (0.023 moles) of chlorodiisopropylphosphine were added dropwise. When the addition was complete, the cooling bath was heated to 0° C. and the reaction mixture was stirred for 1 h. Ether was then removed under vacuum, the product was dissolved in toluene and the solution was filtered. After the frit had been rinsed with 2×10 ml of toluene, the reaction mixture was cooled to −20° C. and 9.3 ml of a 2.5 molar solution of butyllithium in hexane (0.023 moles) were added to form an orange coloured solution. A small fraction was taken for NMR studies and, after separation of the toluene under vacuum and washing of the resulting oil with hexane, a pale yellow solid (18) was obtained. 1H NMR (400 MHz, THF): δ=5.89 (m, 2H); 5.83 (bs, 2H); 1.86 (m, 2H); 1.0-0.8 (m, 12H).
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([O:12]C)=O.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH2:14][C:15](=[O:16])[CH3:17]
Reactant: COC(=O)c1ccccn1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccccn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A sodium methoxide solution (28% in methanol) was added dropwise to a mixture of 10 g (73 mmol) of methyl picolinate and 25 ml (124 mmol) of acetone in 150 ml of tetrahydrofuran. The mixture was stirred at 20° C. for 3 hours and the solvent was removed under reduced pressure. The residue was taken up in water, acidified with 2-molar aqueous hydrochloric acid and extracted with dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure gave 7.940 g of product (60% of theory).
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: CCOCC
Solvent: C1CCOC1
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]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:9]=2[CH3:10])=[CH:16][CH:15]=1
Reactant: C#CCCn1nnc(-c2ccc(F)cc2)c1C
Reactant: Brc1ccccn1
Product: Cc1c(-c2ccc(F)cc2)nnn1CCC#Cc1ccccn1
Yield: 57.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole (87 mg, 0.38 mmol, Example 257(B)) and 2-bromopyridine (66 mg, 0.42 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 68 g (0.22 mmol, 58%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a white powder (M.P.=130-131° C.).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:24])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:31]1[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]1=[O:30])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:24])[S:11][CH:12]=1)=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)COC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 160 mg of isobutyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 90 mg of rhodanine-3-acetic acid, 50 mg of ammonium chloride, 0.05 ml of 28% v/v aqueous ammonia and 2 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](B(O)O)[CH2:38][CH3:39]>>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:11]([CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH2:37][CH2:38][CH3:39])[CH:3]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])=[CH:28][CH:29]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CCCB(O)O
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Br)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Product: CCCc1cc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)ccc1F

Procedure:
The title compound was prepared in analogy to example 3, using N-[2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide (Example B178) and n-propylboronic acid. 552.2 [ISP (M+H)+]