Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)#[CH:2].[CH2:18]1COC[CH2:19]1.CN(CCN(C)C)C.[Li]CCCC.ICC>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)#[C:2][CH2:18][CH3:19]
Reactant: C1CCOC1
Reactant: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCI
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a N2 inlet was charged with 5-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.2 g, 18.6 mmol; Intermediate 2) and anhydrous THF/TMEDA (9:1, 93 mL). This solution was cooled to −78° C. in an IPA/dry ice bath, and n-BuLi (17.4 mL solution in hexanes, 27.84 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred for 30 minutes at −78° C., and then iodoethane (2.23 mL, 27.84 mmol) was added dropwise over 5 minutes. The mixture was gradually warmed to room temperature, stirred for 1 h, and then heated at 40° C. overnight. Upon completion by LCMS, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (100 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-10% ethyl acetate in hexanes) to give the title compound (1.42 g) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.69 (d, 1H), 7.39 (d, 1H), 5.84 (dd, 1H), 3.89-3.86 (m, 1H), 3.76-3.72 (m, 1H), 2.45-2.36 (m, 3H), 2.04-1.94 (m, 2H), 1.74 (m, 1H), 1.57-1.20 (m, 2H), 1.16 (t, 3H); LCMS: 255 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:19]=2[O:18][CH2:17][C@H:16]([NH:33][CH3:34])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>>[C:45]([O:44][C:43]([NH:42][CH2:41][CH2:40][N:33]([CH3:34])[C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:35]([O:37][CH3:38])=[O:36])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:19]=2[O:18][CH2:17]1)=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: CN[C@H]1COc2c(CN3CCCCC3)cccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: CC(C)(C)OC(=O)NCC=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1c(CN2CCCCC2)cccc1-3

Procedure:
The compound was prepared in analogy to Example 1, Step 6 from methyl (7R)-14-cyclohexyl-7-(methylamino)-4-(piperidin-1-ylmethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate and tert-butyl (2-oxoethyl)carbamate. The compound was used without further purification. (ES+) m/z 659 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:19]([F:24])[CH:18]=1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Reactant: Nc1ccc(Cl)cc1F
Product: COc1ccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c1

Procedure:
In the manner of Example 274 reaction of 4-chloro-7-methoxy-3-quinolinecarbonitrile with 4-chloro-2-fluoroaniline gave the title compound as an amber solid, mp 208-210° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Br-].[CH2:24]([Zn+])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH2:24]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccccc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(Cc2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
THF (4 ml) was added to an argon purged glass tube (20 mL) containing methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (135 mg; 0.423 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.47 mg; 0.021 mmol). The mixture was stirred at room temperature for 10 min and, after dissolution of the solids, benzylzinc bromide (1.694 ml; 0.847 mmol; 0,5 M in THF) was added dropwise. Stirring at room temperature was continued for 15 min followed by stirring at 60° C. for 8 h. The reaction was quenched by adding a saturated ammonium chloride solution. To this suspension was added a saturated disodium ethylenediamine tetraacetate solution and the mixture was stirred at room temperature for 15 min. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine and dried over magnesium sulphate. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 101 mg (64%) of the title compound. ESI/APCI(+): 375 (M+H). ESI/APCI(−): 373 (M−H).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[Se](=O)=[O:26]>O1CCOCC1.O>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:26])=[O:23])[CH:17]=[CH:16]3
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (500 mg, 1.66 mmol, described in Intermediate 6) and selenium dioxide (552 mg, 4.97 mmol) in dioxane (30 mL) and H2O (3 mL) was heated at reflux for 18 h. The reaction mixture was allowed to cool, then it was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=332 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)ccc1F

Procedure:
Following the procedure of Example 1(10), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a slightly yellow oil (yield: 79.1%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C[N:13](C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:13])=[O:7]
Reactant: CN(C)C=O
Reactant: CSc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CSc1cccc(C(N)=O)c1
Temperature: 120 °C

Procedure:
10 g of 3-methylsulfanylbenzoic acid and 0.05 ml of DMF were suspended in 50 ml of DCM. 9 ml of thionyl chloride were added and the mixture was heated under reflux for 4 h. The volatiles were removed in vacuo and the residue was taken up in 30 ml of toluene and transferred to a pressure bottle. 180 ml of a 0.5 M solution of ammonia in dioxane were added, the bottle was sealed and the mixture was heated to 120° C. for 5 h. The solvent was removed in vacuo and the residue taken in water and EA. The phases were separated and the aqueous layer was extracted with EA. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 8.6 g of the title compound were obtained as a brown solid.
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][CH2:6][S:7][CH2:8]2)=[CH:3][C:2]=1[CH2:10][OH:11]>C(Cl)(Cl)Cl.O=[Mn]=O>[N:1]1[N:9]2[C:4]([CH2:5][CH2:6][S:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1cc2n(n1)CSCC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CSCC2

Procedure:
To a 17.2 gram of the crude (4,5-dihydro-6-thia-1,7a-diazainden-2-yl) methanol in 520 mL of CHCl3 was added activated MnO2 (88.0 g) under a nitrogen atmosphere at room temperature, and then refluxed for 2 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was applied to silicagel column chromatography, and then the column was eluted with hexane-AcOEt (2:1). The titled compound was obtained as yellow crystals (13.0 g, 74.5%)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].CC1(C)CCCC(C)(C)N1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>C(#N)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:5][CH2:4][CH2:3][CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCC(O)c1ccccc1
Reactant: Fc1ccccc1CCl
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: OC(CCNCc1ccccc1F)c1ccccc1
Yield: 52.5 %

Procedure:
A mixture of 3-hydroxy-3-phenylpropylamine (7.0 g, 46 mM) and 2,2,6,6-tetramethylpiperidine (7.9 ml, 46 mM) in acetonitrile (100 ml) was treated with a solution of o-fluorobenzyl chloride (6.75 g, 46 mM) in acetonitrile (10 ml). After 24 hours the resulting precipitate was removed by filtration and washed with acetonitrile (2×10 ml). The combined filtrate and washings were evaporated under reduced pressure and the residue partitioned between 2 N hydrochloric acid (50 ml) and ether (100 ml). The aqueous layer was basified by extracted with ether, the ether extracts dried and evaporated. Chromatography on Grade 3 silica using 2% methanol in chloroform as eluant followed by distillation gave the title compound (6.3 g) b.p. 156°-160° C. (0.2 mbar). Found: C, 73.9; H, 7.1; N, 5.2%; C16H18FNO requires: C, 74.1; H, 7.0; N, 5.4%.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[O:13][B:14](OC)[O:15]C>O1CCCC1.CCOCC>[CH2:5]([C:6]1[CH:11]=[CH:10][C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=1)[CH2:4][CH3:3]
Reactant: COB(OC)OC
Reactant: BrCCCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal along with a solution of 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 minutes to a solution of trimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at -78° C. After 30 minutes, the solution was warmed to room temperature where stirring continued for 90 minutes, then the reaction was quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofuran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3×25 mL). The combined ether extracts was extracted with 1M NaOH (3×25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then reextracted back into diethyl ether (3×25 mL). The combined organic layers was washed with water (1×25 mL), brine (1×25 mL) and dried over magnesium sulfate. Evaporation of solvent left a brown solid which was filtered through a small plug of silica gel using 11.0 MeOH/CACl3. Evaporation left 448 mg (32%) of a brown solid, m.p. 90°-93° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:22](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:4]([C:5]2[O:6][CH:22]=[N:8][N:7]=2)[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NN)ccc(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc(I)ccc1Nc1c(-c2nnco2)ccc(F)c1F
Yield: 79 %

Procedure:
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (146 mg, 0.36 mmol) was suspended in 7 mL of absolute EtOH and 2 mL of HC(OEt)3 was added along with approximately 3 mg of pTsOH> The reaction was heated to reflux for 3 h, cooled and concentration on a rotary evaporator. The reaction was purified (SiO2, 4:1 Hexane/EtOAc) to afford 117 mg (79%) of (2,3-difluoro-6-[1,3,4]oxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine as a yellow powder. M.p. =144.4-145.5° C. 1H NMR (400 MHz, CDCl3) δ8.89 (s, 1H), 8.44 (s, 1H), 7.66 (m, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1 H), 6.83 (m, 1H), 6.14 (dd, J=8.5, 5.9 Hz, 1 H), 2.37 (s, 3 H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][N:9]=[C:8]([S:17][CH3:18])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([NH:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([S:17][CH3:18])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(NC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
In a round-bottomed flask ethyl 4-(tert-butylamino)-2-(methylthio)pyrimidine-5-carboxylate (3.2 g, 11.88 mmol) was dissolved in ethanol (40 mL) followed by the addition of 1M aqueous sodium hydroxide solution (35.6 mL, 35.6 mmol). The resulting mixture was stirred overnight at room temperature and then the solvent was evaporated under reduced pressure. After that 2M aqueous citric acid solution (35.6 mL, 71.3 mmol) was slowly added and the resulting mixture was stirred for 0.5 h at room temperature. The suspension was filtered and the solids were washed twice with water (2×50 mL) and then dried in a vacuum oven at 45° C. overnight to afford 4-(tert-butylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (2.83 g, 11.73 mmol, 99% yield). MS (ESI) m/z 242.3 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH:13][C:21](=[O:22])[O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1noc(-c2cccc(N)c2)n1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1noc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 3-[3-methyl(1,2,4-oxadiazol-5-yl)]phenyl amine (1.00 g, 5.7 mmol, prepared in sequence by the procedures described by Lin et al., J. Org. Chem., 1979, 44, 4160 and Bellamy and Ou, Tetrahedron Letters, 1984, 25, 839) in acetonitrile (25 mL) and pyridine (0.46 mL, 0.45 g, 5.7 mmol) under argon at 0° C. was treated with p-nitrophenyl chloroformate ( 1.15 g, 5.7 mmol) and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 10% citric acid, resulting in separation of a solid insoluble in either phase. The solid was collected, triturated with hexane and dried in vacuo to yield 1.59 g (82%) of the title compound, m.p. 217°-220° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:.2), Rf =0.75; M.S. (M+H)+ at 341, M.W. 340. This material contained minor impurities and was used without further purification.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)([CH3:33])[CH:31]=O.O>O1CCCC1>[Br:2]/[CH:3]=[CH:31]/[C:30]([CH3:33])([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)[CH3:29]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(/C=C/Br)c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 101.0 grams (0.23 mole) of bromomethyl triphenylphosphonium bromide in 400 mL of tetrahydrofuran was cooled in a dry ice-acetone bath, and 26.0 grams (0.23 mole) of potassium tert.-butoxide was added portionwise while maintaining the reaction mixture temperature between -70° and -75° C. Upon completion of addition, the reaction mixture was stirred at -75° C. for about 90 minutes. After this time a solution of 50.0 grams (0.23 mole) of 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde (prepared in Step C of this Example) in 100 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 500 mL of water and extracted with two 300 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 40.9 grams of cis/trans-1-bromo-3-methyl-3-(4-trifluoromethylphenyl)-1-butene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.O>CS(C)=O>[N:11]1[N:10]=[CH:9][N:8]([NH:7][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([CH:22]=2)=[N:19][O:20][N:21]=3)[CH:12]=1
Reactant: Fc1ccc2nonc2c1
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1cc2nonc2cc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
26.70 Grams of potassium tert-butoxide was dissolved in 100 ml of anhydrous dimethylsulfoxide and 20.00 g of 4-amino-4H-1,2,4-triazole was added thereto, followed by stirring for 2 hours at room temperature. Next, 50 ml of an anhydrous dimethylsulfoxide solution containing 11.00 g of 5-fluorobenzofurazane was added dropwise to the solution over a period of 20 minutes and then the mixture was stirred for 15 minutes. The reaction mixture was poured into 500 ml of water and 500 g of ice and then washed with 200 ml of ethyl acetate. The solution was then adjusted to have pH of 7.0 with 1N hydrochloric acid to give crystals. The crystals were collected by filtration, and the remaining mother liquid was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude crystals thus obtained were recrystallized from ethanol. These were combined with the previously obtained crystals to give 12.49 g of 5-[(4H-1,2,4-triazol-4-yl)amino]benzofurazane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:18]=1[O:19][C@@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH2:32][OH:33])[CH2:21]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:18]=3[O:19][C@H:20]3[CH2:21][C@@H:22]([CH2:32][OH:33])[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2cc(F)ccc2N)C[C@H]1CO
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c2c1C

Procedure:
Prepared analogously to example 1.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (2S,4S)-tert-butyl 4-(2-amino-5-fluorophenoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH3:15])[CH:10]=2)[N:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH3:15])[CH:10]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:17]=2)[N:3]=1
Reactant: OB(O)c1cncnc1
Reactant: CCn1ccc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCn1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)N(C)C2=O)c1
Yield: 75.7 %

Procedure:
To a solution of 2-amino-5-(3-bromophenyl)-5-(1-ethyl-1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one (80 mg, 0.22 mmol) in DME (3 mL) is added pyrimidin-5-ylboronic acid (57 mg, 0.44 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmo) and a solution sodium carbonate (93 mg, 0.88 mmol) in H2O (0.5 mL) at room temperature. The reaction mixture is refluxed for 1 h and cooled. After evaporation of the solvent, the crude material is purified by chromatography (silica gel, EtOAc/2M ethanolic NH3: 92/8) to give the title compound (60 mg, 75%) as a solid. mp: 100-102° C.; MS(+) ES: 361 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:39]([F:42])([F:41])[F:40])=[C:34](B(O)O)[CH:35]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:39]([F:40])([F:41])[F:42])=[C:34]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:35]=1
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 54 mg (0.24 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After aqueous work-up, the crude product was triturated with water and the solid was filtered off, dried and purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 124 mg (quant.)