Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=O.[Na+].[ClH:21]>[Cu]Cl>[Cl:21][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cl
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CC(=O)c1cc(Cl)cc(S(F)(F)(F)(F)F)c1
Reaction time: 8 h

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (150 mg, ex. 22a) was dissolved in semiconcentrated hydrochloric acid (6 ml). While stirring and cooling, sodium nitrite solution (40 mg dissolved in water) was added dropwise, in the course of which the temperature was not to exceed 5° C. On completion of formation of the diazonium salt, copper(I) chloride solution (68 mg dissolved in 2 ml of concentrated hydrochloric acid) was cooled to 0° C. while stirring and the above diazonium salt solution was slowly added dropwise. Then the cooling bath was removed, and the mixture was stirred at RT for 3 h and left to stand overnight. Then the reaction mixture was diluted with water and extracted repeatedly with EA. The combined EA phases were washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 104 mg of the desired compound were obtained.
Reaction SMILES: [C:1](Cl)(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:13]=1[OH:38])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([NH:24][C:1](=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])=[C:14]([CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:13]=1[OH:38])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 12.3 ml of ethyl chlorooxalate in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g of 3-{3-[4-acetyl-3-hydroxy-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline and 15.3 ml of triethylamine in 400 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 90 minutes. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether gives ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].C1C=CC2N(O)N=[N:19][C:17]=2C=1.CN(C=O)C.CN.C1COCC1>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][CH3:17])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C#N)cc1F
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
4-cyano-2-fluorobenzoic acid (1.20 g), HOBt (1.47 g), WSC•monohydrochloride (2.10 g) and DMF (20 ml) were mixed with one another and stirred for 30 minutes. 2M methylamine-THF solution (11 ml) was added thereto, followed by stirring for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with n-hexane, to obtain 4-cyano-2-fluoro-N-methylbenzamide (1.03 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[BH4-].[Na+].Cl.[C:17](O)(=[O:19])C>>[CH3:17][O:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[CH3:17][O:19][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[CH2:11][O:13][C:4]2=[O:6]
Reactant: CC(=O)O
Reactant: O=C(O)C1C=CC=CC1(O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC1(C(=O)O)C=CC=CC1C(=O)O
Product: COc1cccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous 2-methoxyphthalic acid (640 mg), which was prepared with using anhydrous 2-hydroxyphthalic acid by the same procedure as reference example 12, was suspended in tetrahydrdofuran (20 ml). Acetic acid (430 mg) and sodium borohydride (135 mg) were added to the suspension. The mixture was stirred for 30 min. at room temperature and for 2 hr. at 50° C. The reaction solution was cooled. 1N hydrochloric acid (7 ml) was added to the cooled solution. The solution was stirred for 15 min. The reaction solution was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (314 mg) having the following phsysical data.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1.CCCCCC>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)pyridin-2-amine (47 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 35.8 mg) and 2-chloroethanesulfonyl chloride (88 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (53.2 mg) as a white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[C:24]([NH:29][CH3:30])[N:23]=1.[OH-].[Na+]>>[Cl:21][C:22]1[N:23]=[C:24]([NH:29][CH3:30])[N:25]=[C:26]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])=[O:12])[CH2:14][CH2:15]2)[N:27]=1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Reactant: CNc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
N-{[2-(Trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (464 mg, 1.63 mmol, 1.00 equiv) was added to the suspension prepared in step b. The resulting mixture was heated to 40° C. and treated with 1 N NaOH to maintain a pH of 9-10. The reaction mixture was stirred for 2 h and then used immediately in the next step without workup or purification. MS (ES+): m/e 428.9 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN([CH:22]=[O:23])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][CH:11]=[C:10]2[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Cc1cc2[nH]ccc2cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2[nH]cc(C=O)c2cc1Br
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
Phosphorus oxychloride (0.73 g, 4.79 mmol) and DMF (5.0 mL) were mixed together and stirred for 5 min. A solution of 5-bromo-6-methyl-1H-indole (500 mg, 2.39 mmol) in DMF (3.0 mL) was added to the solution slowly and complete solid was formed which stopped stirring. The solution was adjusted to pH=10 with 1N NaOH, then heated to 100° C. for 1 min. The reaction was cooled to room temperature. The precipitated solids were filtered and dried to give the title compound (480 mg, 85%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 9.88 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.49 (s, 1H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C(O)(=O)C.[N+:15]([CH3:18])([O-:17])=[O:16]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:18]/[N+:15]([O-:17])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Cl)ccc1/C=C/[N+](=O)[O-]
Temperature: 140 °C
Yield: 64.9 %

Procedure:
Under an atmosphere of nitrogen was added to a solution of 4-chloro-2-methylbenzaldehyde (10.0 g, 64.9 g) in acetic acid (70 mL) ammonium acetate (11.5 g, 149 mmol) and nitromethane (10.0 ml, 185 mmol). The solution was stirred at reflux (oil bath 140° C.) for 2 h. After cooling to ambient temperature water (70 mL) was added and extracted twice with ethyl acetate (70 mL). The organic layers were washed with water (70 mL) and brine (70 mL) and were dried over sodium sulfate. The filtrated was concentrated and the resulting solid was suspended in methanol (30 mL), at 0° C. filtered off and was washed with cold methanol (10 mL) affording the title compound (8.30 g, 65%) as a yellow solid. MS m/e: 197.0 [M]+.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[CH3:36].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:32]2[CH:33]=[CH:34][C:35]([CH3:36])=[C:30]([F:29])[CH:31]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
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: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(C)c(F)c2)c1N1CCC(C)(C)CC1
Reaction time: 9 h
Yield: 50 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.02 g, 0.044 mmol), (3-fluoro-4-methylphenyl)boronic acid (0.014 g, 0.088 mmol) and 2M Na2CO3 (0.055 ml, 0.110 mmol) in DMF (1 mL) was degassed for 3 min. Then, Pd(Ph3P)4 (5.07 mg, 4.39 μmol) was degassed for 1 min and placed in a pre-heated oil bath at 90° C. After 9 h, cooled and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(3-fluoro-4-methylphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0105 g, 0.022 mmol, 49.3% yield) as brown paste. LCMS (M+H)=485.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[N:7]=1.C[Al](C)C.[CH:20]([NH2:23])([CH3:22])[CH3:21]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:13])[N:10]=2)[N:7]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (250 mg, 1.11 mmol) was taken up in tetrahydrofuran and cooled to 0° C. Trimethylaluminum (6.6 mL, 13.3 mmol) was added dropwise followed by the addition of isopropylamine (0.4 mL, 2.2 mmol). The cold bath was removed and the reaction was allowed to proceed overnight at room temperature. The reaction was then quenched slowly with methanol, and stirred for 10 minutes. The resulting mixture was filtered, washing the solids with ethyl acetate and water. The filtrate was collected, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were concentrated under and purified via flash chromatography (0-15% methanol in dichloromethane) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>C1COCC1.CN(C1C=CN=CC=1)C>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: Cc1cccc(C)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 1 °C
Reaction time: 17 h
Yield: 76.4 %

Procedure:
2,6-Dimethylphenol (0.257 g, 2.1 mmol) and 4-[(tert-butoxycarbonyl)amino]butanoic acid (0.427 g, 2.1 mmol) were dissolved in THF (10 ml, dry) and DMAP (0.005 g, 0.04 mmol) was added. After cooling down to 0-2° C., EDC (0.483 g, 2.52 mmol) was added portionwise under nitrogen atmosphere. The ice bath was removed and stirring was continued over night at rt. After 17 h, the mixture was diluted with DCM (50 ml) and extracted with water (20 ml), HCl (2N, 20 ml) and water (20 ml) again. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel, using DCM/MeOH (95:5) as eluent, to give the title compound (0.493 g, 76%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 1.45 (s 9H), 1.94-2.01 (m, 2H), 2.14 (s, 6H), 2.66 (t, 2H), 3.24-3.29 (m, 2H), 4.66 (bs, 1H), 7.05 (s, 3H); Mass Spectrum: M-tert-Bu+H+ 252.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:24][CH2:23][C:22]5[N:21]=[C:20](SC)[N:19]=[CH:18][C:17]=5[C:16]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[OH:29][S:30]([O-:33])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+].[CH3:56]O.O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:24][CH2:23][C:22]5[N:21]=[C:20]([S:30]([CH3:56])(=[O:33])=[O:29])[N:19]=[CH:18][C:17]=5[C:16]=4[C:11]=3[CH:10]=[N:9]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(SC)ncc2-4)cc1
Reactant: O=S(=O)([O-])O
Reactant: CO
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(S(C)(=O)=O)ncc2-4)cc1
Reaction time: 18 h
Yield: 77 %

Procedure:
To a suspension of 3-(4-methoxybenzyl)-9-(methylsulfanyl)-6,7-dihydro-3H-pyrazolo[4′,3′:5,6]pyrido[4,3-f]quinazoline (1.9 g, 4.8 mmol) in 2:1 mixture of methanol-water (100 mL) was added potassium monopersulfate triple salt (Oxone®, 9.2 g, 15 mmol) and the suspension stirred for 18 hours. On completion of the reaction, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with water (2×20 mL), dried using anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired product, 3-(4-methoxybenzyl)-9-(methylsulfonyl)-6,7-dihydro-3H-pyrazolo[4′,3′:5,6]pyrido[4,3-f]quinazoline (1.5 g, 77%) as a tan solid. LCMS [M+H]: 422. The compound was used without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][CH:31]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 23 mmol) was dissolved in 250 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (11.3 mL, 139 mmol) followed by the dropwise addition of oxalyl chloride (6.1 mL, 69 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off white oil. Redissolved (3.66 g, 15 mmol) oil in 40 mL dry DCM under Ar, cooled to 0° C., added 4.6 mL pyridine followed by 4-bromoaniline (2.7 g, 15 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (2×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound. (4.56 g, 80%) APCI (AP−): 369.0, 370.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[C:15]([F:34])[CH:14]=3)[CH:9]=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[CH:35]([Mg]Br)=[CH2:36]>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[C:15]([F:34])[CH:14]=3)[CH:9]=[C:10]([CH:11]([OH:12])[CH:35]=[CH2:36])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C=C[Mg]Br
Reactant: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Solvent: C1CCOC1
Product: C=CC(O)c1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn12
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a stirred solution of 1-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl) -2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (450 mg, 0.95 mmol) dissolved in THF (10 mL), was added vinyl magnesium bromide (9.45 mL, 9.45 mmol, 1.0 M in THF) at rt. The reaction was allowed to stir for 1 hr and then quenched with MeOH (1 mL). The mixture was partitioned between EtOAc (250 mL) and saturated aq. Na2CO3 (100 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), and concentrated to dryness. Trituration with Et2O afforded 300 mg (63%) of the desired product. 1H-NMR (DMSO-d6) δ 8.65 (d, J=7.8 Hz, 1H), 8.27 (t, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.36-7.27 (m, 5H), 7.13-7.07 (m, 1H), 6.90 (s, 1H), 6.70-6.60 (m, 1H), 4.29 (dd, J=1.5, 5.7 Hz, 1H); MS [M+H]+=505.2; LCMS RT=2.85 min.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(Sc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and thiophenol, there is obtained phenyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate as a syrup, mass spectrum m/e: M+ 330 (3), 220 (70), 179 (100), 165 (85), 110 (74);
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Br:5]N1C(=O)CCC1=O.[C:13]1([OH:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)C=C[CH:14]=1>O>[Br:5][C:14]1[C:13](=[O:23])[C:22]2[C:17]([C:1](=[O:4])[CH:2]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: Oc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O
Solvent: O
Product: O=C1C=C(Br)C(=O)c2ccccc21
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A 3-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a 500-mL addition funnel and a thermometer was changed with glacial acetic acid (500 mL), water (1000 mL) and N-bromosuccinimide (71.2 g, 0.40 mol). The mixture was warmed to 45° C. during which time a yellow solution was obtained. An acetic acid (500 mL) solution of 1-naphthol (14.4 g, 0.10 mol) was then added dropwise over a period of 75 min so as to give a red solution, the latter of which was stirred an additional 30 min at 45° C. before cooling to room temperature. The resulting mixture was diluted with water (1500 mL) and extracted with methylene chloride (6×400 mL). The combined organic extracts were in turn washed with water (4×400 mL) and saturated sodium bicarbonate solution (4 ×300 mL). Rotary evaporation of the solvent following drying over magnesium sulfate yielded a yellow solid that was recrystallized from 95% ethanol to yield pure 2-Bromo-1,4-naphthoquinone (18.50 g, 78%); mp 130.5°-132° C. (lit. mp 131°-132° C.). IR(KBr) 3050, 1675, 1655, 1585, 1570, 1330, 1310, 1295, 1270, 1245, 1220, 1120, 1060, 910, 890, 820, 790, 775, 670, 665 cm-1 ; 1H NMR (CDCl3) δ 8.21-8.14 (m, 1 H), 8.11-8.05 (m, 1 H), 7.80-7.73 (m, 2 H), 7.52 (s, 1 H); 13C NMR (CDCl3) 182.4 (0), 177.8 (0), 140.3 (1), 140.1 (0), 134.4 (1), 134.1 (1), 131.7 (0), 130.9 (0), 127.8 (1), 126.9 (1) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C:13]([NH:17]C(=O)OC(C)(C)C)([CH3:16])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH2:26]([C@@H:28]1[CH2:37][C:36]2[N:35]=[C:34]([CH3:38])[N:33]=[C:32]([N:39]3[CH2:45][C:44]4[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][C:43]=4[O:42][CH2:41][CH2:40]3)[C:31]=2[CH2:30][CH2:29]1)[CH3:27]>>[NH2:17][C:13]1([CH3:16])[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:47]3[CH:48]=[CH:49][C:43]4[O:42][CH2:41][CH2:40][N:39]([C:32]5[C:31]6[CH2:30][CH2:29][C@H:28]([CH2:26][CH3:27])[CH2:37][C:36]=6[N:35]=[C:34]([CH3:38])[N:33]=5)[CH2:45][C:44]=4[CH:46]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5CCC(C)(N)C5)c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using 1,1-dimethylethyl {1-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-3-methylpyrrolidin-3-yl}carbamate (reagent preparation 25) and {4-[(7S)-7-ethyl-2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.37 (s, 1H), 7.97 (s, 1H), 7.41 (s, 1H), 7.29 (d, 1H), 6.94 (d, 1H), 4.64 (m, 2H), 4.27 (m, 1H), 4.05 (m, 1H), 3.94 (m, 2H), 3.47 (m, 1H), 3.31 (m, 1H), 3.12 (m, 2H), 2.81 to 2.66 (m, 2H), 2.49 (m, 1H), 2.28 (s, 3H), 2.21 (m, 1H), 1.90 (m, 1H), 1.84 (m, 2H), 1.62 (m, 1H), 1.36 (m, 2H), 1.14 (s, 3H), 1.09 (m, 1H), 0.99 (t, 3H); MS (EI) for C30H39N7O3S: 578 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: N#Cc1cc(I)ccc1OCCN1CCCC1
Product: N#Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile (300 mg, 0.88 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (206 mg, 0.97 mmol).