Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:9]C1C=CC(OC)=CC=1.CN(C=O)C>C1COCC1.[Zn+2].[Br-].[Br-].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>[I:9]/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COc1ccc(I)cc1
Reactant: C#CCCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCC/C=C/I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of oct-1-yne (56.2 mg, 0.5 mmol) and Cp2ZrCl2 (206.7 mg, 1.4 mmol, 1.4 eq.) in THF (2.5 mL) at RT was rapidly added a 1 M THF solution of LiAlH(Ot-Bu)3 (0.7 mL, 1.4 mmol, 1.4 eq.). A resulting dark red solution was stirred at RT for 15 min. At that time, dry ZnBr2 (157.7 mg, 1.4 mmol, 1.4 eq., Aldrich) and THF (1 mL) were added at RT. After 30 min., 1-iodo-4-methoxybenzene (165.5 mg, 1.4 mmol, 1.4 eq., Aldrich), Pd(PPh3)4 (11.6 mg, 0.001 mmol, 0.02 eq.) and DMF (1 mL) were added. The resultant mixture was stirred at RT for 5 h and then quenched with 1 N HCl, and extracted with EtOAc (4×5 mL). Organic extracts were combined and washed with H2O and brine, dried over MgSO4 and concentrated via evaporation under reduced pressure. Purification of the residue was performed using a silica gel column (silica gel 60, 230-400 mesh) with CH2Cl2/hexanes as eluent. (E)-1-iodooct-1-ene (41.3 mg, 38% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 7.27 (d, J=8.62 Hz, 21-1), 6.83 (d, J=8.64 Hz, 2H), 6.31 (d, J=15.79 Hz, 1H), 6.08 (dt, J=14.23, 6.89 Hz, 1H), 3.79 (s, 3H), 2.17 (td, J=7.14, 7.07 Hz, 2H), 1.50-1.40 (m, 2H), 1.38-1.27 (m, 6H), 0.89 (t, J=6.31 Hz, 3H) 13C NMR (101 MHz, CDCl3) δ ppm: 158.59, 130.84, 129.09, 128.99, 126.93 (2C), 113.89 (2C), 55.27, 33.02, 31.77, 29.50, 28.91, 22.63, 14.09. Physical and spectral data were consistent with those previously reported (see Nakao, Y.; Imanaka, H.; Sahoo, A. K.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 6952-6953.)
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[Br:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Br)cccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Br)cccc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
A mixture of methyl 4-bromobenzo[b]thiophene-2-carboxylate (101 g), sodium hydroxide (63 g), methanol (1200 ml) and water (600 ml) was stirred at ambient temperature for 16 hours, the methanol was removed in vacuo, and the resulting suspension was cooled to 0° C. and acidified by dropwise addition of concentrated hydrochloric acid. The mixture was stirred for 20 minutes and the resulting solid was collected by filtration, washed with water (3×250 ml) and dried in vacuo at 110-120° C. to give 4-bromobenzo[b]thiophene-2-carboxylic acid (62 g) as a cream solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:31][CH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a stirred solution of (4E)-3-(4-chlorophenyl)-4,5-difluoro-6-(3-phenoxyphenyl)-4-hexen-1-ol (0.10 g, 0.24 mmol) in ether (5 ml) under nitrogen was added carbon tetrabromide (0.085 g, 0.256 mmol), followed by triphenylphosphine (0.067 g, 0.255 mmol), and the resulting mixture was stirred overnight at room temperature. Additional quantities of carbon tetrabromide (0.17 g, 0.51 mmol) and triphenylphosphine (0.134 g, 0.51 mmol) were added, and the reaction mixture was stirred for five hours. The reaction mixture was concentrated in vacuo and the residue chromatographed on preparative thin layer silica gel plates, developing with methylene chloride to afford the title compound as a colorless oil (0.08 g) which was characterized by 1MMR, 19FNMR and mass spectral analysis.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:24][P:25]([CH:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].N1C=CC=CC=1>C(Cl)Cl>[CH2:22]([O:24][P:25]([CH:30]([Br:1])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
90 g of bromine, dissolved in 250 ml of methylene chloride, were added dropwise to a solution of 131 g (0.5 mol) of triphenylphosphine in 500 ml of methylene chloride at 30°-35° C., with exclusion of moisture. The mixture was subsequently stirred at room temperature for 1 hour, a solution of 122 g (0.5 mol) of α-hydroxybenzylphosphonic acid diethyl ester in 250 ml of methylene chloride was then added dropwise at -20° C. in the course of 1 hour, the mixture was subsequently stirred at -20° C. for 1 hour and 40 g of pyridine, dissolved in 250 ml of methylene chloride, were then added dropwise at -20° C. in the course of one hour. The mixture was subsequently stirred for 20 hours, the temperature slowly rising to +20° C. The reaction mixture was transferred to a pear-shaped flask and the solvent was distilled off under a waterpump vacuum. The residue was extracted by stirring with one liter of ether and the undissolved triphenylphosphine oxide was filtered off (120 g of triphenylphosphine oxide=86% of theory). The mother liquor was concentrated in vacuo and the residue was distilled under a high vacuum. 112 g (72% of theory) of α-bromobenzyl-phosphonic acid diethyl ester were obtained as a pale yellow oil with a boiling point of 110° C./0.01 mm Hg and a purity of 95.9% (gas chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2[CH2:9][C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>O.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2/[C:9](=[CH:21]\[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)/[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cn1)CC(=O)CCC2
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(cn1)/C(=C\c1ccccn1)C(=O)CCC2
Temperature: -70 °C

Procedure:
A flask was charged with 3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (126) (23.0 g, 120 mmol), THF (1000 mL) and picolinaldehyde (32.2 g, 301 mmol). The mixture was cooled to an internal temperature of about −70° C. then lithium bis(trimethylsilyl)amide [1 M solution] (126 mL, 126 mmol) was added over about 30 min keeping the internal temperature below about −65° C. The mixture was allowed to warm to about −10° C. in the cold bath. Acetic acid (13.8 mL, 241 mmol) then water (150 mL) were added. The mixture was concentrated under reduced pressure then partitioned between water (250 mL) and EtOAc (250 mL). The aqueous layer was extracted with EtOAc (150 mL). The combined organic solutions were with brine (100 mL) then dried over MgSO4 then filtered The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using a gradient from 0-75% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (E)-3-methoxy-9-(pyridin-2-ylmethylene)-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (127, R5=Pyridin-2-yl) (36.15 g, 107%) 1H NMR showed material to contain picolinaldehyde and EtOAc. The material was used in the next step without further purification; LC/MS, method 3, Rt=1.90 min, MS m/z 281 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.54-8.52 (m, 1H), 7.73 (s, 1H), 7.68-7.65 (m, 1H), 7.65 (s, 1H), 7.29-7.25 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.84 (s, 1H), 3.83 (s, 3H), 2.78 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.1 Hz, 2H), 2.05-1.94 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:22]#[N:23])[N:14]2[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=12.[CH2:24]([CH:27]([NH2:31])[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:22]#[N:23])[N:14]2[C:19]([NH:31][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=12
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3ccc(C(C)C)cc3Br)c2n1
Reactant: CCCC(N)CCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3ccc(C(C)C)cc3Br)cc(C#N)n12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 8-(2-bromo-4-isopropyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (300 mg), 1-propyl-butylamine (267 mg), N,N-diisopropylethylamine (300 mg) in ethanol (1.0 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=20:1) to give 8-(2-bromo-4-isopropyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (321 mg) as a pale brown solid.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[F:24][C:25]1[CH:30]=[C:29]([O:31]C)[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:36][CH2:35]1>>[F:33][C:28]1[CH:27]=[C:26]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:36][CH2:35]2)[C:25]([F:24])=[CH:30][C:29]=1[OH:31]
Reactant: COc1cc(F)c(N2CCC(CCCc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1cc(F)c(N2CCC(CCCc3ccccc3)CC2)cc1F
Yield: 32.2 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(2,5-difluoro-4-methoxyphenyl)-4-(3-phenylpropyl)piperidine (230 mg). The resulting crude product was purified on TLC (developer, hexane: ethyl acetate=3:1) to provide 2,5-difluoro-4-[4-(3-phenylpropyl)piperidino]phenol (71 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH2:13]>C1COCC1>[CH3:12][NH:13][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(Br)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0° C. was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2×25 mL). The combined organic phases were sequentially washed with water (2×25 mL) and a saturated NaCl solution (25 mL), dried (MgSO4) and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12]N.C(Cl)Cl.CO>C(O)C>[C:11]([NH:12][N:10]=[C:2]([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCCCC(=N)OCC
Reactant: CCOC(=O)NN
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCCCC(=NNC(=O)OCC)OCC
Reaction time: 0.33 h

Procedure:
To a solution of 7.0 g (25.3 mmole) of ethyl valerimidate hydrochloride [prepared by method of A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 48, 734 (1926)] in 35 ml of dry ethanol stirred under N2 at -78° C. was added dropwise a solution of 24 g (23 mmole) of ethyl carbazate in 35 ml of dry ethanol. Precipitation occurred during the addition, which took 20 minutes and was accompanied by a rise in the internal temperature to -50° C. The mixture was allowed to stand at 5° C. for 60 hours and then filtered. The filtrate was concentrated, and the residue was flash chromatographed on a silica gel column (elution with 98.5:1.5 CH2Cl2 --MeOH), yielding a clear oil, homogeneous by TLC in 97:3 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 217 (M+1)+. NMR suggested a mixture of syn and anti isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li:20]CCCC>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Li:20])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [Li]CCCC
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=CC2
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Li]C1C=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reaction time: 3 h
Yield: 98 %

Procedure:
5,6-dimethoxy-3-phenyl-1H-indene (1.26 g, 4.99 mmol) was dissolved in a mixture of 15 mL of toluene and 25 mL of hexane and 3.06 mL of 1.6 M n-BuLi were added dropwise via syringe over a 3 min period. The solution developed a yellow-light green precipitate during addition of n-BuLi. The reaction mixture was stirred for 3 h and then filtered, washed with 60 mL of hexane and dried in vacuum to afford the desired product as a yellow solid (1.24 g) in 98 percent yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][C:18](=[O:28])[CH2:19][NH:20]C(=O)OC(C)(C)C)([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:29])[C:3]=1[C:30]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:33]=2[S:32](=[O:46])(=[O:45])[N:31]=1.Cl>O1CCOCC1>[NH2:20][CH2:19][C:18]([NH:17][C:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:30]2[NH:35][C:34]3[CH:36]=[CH:37][C:38]([NH:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][C:33]=3[S:32](=[O:45])(=[O:46])[N:31]=2)[C:4]1=[O:29])=[O:28]
Reactant: CC(C)CCC1(NC(=O)CNC(=O)OC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CCC1(NC(=O)CN)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
A mixture of the product of Example 45 (4 mg, 0.0059 mmol) and 4 N HCl in dioxane (0.25 mL) was stirred at room temperature for 2 h. After which, the solution was concentrated in vacuo to afford the title compound as a white solid (3.5 mg, 97%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.57-0.74 (m, 6H), 0.79-0.94 (m, 1H), 1.19-1.39 (m, 2H), 1.75-1.90 (m, 1H), 1.92-2.12 (m, 1H), 3.05 (s, 3H), 7.42-7.66 (m, 5H), 7.88-7.97 (m, 2H), 8.10 (d, J=7.72 Hz, 1H), 9.39 (s, 1H), 10.15 (s, 1H), 14.19 (s, 1H); MS m/z 575.7 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][O:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][O:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CN(C)C(=O)COCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN(C)C(=O)COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethoxy)-N,N-dimethyl-acetamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 333. NMR: CDCl3: 3.02 (6 H, s, Me), 3.96-3.99 (4 H, m, CH2), 4.09-4.13 (4 H, m, CH2), 4.31 (2 H, s, CH2), 4.95 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar), 9.03 (1 H, s, Ar) and 10.30 (1 H, s, NH). MS: (ESI+): MH+ 453.20
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15]C)=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:17].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:17]
Reactant: COC(=O)CC1Cc2ccc(OC)cc2NC1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(O)cc2NC1=O
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A suspension of (7-methoxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (5.4 g, 21.7 mmol) in 50 ml of methylene chloride at 0° C. was treated with 1.0 M BBr3—CH2Cl2 (200 ml, 200 mmol) under inert gas for 1 hour. The reaction mixture was allowed to warm to room temperature over an additional 2 hours. The volatiles were evaporated in vacuo to a brown oil which was treated with ice-cold methyl alcohol (400 ml×2) and evaporated after each treatment to a residue. The residue was refluxed with 5 ml of 12 N HCl and 100 ml of methyl alcohol for 2 hours and evaporated to a residue which was crystallized from methyl alcohol (25 ml) to give the title compound, (3.9 g) as fluffy tan needles, mp 178-179.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:28]([N:31](CC3C=CC(OC)=CC=3)[C:32]3[S:33][CH:34]=[CH:35][N:36]=3)(=[O:30])=[O:29])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:28]([NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)(=[O:29])=[O:30])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(Cl)ccnc3c2)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)cc(C)c12

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.16 mg, 0.014 mmol), 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol), potassium phosphate tribasic (3.24 μl, 0.039 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.924 mg, 1.304 μmol) was added dioxane (52.3 μl) and water (17.44 μl). The mixture was irradiated at 100° C. for 30 min affording conversion to desired product according to LC-MS, 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide. m/z (ESI) 600.2 (M+H)+. The mixture was dried under reduced pressure. To the crude oil was added DCM (0.9 ml) and TFA (0.3 ml) was added at room temperature. After 1 hr of stirring, LC/MS indicated complete PMB cleavage. The mixture was dried under reduced pressure and purified with a 25 g (15 μm spherical silica) column ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) providing product, obtained as a film. The material was lyophilized from MeOH/H2O providing 4-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (2 mg, 4.17 μmol, 32.0% yield) as a yellow film. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.75 (s, 3H) 6.86 (d, J=4.59 Hz, 1H) 7.28 (d, J=4.59 Hz, 1H) 7.38 (d, J=4.27 Hz, 1H) 7.41-7.48 (m, 2H) 7.49 (s, 1H) 7.63 (s, 1H) 8.32-8.39 (m, 1H) 8.99 (d, J=4.27 Hz, 1H). m/z (ESI) 480.2 (M+H)+.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(N)=O)C)=O)CC1C=CC=CC=1.[NH:28]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:29]([C:40]([OH:42])=O)[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[NH:28]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:29]([C:40]([NH:60][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:42])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: NCc1ccccc1
Agent: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1
Yield: 89 %

Procedure:
The coupling procedure described above for the preparation of Cbz-Phe-Ala-NH2 was employed using 10.0 g of Cbz-Trp-OH (Sigma Chemical Company) and 4.84 mL of freshly distilled BnNH2 in dry THF to give 11.3 g (89% yield) of crystalline Cbz-Trp-NHBn. Characteristic analytical data are as follows: mp 104°-105° C.; 1H NMR (300 MHz, CDCl3) δ8.00-6.88 (m, 16H, Ar), 5.85 (br, 1H, H-α), 5.45 (br, 1H, H--N), 5.10 (s, 2H, CH2 --O), 4.57-4.45 (br, H--), 4.27 (t, 6H, CH2 --N), 3.38 (dd, J=4, 14 Hz, 1H, H-β), 3.16 (dd, J=8, 14 Hz, 1H, H-β); mass spectrum (EI), m/e 427 (M+), 336 (M+ -Bn), 277 (M+ -Cbz-NH), 130 (M30 -Cbz-NH--CH--CONH-Bn), 91 (Bn+); [α]D25 +7.0° (c=0.20, EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](=[S:26])[NH2:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[CH2:28][C:29]([CH3:31])=O.C([O-])(O)=O.[Na+].O>CN(C=O)C.CCOC(C)=O.CCCCCC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[N:4][C:3]=1[C:24]1[S:26][CH:28]=[C:29]([CH3:31])[N:25]=1
Reactant: CC(=O)CCl
Reactant: CC(C)n1nc(-c2nc(C(N)=S)c(N)nc2-c2ccccc2)ccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1csc(-c2nc(-c3ccc(=O)n(C(C)C)n3)c(-c3ccccc3)nc2N)n1
Yield: 52.5 %

Procedure:
A solution of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbothioamide (100 mg) and 1-chloroacetone (37.9 mg) in DMF (0.27 ml) was heated at 100-105° C. for 10 hours. After cooling, sat. aq. NaHCO3 solution (0.5 ml) and water (1 ml) were added to the mixture to yield a precipitate. The precipitate was collected by filtration, dissolved in CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 6-[5-amino-6-(4-methyl-thiazol-2-yl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (58 mg).