Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:40][CH:37]3[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reaction time: 2 h
Yield: 62.9 %

Procedure:
(S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamine (24 grams, 0.117 mole) was dissolved in dichloroethane (300 ml) and sodium triacetoxyborohydride (37.2 grams, 0.176 mole) was added. After stirring for 5 minutes N-methanesulfonylpiperidine-4-carboxaldehyde (22.4 grams, 0.117 mole) was added and the mixture was stirred for another 2 hours. 5% sodium carbonate (600 ml) was added and the mixture was extracted with dichloromethane. Evaporation of the solvent gave an oil which was recrystallized from ether to give (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (28 grams, 63%), m.p. 99-101° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].Cl[CH:6]([O:8][C:9]([O:11][CH:12]([CH3:20])[CH2:13][NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:10])[CH3:7]>C1COCC1>[C:1]([O:4][CH:6]([O:8][C:9]([O:11][CH:12]([CH3:20])[CH2:13][NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:10])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C=C(C)C(=O)NCC(C)OC(=O)OC(C)Cl
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCC(C)OC(=O)OC(C)OC(C)=O
Reaction time: 96 h
Yield: 24.8 %

Procedure:
A THF solution (100 ml) of TBA acetate (6.93 g, 23 mmol) prepared by freeze-drying an aqueous solution of equimolar TBA-OH and acetic acid, was added to a stirred solution of N-[2-(1-chloroethoxycarbonyloxy)propyl]methacrylamide (4.736 g, 19 mmol) from Example It(i) above in THF (100 ml) at room temperature. Following stirring for 4 days the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with water (5×20 ml ). The organic phase was dried (MgSO4 ) and the solvent removed under reduced pressure. Flash chromatography (silicagel, hexane/ethyl acetate (3:4)) gave 1.29 g (25%) of the title product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]#[N:13])[CH:4]=[CH:3]1.[OH-:14].[K+].O>C(O)(C)(C)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:13])=[O:14])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(CC#N)c21
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cn1ccc2cccc(CC(N)=O)c21
Yield: 65.5 %

Procedure:
A slurry of (1-methyl-1H-indol-7-yl)-acetonitrile (137 mmol, crude material prepared as described above) in tert-butanol (240 mL) was heated to reflux, KOH (85%, 88.3 g, 1.57 mol) was added and mixture was stirred at reflux for 15 minutes. H2O (1 mL) was introduced and the mixture was heated at reflux for an additional 5 minutes. The solution was allowed to cool, decanted, and diluted with EtOAc (1 L) and H2O. The two layers were separated and the organic solution was washed with H2O and brine. The crude solution was dried (MgSO4), filtered and concentrated to an off-white solid. Trituration with refluxing ether gave the title compound (16.90 g, 65% from 1H-indole-7-carboxaldehyde). 1H NMR (400 MHz, DMSO-d6) 3.87 (s, 2H), 4.03 (s, 3H), 6.39 (d, J=3.2 Hz, 1H), 6.83–7.01 (m, 3H), 7.20 (d, J=3.3 Hz, 1H), 7.30–7.46 (m, 2H). MS (electrospray, m/z) 189.0 (M++1). Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.03; H, 6.41; N, 14.63.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.N1CCCCC1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].CCN(CC)CC>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccc(Br)cn2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: CN1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)-4-methylpiperazine (501.7 mg, 1.96 mmol), PdCl2(PPh3)2 (51.1 mg, 0.073 mmol) and copper(I) iodide (39.9 mg, 0.21 mmol) was flushed with argon for 10 min prior to addition of piperidine (1.25 mL, 12.7 mmol) and trimethylsilylacetylene (1.40 mL, 9.9 mmol). The resulting mixture was heated at 90° C. in a sealed vial for 3 d. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. Chromatography on Biotage (silica, SNAP-25 g, 5-15% MeOH in DCM) yielded an impure product. A second chromatography on Biotage (silica, SNAP-25 g, 0-3% Et3N in Et2O) gave 1-methyl-4-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)piperazine (325.7 mg, 61%). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=1.3 Hz, 1 H), 7.53 (dd, J=8.9, 2.4 Hz, 1 H), 6.55 (d, J=8.8 Hz, 1 H), 3.67-3.52 (m, 4 H), 2.57-2.44 (m, 4 H), 2.35 (s, 3 H); MS ESI [M+H]+ 274.0, calcd for [C15H23N3Si+H]+ 274.2.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (from Step 2 of Example 202, 210 mg, 0.436 mmol) in dichloromethane (2 mL), was added N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) and methanesulfonyl chloride (0.043 mL, 0.52 mmol) at rt. The mixture was stirred at rt for 2 h. The reaction was then quenched with water, diluted with dichloromethane, washed with aq. sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude was tritrated in ether and filtered to give 6-bromo-4-(((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (136 mg, 72% yield) as a yellow solid. MS (ES+) m/z: 432.3, 463.1 (M+H); LC retention time: 2.31 min (analytical HPLC Method H).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[Br:27]>>[Br:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[NH:20][S:2]([C:5]1[S:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2cccc3ccccc23)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccc4ccccc34)s2)c1Br
Yield: 22.4 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-napthyl)thiophene-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(1-napthyl)thiophene (200 mg, 0.65 mmol) with 5-amino-4-bromo-3-methylisoxazole (0.65 mmol), after purification by column chromatography using 1% MeOH/CHCl3, gave 65.3 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-napthyl)thiophene-sulfonamide as a brown solid, (22% yield, m.p. 118° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1.CCN(CC)CC.[CH:25](O)([CH3:27])[CH3:26]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1)([CH3:27])=[CH2:26]
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cn1
Reactant: CC(C)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(C(=O)OCc2ccccc2)nc1
Temperature: 80 °C

Procedure:
A mixture of benzyl 5-bromopicolinate (2.92 g, 10 mmol), potassium isopropenyl trifluoroborate (3.05 g, 21 mmol), Pd(dppf)Cl2 (445 mg, 0.54 mmol), and Et3N (1.4 mL) in isopropyl alcohol (20 mL) was degassed with N2 and heated at 80° C. for 7 h. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with H2O, 5% citric acid, sat.NaHCO3(aq.) and brine, then dried (MgSO4) and concentrated. The product benzyl 5-isopropenylpicolinate (1.27 g) was obtained by silica gel chromatography (elution with 0-16% EtOAc/Hex).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[C:25]([F:39])[CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[C:31](=[CH:20][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=2[CH3:1])[C:32](=[O:38])[NH:33]3)=[C:25]([F:39])[CH:24]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 44.2 %

Procedure:
The title compound was prepared under the same conditions as described, in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(4-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(4-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (45 mg, 44.2%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.[CH2:39]([C:41](=[CH2:47])[C:42](OCC)=[O:43])[CH3:40]>C(O)CCC>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:42](=[O:43])[C@H:41]([CH2:39][CH3:40])[CH2:47][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:42](=[O:43])[C@@H:41]([CH2:39][CH3:40])[CH2:47][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: C=C(CC)C(=O)OCC
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: CCCCO
Product: CC[C@@H]1CN2C[C@@H](COc3ccc(C4CCCCC4)cc3)OC2=NC1=O
Product: CC[C@H]1CN2C[C@@H](COc3ccc(C4CCCCC4)cc3)OC2=NC1=O
Temperature: 90 °C

Procedure:
A solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.85 g, 3.09 mmol), prepared in accordance with the procedures in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, and ethyl ethylacrylate (1.0 g, 7.57 mmol) in n-butanol (2 ml) was heated at 90° C. for 18 hrs. The reaction mixture was concentrated and loaded onto a silica gel column, and eluted with 2-6% isopropanol/methylene chloride to afford (2S,6R)-2-(4-cyclohexyl-phenoxymethyl)-6-ethyl-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one (0.24 g) and (2S,6S)-2-(4-cyclohexyl-phenoxymethyl)-6-ethyl-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one (0.34 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C[C:14](C)([OH:17])C#N.[CH3:19][N:20](C)C(N(C)C)=N.CO>C(#N)C.C(OCC)C>[NH:20]=[C:19]([O:17][CH3:14])[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(O)C#N
Reactant: CN(C)C(=N)N(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: COC(=N)Cc1ccc(C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl 4-(bromomethyl)benzoate (5.00 g, 21.8 mmol) and acetone cyanohydrin (3 ml, 32.7 mmol) stirring at room temperature in acetonitrile (200 ml) was added 1,1,3,3-tetramethylguanidine (5.8 ml, 45.8 mmol) and the mixture stirred for 16 hours. The solvent was removed under reduced pressure. The residue was triturated with diethyl ether (×3), filtered and the filtrate evaporated under reduced pressure. The residue was purified by filtering through a pad of silica, eluting with diethyl ether to afford a colorless oil, 4.0 g. The oil was dissolved in 200 ml of diethyl ether and gaseous hydrogen chloride was bubbled though the solution until saturated while stirring at 0° C. Methanol (1.5 ml, 37.2 mmol) was added and the mixture stirred for 1 hour. The solvents were removed under reduced pressure and the residue was basified using saturated sodium carbonate solution and extracted with dichloromethane (×3). The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a colourless oil, 4.20 g.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21]>CC(C)=O>[CH3:5][C:4](=[CH:3][CH2:2][S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[CH3:13])[CH3:6]
Reactant: Cc1ccc(C)c(S)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCSc1cc(C)ccc1C
Yield: 100.3 %

Procedure:
80 ml of acetone, 9.1 g (0.06 mol) of 1-bromo-3-methyl-2-butene and 8.0 g (0.058 mol) of anhydrous potassium carbonate were added to 8.0 g (0.058 mol) of 2,5-dimethylthiophenol, and the mixture was refluxed under heat for 1 hour. After the completion of the reaction, a formed salt was removed by filtration, and the acetone was distilled off under reduced pressure. Then, ethyl acetate was added to the residue, and the mixture was washed with a saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, and then the ethyl acetate was distilled off to give 12 g (yield 100%) of 2-methyl-4-(2,5-dimethylphenyl)thio-2-butene.
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: COC(=O)C(CCSC)OC(C)=O
Reactant: CSCC=COC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC#N
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 120 °C
Yield: 10 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z:E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P)2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of CH3CN as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 500 psi (at room temperature) was charged to the bomb, and the bomb was heated to 120° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 3 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 10 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH3:24])=[C:12]([CH3:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2)c1C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as in Example 61) (90 mg, 0.32 mmol) in 3 mL of dry DMF was added bromoethane (108 mg, 1.0 mmol) and K2CO3 powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(4-ethoxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 314 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccccn3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 2-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 160° C., Rf=0.4 (CH2Cl2/MeOH=15:1) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.[O-2].[Mg+2].S(Cl)(Cl)(=O)=O.N>ClC1C=CC=CC=1.O>[NH2:11][C:9]1[S:10][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]=1
Reactant: NC(=S)Nc1ccc(Br)cc1
Agent: N
Agent: [Mg+2]
Agent: [O-2]
Solvent: Clc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: Nc1nc2ccc(Br)cc2s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A solution of N-(4-bromophenyl)thiourea (16.18 g) and magnesium oxide (1.41 g) in chlorobenzene (100 mL) was heated to 50° C., and a solution of sulfuryl chloride (8.43 mL) in chlorobenzene (9 mL) was added dropwise to the solution over 1 hour or longer, followed by stirring at 50° C. overnight. The reaction mixture was returned to room temperature, and water (20 mL) was added thereto. The pH of the mixture was adjusted to about 8 by use of concentrated aqueous ammonia, and the precipitates were recovered through filtration. The obtained solid was recrystallized from 90% ethanol, to thereby yield the title compound (7.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:4]=1.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[C:24]2[CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)#[N:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C@@H:34]3[CH2:33][CH2:32][C@H:31]([C:24]4[C:23]5[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=5)[N:26]([CH3:30])[CH:25]=4)[CH2:36][CH2:35]3)[CH2:15][CH2:14]2)[CH:4]=1
Reactant: COc1cc(N2CCNCC2)c2nccnc2c1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methoxy-5-piperazin-1-yl-quinoxaline (160 mg, 0.66 mmol), 4-(5-cyano-1-methyl-1H-indol-3-yl)-cyclohexanone (170 mg, 0.66 mmol), and sodium triacetoxyborohydride (210 mg, 0.98 mmol) in dichloroethane (30 mL) was added acetic acid (0.1 mL, 1.3 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (100 mL) then extracted in CH2Cl2 (75 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc) affording 120 mg (38%) of the cis isomer as a bright yellow solid: mp 226-229° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[C:12]([C:16]1[C:17](=[O:33])[CH2:18][CH:19]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([NH2:31])[C:24]=2[CH3:32])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH2:13][CH3:14]>C(Cl)Cl>[C:12]([C:16]1[C:17](=[O:33])[CH2:18][CH:19]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([NH:31][S:8]([CH3:7])(=[O:10])=[O:9])[C:24]=2[CH3:32])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reaction time: 8 h

Procedure:
Pyridine (0.53 ml, 6.6 mmol) followed by methane sulfonyl chloride (0.52 ml, 6.6 mmol) was added to a stirred solution of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.3 mmol)in methylene chloride (10 ml). Stirring was continued at 20° for 8 hr. The organic layer was washed with water, dilute hydrochloric acid and further water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product. The crude material was purified by column chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to give 2-propionyl-3-hydroxy- 5-(3-methylsulphonamido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a yellow waxy solid (0.6 g, 50%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.17 (3H,t); 2.35 6H, s); 2.46 (3H,s); 3.0 (3H,s); 2.4-4.1 (7H,m); 6.78 (1H,s); 6.89 (1H,s); 18.15 (1H,brs).