Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li:5])CCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N12CCN(CC1)CC2.ClC1C(OCOC)=C(C(C2C=CC=CC=2OCOC)=C)C=CC=1>CCCCCC.O1CCCC1.CCOCC>[C:6]1([S:12][CH2:13][Li:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: CSc1ccccc1
Agent: C1CN2CCN1CC2
Agent: C=C(c1ccccc1OCOC)c1cccc(Cl)c1OCOC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]CSc1ccccc1
Temperature: 0 °C

Procedure:
Phenylthiomethyl lithium was prepared by adding 120 ml of 2.5M butyl lithium in hexane to a solution of 37.3 g of thioanisole and 33.7 g of 1,4-diazabicyclo[2,2,2]octane in 400 ml of tetrahydrofuran dropwise with stirring at 0° C. and then allowing the mixture to react for 45 min at 0° C. and 1 hour at room temperature. A solution of 50.2 g of 1-(3-chloro-2-methoxymethoxyphenyl)-1-(2-methoxymethoxyphenyl)ethene dissolved in 100 ml of tetrahydrofuran was added slowly to this at ambient temperature with stirring. A brick red color developed. The mixture was heated to reflux for about 30 min. Analysis by gas-liquid chromatography indicated that the reaction was complete. The mixture was cooled, diluted with ether, and quenched with water. The solution was extracted several times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 80 ml of a pale orange oil. This was subjected to a bulb-to-bulb distillation at up to 120° C. and 0.3 mm of mercury pressure. The thioanisole impurity was removed and a product cut of less than 5 ml was collected. Considerable decomposition took place. The product cut was partially purified by liquid chromatography, eluting with a 95:5 mixture of hexane and ether to obtain 1.8 g of the title compound of about 82 percent purity (gas-liquid chromatography) as a viscous oil. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[C:11]([F:29])=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31].[Cl-].[Li+]>O1CCOCC1.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>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([NH2:9])=[C:3]([C:10]2[C:11]([F:29])=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)[C:2]=1[CH:30]=[CH2:31]
Reactant: Nc1cnc(Cl)c(Br)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1c(Cl)ncc(N)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (93 mg, 0.19 mmol), vinyltributyl tin (63 μL, 0.21 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol %) and lithium chloride (25 mg, 0.59 mmol) in 1,4-dioxane (1.0 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, diluted with water (10 mL) and extracted with DCM (3×20 mL). The combined organic layer was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 4 g column, ISCO, 0-10% MeOH in DCM) to afford the title compound as a beige powder (77 mg, 82%). 1H NMR (CDCl3, 400 MHz): 8.50 (dd, J=2.5, 1.0 Hz, 1H), 7.94 (s, 1H), 7.88 (dd, J=8.5, 2.5 Hz, 1H), 7.54-7.47 (m, 4H), 6.53 (dd, J=18.0, 11.5 Hz, 1H), 5.37 (dd, J=11.5, 1.0 Hz, 1H), 5.11 (dd, J=18.0, 1.0 Hz, 1H), 3.60 (s, 2H), 3.55-3.50 (m, 2H), 2.48-2.35 (m, 4H), 1.68-1.58 (m, 4H), 1.50-1.44 (m, 2H). LCMS (Method B): RT=2.32 min, M+H+=423/425.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[C:12]=2[N:13]=1)=[O:7].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([C:18]([CH:14]3[C:12]4[N:13]=[C:9]([NH:8][C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:7])[S:10][C:11]=4[CH2:17][CH2:16][CH2:15]3)=[O:20])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Nc1nc2c(s1)CCCC2C(=O)O)c1ccco1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nc2c(s1)CCCC2C(=O)N1CCN(c2ccccc2)CC1)c1ccco1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Carbonyldiimidazole (CDI, 0.31 g, 1.9 mmol) was added to a solution of 2-[(furan-2-carbonyl)amino]-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (0.5 g, 1.7 mmol) in CH2Cl2 (10 mL), and the resultant mixture was stirred for a period of 2 hours at room temperature. Following cooling of the suspension to 0° C., N-phenylpiperazine (0.28 g, 1.73 mmol), dissolved in CH2Cl2 (10 mL), was added dropwise over a period of 5 minutes. After stirring for 30 min at 0° C. and overnight at room temperature, there were added a few drops of water. Following drying over Na2SO4 and filtration, the solvent was removed and the residue was purified via column chromatography. The product furan-2-carboxylic acid(4-(4-phenylpiperazin-1-carbonyl)-4,5,6,7-tetrahydrobenzthiazol-2-yl]amide was obtained in a yield of 514 mg (corresponding to 69% of the theoretical yield).
Reaction SMILES: [CH2:1]([CH:5]([Sn])C=C(CCCC)CCCC)[CH2:2]CC.Br[C:18]1[C:19]([F:38])=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]1[C:27]([CH2:36][CH3:37])([CH2:31][C:32]([O:34][CH3:35])=[O:33])[O:28][CH2:29][CH2:30][C:23]2=1>C1C=CC=CC=1.[Pd].CCOCC.[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>[CH2:36]([C:27]1([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]2[NH:25][C:26]3[C:22]([C:23]=2[CH2:30][CH2:29][O:28]1)=[CH:21][CH:20]=[C:19]([F:38])[C:18]=3[CH2:5][CH:1]=[CH2:2])[CH3:37]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(Br)c(F)ccc21
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 80 °C
Reaction time: 42 h
Yield: 78 %

Procedure:
According to the procedure of Kosugi et al, Chem. Letters 301 (1977) tetrakis-(triphenylphosphine) palladium [O] (60 mg) was added to a mixture of tributylallyltin (1.75 g, 0.0053 mol) and 8-bromo-1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid, methyl ester (1.6 g, 0.0043 mol) in benzene (4.0 mL) under N2. The sealed tube was then heated to 80° C. for 15 hours, more palladium catalyst was added (30 mg), and heating continued for 42 hours at 110°-120° C. The cooled reaction mixture was diluted with Et2O, then filtered through a glass wool plug. The ether was washed twice with brine, then dried (MgSO4) to yield an oil that was purified via flash chromatography. Using 1:7 EtOAc:hexane to afford 1.12 g, (~78%) of 1-ethyl-7-fluoro-1,3,4,9-tetrahydro-8-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid, methyl ester as a colorless oil. The oil was dissolved in ethanol (40 mL) and 1N sodium hydroxide added (15 mL). The mixture was heated to reflux for 2 hours then cooled and concentrated. 1N HCl was added and the aqueous solution extracted with ether. The ether layers were washed (brine), dried (MgSO4) and concentrated to yield a foamy oil. This was purified by flash chromatography on SiO2 -pretreated with 2% H3PO4 -MeOH. Using 1:2 EtOAc:hexane to give 1 g (73%) of 1-ethyl-7-fluoro-1,3,4,9-tetrahydro-8-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid as a colorless oil which crystallized from toluene:petroleum ether, m.p. 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Br(O)(=O)=O.[NH2:47][C:48]1[S:49][C:50]([Br:53])=[CH:51][N:52]=1>C(Cl)(Cl)Cl.O>[Br:53][C:50]1[S:49][C:48]([NH:47][C:35]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[Cl:1])=[O:41])=[N:52][CH:51]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: [O-][Br+2]([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ncc(Br)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added thereto, and the mixture was stirred at room temperature for 30 min. Next, a solution of 2-amino-5-bromothiazole bromate (106 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 6 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C@@H:13]1[C:49]([CH3:51])([CH3:50])[C@H:48]2[C@@:16]3([O:44][C:20]4[C:21]5[CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24](=[O:36])[C:25]=5[CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:19]=4[CH2:18][C@:17]3([CH3:53])[C@@H:45]([CH3:52])[CH2:46][CH2:47]2)[CH2:15][CH2:14]1>ClCCl>[C:8]([NH:12][C@@H:13]1[C:49]([CH3:51])([CH3:50])[C@H:48]2[C@@:16]3([O:44][C:20]4[C:21]5[CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24](=[O:36])[C:25]=5[CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:19]=4[CH2:18][C@:17]3([CH3:53])[C@@H:45]([CH3:52])[CH2:46][CH2:47]2)[CH2:15][CH2:14]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CN(C(=O)OC(C)(C)C)C5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C1(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
Under nitrogen, 25 μl (0.18 mmol) of triethylamine and 8 μl (0.11 mmol) of acetyl chloride was added to a solution of Compound (45a) (50 mg, 0.087 mmol) in 2.0 ml of dry dichloromethane under ice-cooling, and the mixture stirred for 40 min at the same temperature. After addition of ice-water, the reaction was extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=30:1) to give 44 mg (82%) of Compound (45b).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[S:11]2(=[O:19])=[O:18])[CH:3]=1.Cl>C(Cl)Cl.C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[S:11]2(=[O:19])=[O:18])[CH:3]=1
Reactant: CN1C(C)(C)CN(c2cc(F)ccc2C#N)S1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CN1C(C)(C)CN(c2cc(F)ccc2CN)S1(=O)=O
Reaction time: 22 h

Procedure:
To a solution of 4-fluoro-2-(4,4,5-trimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)benzonitrile (3.34 g, 11.8 mmol) in CH2Cl2 (30 mL), ethyl acetate (30.0 mL) and ethanol (30.0 mL) was added 1N HCl (12 mL) followed by 10% palladium on carbon (0.377 g, 3.54 mmol). The mixture was shaken under H2 at 50 psi for 22 h then filtered over CELITE® and concentrated. The solids were triturated with H2O and removed by filtration. The aqueous solution was washed with ethyl acetate and lyophilized to give the title compound, as the HCl salt, as a white powder (3.44 g, 90% yield). LCMS (M+H) calcd for C12H19FN3O2S: 288.11; found: 288.19. 1H NMR (300 MHz, DMSO) δ: 8.35 (2H, brs), 7.71 (1H, dd, J=8.6, 6.4 Hz), 7.54 (1H, dd, J=9.9, 2.6 Hz), 7.43 (1H, td, J=8.4, 2.6 Hz), 4.19 (2H, s), 3.75 (2H, s), 2.63 (3H, s), 1.35 (6H, s).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([NH2:22])=[O:21].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][N:11]([CH2:27][NH:22][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([F:26])=[C:17]([F:16])[CH:18]=2)[CH2:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: NC(=O)c1ccc(F)c(F)c1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CC=C(c2ccccn2)CC1)c1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), 3,4-diflurobenzamide (79 mg, 0.5 mmol, Lancaster), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 18 mg (55%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.58 (m, 2H), 2.79 (t, J=4 Hz, 2H), 3.32 (m, 2H), 4.28 (d, J=5 Hz, 2H), 6.71 (m, 1H), 7.22 (m, 1H), 7.55 (m, 2H), 7.83 (m, 2H), 7.95 (t, J=6 Hz, 1H), 8.52 (m, 1H) 8.95 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 328 (M−H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[CH2:31].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:31]=[CH:30][C:32]2[S:36][CH:35]=[N:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=Cc1cncs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cncs3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 80 °C

Procedure:
A pressure vessel is charged with 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (828 mg, 1.52 mmol), 5-vinyl thiazole (186 mg, 1.68 mmol), triethylamine (0.32 mL, 2.28 mmol) and tri-o-tolylphosphine (37 mg, 0.12 mmol) in CH3CN (1.5 mL). The vessel is degassed and palladium(II) acetate (6.80 mg, 0.03 mmol) is added. The vessel is sealed and heated at 80° C. for 20 h. The reaction mixture is concentrated and dissolved in EtOAc, washed with 1N HCl , dried over MgSO4 and concentrated. The residue is purified by column chromatography to afford the title compound as a yellow solid; (M+H)+=528.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12](C)([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:23][PH:24]([O-])([O-:28])[O:25][CH2:26][CH3:27].CCN(CC)CC>C1COCC1.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]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([NH:9][S@@:10]([CH:12]([CH3:13])[CH3:14])=[O:11])[C:5]2[CH:6]=[CH:7][C:2]([P:24]([CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)=[CH:17][CH:18]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)C)c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
To (R)—N—((R)-(4-bromophenyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 18-c, (10 g, 0.026 mol), ethyl methylphosphite (5.6 g, 0.052 mol) and Et3N (7.88 g, 0.078 mol) in THF (100 ml) was added PdCl2(dppf) (2.2 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the product, 18-d, (6.9 g, 68%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16]N(C3C=CC(OC(C)C)=CC=3)CN(C3C=CC(OC(C)C)=CC=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(OC(Cl)(Cl)Cl)=[O:39].[CH:45]([NH:49][C:50]([NH:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[S:51])([CH2:47][CH3:48])[CH3:46].[OH-].[Na+]>>[C:53]([N:52]=[C:50]1[N:49]([CH:45]([CH2:47][CH3:48])[CH3:46])[C:16](=[O:39])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[CH2:12][S:51]1)([CH3:54])([CH3:56])[CH3:55]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)Oc1ccc(N2CN(c3ccc(OC(C)C)cc3)CN(c3ccc(OC(C)C)cc3)C2)cc1
Reactant: CCC(C)NC(=S)NC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)N1C(=O)N(c2ccc(OC(C)C)cc2)CSC1=NC(C)(C)C
Yield: 66.2 %

Procedure:
Similarly, 2.8 g (0.006 mole) of 1,3,5-tris(p-isopropoxyphenyl)-hexahydro-s-triazine, 1.8 g (0.009 mole) of trichloromethyl chloroformate, 3.0 g (0.016 mole) of 1-s-butyl-3-t-butylthiourea, and 15 g of a 10% aqueous sodium hydroxide solution were used to obtain 1.5 g (25% yield) of 2-t-butylimino-3-s-butyl-5-(p-isopropoxyphenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 374)of the formula, ##STR173## as colorless oily substance (nD20 1.5402).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([F:16])[C:3]=1[CH3:17].[C:18](OC(=O)C)(=O)[CH3:19].CO[CH:27](OC)[N:28]([CH3:30])C>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8](=[CH:30][NH:28][CH:27]2[CH2:19][CH2:18]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([F:16])[C:3]=1[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(Br)c(C)c1F
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1ccc(Br)c(C)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
In 14 ml of methylene chloride was dissolved 0.70 g of ethyl 4-bromo-2-fluoro-3-methyl-benzoylacetate, followed by adding thereto 0.29 g of acetic anhydride and 0.33 g of N,N-dimethylformamide dimethyl acetal, and the resulting mixture was stirred at room temperature for 2 hours and then distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in 10 ml of ethanol, followed by adding thereto 0.16 g of cyclopropylamine. The resulting mixture was stirred at room temperature for 12 hours and the crystals precipitated were collected by filtration to obtain 0.72 g of colorless ethyl 2-(4-bromo-2-fluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH3:17].O>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([CH3:17])[CH:12]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Cc1cc(Cl)ccc1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccccc1
Yield: 89 %

Procedure:
1.03 mol of a phenylmagnesium chloride solution (26% by weight in THF) are added dropwise in the course of 60 minutes to a boiling solution of 1.0 mol of 2-bromo-5-chlorotoluene and 0.2 g of Pd(dppf) Cl2 *CH2Cl2 in 200 ml of THF. After stirring under reflux for eight hours (conversion >97%), the mixture is hydrolyzed with water. After purification by distillation, 4-chloro-2-methylbiphenyl is obtained as a colorless liquid in a yield of 89%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:17])=[O:16].[CH3:18][N:19]=[C:20]=[O:21].N12CCCN=C1CCCCC2>C(#N)C.O>[CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH:15][C:20]([NH:19][CH3:18])=[O:21])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:17])=[O:16]
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: CN=C=O
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)C2
Temperature: 25 °C

Procedure:
A solution of 24.96 g of 3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonamide in 120 ml of absolute acetonitrile is cooled to +8° C. After the addition of 6 ml of methyl isocyanate, a solution of 13.4 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 15 ml of acetonitrile is added dropwise over 15 minutes at 10° C. The reaction mixture is stirred for a further hour at room temperature. The mixture is subsequently diluted with 180 ml of water. The product is precipitated by the dropwise addition of 48 ml of 2N hydrochloric acid. The precipitate is isolated and dried, affording 26.4 g of N-(3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-methylurea with a melting point of 235°-238° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:9]1[N:10]=[C:11]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][N:14]=1
Reactant: CC(=O)NCCN
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)NCCNc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.84 g of 2-acetylamino-ethylamine dissolved in 10 ml of dioxane are added to 3.91 g of 2,4-dichloro-5-trifluoromethyl-pyrimidine in 20 ml dioxane at ambient temperature. Then 3.7 ml of 5 M potassium carbonate solution are added and the mixture is stirred for three days at ambient temperature. It is then filtered through Alox B and washed with dioxane. The filtrate is concentrated by evaporation and the residue separated by chromatography through a silica gel column with cyclohexane:ethyl acetate:methanol (5:4:1).
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1>C(OCC)C.O1CCOCC1>[I:1][CH2:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CI)C1
Yield: 93.1 %

Procedure:
Iodine (1.91 g) was added in portions to a vigorously stirred, ice cooled suspension of imidazole (0.681 g) and triphenylphosphine (1.97 g) in diethyl ether (12 mL). The mixture was then stirred for 10 minutes before a solution of tert butyl (R)-3-hydroxymethylpyrrolidine-1-carboxylate (1 g) in dioxane (6 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight, then diluted with diethyl ether and filtered. The solid was washed with diethyl ether and the combined filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-20% to give tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (1.44 g) as an oil.