Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1)=[CH2:2].[CH2:9]([SiH:12]([Cl:14])[Cl:13])[CH:10]=[CH2:11]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:6]([CH2:5][CH2:4][Si:12]([Cl:14])([Cl:13])[CH2:9][CH:10]=[CH2:11])[CH2:7][CH:8]=[CH:3][CH2:1][CH3:2]
Reactant: C=CC[SiH](Cl)Cl
Reactant: C=CC1CC=CCC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CCCCC=CCC
Yield: 76753.6 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 37.8 g (0.35 mol) of 4-vinylcyclohexene and 60 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 10.0 g (0.07 mmol) of allyldichlorosilane for 30 min at 80° C. and the solution was further reacted for 3 hrs to complete the reaction. Vacuum distillation (70-73° C./0.5 torr) of the product mixture gave 13.5 g (78%) of 6-(3-hexenyl)-4,4-dichloro-4-sila-1-hexene.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C=C(c2ccccc2)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Yield: 94.5 %

Procedure:
Methyl 4-[(1,1-dimethyl-3-phenyl-1H-indene-5-carbonyl)amino]benzoate (359 mg, 0.90 mmol) was stirred with 4.5 mL of 2N NaOH in 5 mL of methanol and 5 mL of tetrahydrofuran for 10 hours. The solution was acidified with 1N HCl and concentrated under reduced pressure. After addition of 15 mL of water, the mixture was extracted with ethyl acetate (15 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in ether-hexane to give 326 mg (94% yield) of the title compound as solids; 1H-NMR (DMSO-d6) δ 1.39 (s, 6H), 6.68 (s, 1H), 7.39-7.53 (m, 3H), 7.64-7.68 (m, 3H), 7.85-7.97 (m, 6H), 10.54 (s, 1H), 12.75 (bs, 1H); MS m/e 384 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl[C:42]1[C:51]([CH3:52])=[C:50]([Cl:53])[C:49]2[C:44](=[CH:45][C:46]([F:54])=[CH:47][CH:48]=2)[N:43]=1.[C:55]1(=[O:61])[NH:60][CH2:59][CH2:58][CH2:57][CH2:56]1>CC(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:53][C:50]1[C:49]2[C:44](=[CH:45][C:46]([F:54])=[CH:47][CH:48]=2)[N:43]=[C:42]([N:60]2[CH2:59][CH2:58][CH2:57][CH2:56][C:55]2=[O:61])[C:51]=1[CH3:52]
Reactant: O=C1CCCCN1
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(N2CCCCC2=O)nc2cc(F)ccc2c1Cl
Temperature: 25 °C

Procedure:
Freshly prepared powdered 3 Å molecular sieves were transferred to a round bottom flask and activated by heating under vacuum for 3 min. After this time the flask was allowed to cool to rt for 10 min. At this time, K2CO3 (601 mg, 4.35 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (209 mg, 0.435 mmol), Pd2dba3 (199 mg, 0.217 mmol), 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.173 mmol), delta-valerolactam (215 mg, 2.173 mmol) and the previously activated molecular sieves were suspended in tBuOH (4 mL) and heated in the microwave for 1 h at 150° C. After this time the reaction was partitioned between EtOAc (70 mL) and water (40 mL). The separated aqueous layer was extracted with EtOAc (40 mL) and the combined organic extracts were washed with water (20 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 2:1) gave 1-(4-chloro-7-fluoro-3-methylquinolin-2-yl)piperidin-2-one. 1H NMR (400 MHz, chloroform-d) δ ppm 8.12-8.29 (1H, m), 7.63 (1H, dd, J=9.8, 2.5 Hz), 7.35-7.47 (1H, m), 4.07-4.22 (1H, m), 3.39-3.53 (1H, m), 2.54-2.70 (2H, m), 2.35-2.50 (3H, m), 1.90-2.15 (4H, m). Mass Spectrum (ESI) m/e=293.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([NH2:16])=[CH:14][C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][N:11]=2)=[C:5]([CH3:23])[CH:4]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([F:36])=[CH:32][C:33]=2[F:35])[N:28]=[C:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:26]=1[CH3:43].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:35][C:33]1[CH:32]=[C:31]([F:36])[CH:30]=[C:29]2[C:34]=1[C:25]([NH:16][C:15]1[C:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:23])=[N:11][CH:12]=[C:13]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:14]=1)=[C:26]([CH3:43])[C:27]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[N:28]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cc(C)c(-c2ncc(N3CCOCC3)cc2N)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c(C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(4-methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-amine (41 mg, 0.13 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (57 mg, 0.2 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (7.9 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.8 mg, 8.5 μmol), and sodium tert-butoxide (36.9 mg, 0.38 mmol) in dry toluene (2 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-60% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(2-(4-methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.7, 1.3 Hz), 8.00 (1H, d, J=2.5 Hz), 7.93 (2H, m), 7.63 (1H, m), 7.38 (1H, ddd, J=6.1, 4.8, 2.7 Hz), 6.95 (1H, ddd, J=13.3, 8.6, 2.5 Hz), 6.75 (2H, s), 6.60 (2H, m), 3.95 (7H, m), 3.28 (4H, m), 2.21 (3H, s), 2.15 (6H, s). Mass Spectrum (pos.) m/e: 568.2 (M+1).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:27](#[N:31])[CH2:28][C:29]#[N:30]>C(O)(=O)C>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[C:28]([C:27]#[N:31])[C:29]#[N:30])[CH3:25])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: N#CCC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
Hexamethyldisilazane (2.50 mL, 1.937 g, 12.0 mmol) was added to 1-(4-(benzyloxy)phenyl)ethanone (2.263 g, 10 mmol) in acetic acid (6 mL) at a rate to maintain the internal temperature below 74° C. After the addition was over, malononitrile (1.32 g, 20 mmol) in acetic acid (6 mL) was added to the solution. The reaction was heated at 90 C.° for 12 hours. After cooling, the reaction was poured into ice/water, extracted with EtOAc, dried, and concentrated under reduced pressure to give the crude product. The solid was triturated with 1:9 EtOAc/hexanes to provide 2.74 g of the desired product. 1H NMR (DMSO-d6): δ 7.72-7.75 (m, 2H), 7.35-7.49 (m, 5H), 7.18-7.21 (d, 2H), 5.22 (s, 2H), 2.61 (s, 3H). MS (ESI(+)): m/z 291 (M+NH4).
Reaction SMILES: [H-].[Na+].C(OCC)(=O)[CH2:4][C:5]([O:7]CC)=[O:6].Br[CH2:15][C:16]1[O:20][C:19]([CH3:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1>CN(C)C=O.O>[Cl:28][C:24]1[CH:23]=[C:22]([C:17]2[N:18]=[C:19]([CH3:21])[O:20][C:16]=2[CH2:15][CH2:4][C:5]([OH:7])=[O:6])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(-c2cccc(Cl)c2)c(CBr)o1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cccc(Cl)c2)c(CCC(=O)O)o1

Procedure:
60% Sodium hydride in oil (0.47 g) was added portionwise to a solution of diethyl malonate (3.4 g) in N,N-dimethylformamide (20 ml) and under ice-cooling a solution of 5-bromomethyl-4-(3-chlorophenyl)-2-methyloxazole (3 g) in N,N-dimethylformamide (10 ml) was added. The mixture was stirred under ice-cooling for 30 minutes, diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was dissolved in ethanol (20 ml), followed by addition of 2N sodium hydroxide (20 ml). The mixture was refluxed for 5 minutes, diluted with water and washed with ethyl ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl ether The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue (mostly, half-ester) was dissolved in pyridine (20 ml). The solution was refluxed for 2.5 hours. The pyridine was then distilled off and the residue [mostly, ethyl 4-(3-chlorophenyl)-2-methyloxazole-5-propionate] was dissolved in a mixture of ethanol (10 ml) and 2N sodium hydroxide (10 ml). The solution was refluxed for 5 minutes, diluted with water and acidified with hydrochloric acid to give crsytals of 4-(3-chlorophenyl)-2-methyloxazole-5-propionic acid, yield 1.6 g (56.7%), m.p. 159°-160° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([OH:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:23][P:24](Cl)(=[O:28])[O:25][CH2:26][CH3:27])[CH3:22]>C(OCC)(=O)C>[P:24]([O:13][C:5]1[N:4]=[C:3]([N:2]([CH3:14])[CH3:1])[N:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=1)([O:25][CH2:26][CH3:27])([O:23][CH2:21][CH3:22])=[O:28]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CN(C)c1nc(O)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)Oc1cc(C(F)(F)F)nc(N(C)C)n1
Temperature: 40 °C

Procedure:
A mixture of 2-dimethylamino-4-trifluoromethyl-6-hydroxypyrimidine (3.1 G), anhydrous potassium carbonate (2.8 g), and dry ethyl acetate (50 ml) was refluxed together for 1 hour and then cooled to about 40° C. Diethylphosphorochloridate (2.54 g) was then added dropwise to the stirred mixture and when the addition was complete the mixture was refluxed for 16 hours, after which it was allowed to cool to the ambient temperature. After filtration to remove the solids present, the filtrate was washed with water (2 × 50 ml), 10% w/v aqueous sodium hydroxide solution (1 × 50 ml), and finally with water until the washings were neutral. The ethyl acetate solution was dried over anhydrous magnesium sulphate, and after filtering, the the solvent was evaporated under reduced pressure to yield a residual pale yellow oil, which on cooling and scratching yielded crystalline O,O-diethyl 2-dimethylamino-4-trifluoromethylpyrimidin-6-yl phosphate, melting point 22°-24° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C(OCCl)C.[CH3:35][Si:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH2:40]Cl>C1COCC1>[Br:3][C:4]1[C:5]([N:10]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:43])([CH3:42])[CH3:35])[C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 117 mg, 4.88 mol) was added in portions over 10 min to a solution of benzyl 4-{2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.91 g, 4.43 mol) in THF (15 mL) at 0° C. After 0.5 h, 2-trimethylsilyl)ethoxymethyl chloride (0.861 mL, 4.88 mol) was then added slowly, keeping the temperature of the reaction mixture below 10° C. After 4 h, sodium hydride (60 mg) and 2-(trimethylsilyl)ethoxymethyl chloride (0.45 ml) were added and the reaction allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 40 to 70% ethyl acetate: hexanes to give the title compound (1.51 g). MS: m/z=560.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][OH:28])[C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][N:2]([CH2:26][CH2:27][O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N(C)CCO
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccccc1

Procedure:
N-methyl-N-(2-benzoyloxyethyl)erucamide was prepared by the procedure of example 1 from 39.5 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)erucamide and 14 gms. (0.1 mole) of benzoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[C:24]([CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[S:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:38]4([OH:41])[CH2:39][CH2:40][S:35][CH2:36][CH2:37]4)=[C:24]([CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1Br
Reactant: O=C1CCSCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1C1(O)CCSCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(4-Bromo-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (409 mg, 0.8884 mmol) in dry THF (5 mL) cooled to −78° C. is added n-BuLi (1.6 M in hexanes, 1.1 eq., 0.9772 mmol, 0.61 mL). The resulting mixture is stirred at −78° C. for 30 minutes and a solution of tetrahydro-thiopyran-4-one (1.1 eq., 0.9772 mmol, 114 mg) in dry THF (0.5 mL) is then added dropwise. After 30 minutes, the reaction mixture is quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture is diluted with EtOAc and washed sequentially with H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is partially purified by silica gel chromatography (3:1 hexanes/EtOAc) to give crude 4-{4-[4-(4-Hydroxy-tetrahydro-thiopyran-4-yl)-3-methyl-phenoxymethyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[C:10]([O:13][CH2:14]Br)(=[O:12])[CH3:11].Cl[C:17]1[N:22]=[C:21]([O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH:20]=[CH:19][N:18]=1>CN(C=O)C.C(Cl)Cl.[Zn].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:10]([O:13][CH2:14][C:17]1[N:22]=[C:21]([O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH:20]=[CH:19][N:18]=1)(=[O:12])[CH3:11]
Reactant: Clc1nccc(Oc2ccc3[nH]ccc3c2)n1
Reactant: CC(=O)OCBr
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Solvent: BrCCBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OCc1nccc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a suspension of nano zinc metallic powder (Strem Chemicals; average particle size 75-125 nm) (1.34 g, 20.52 mmol) in DMF (8 ml) is added 1,2-dibromoethane (0.19 mL, 2.2 mmol). The heterogeneous mixture is heated to 60° C. and then stirred for 10 min. The mixture is cooled to room temperature and charged with chlorotrimethylsilane (0.24 mL, 1.8 mmol). The reaction vessel is then sonicated in a room temperature water bath for 30 min. The suspension is then left standing for ca. 30 min to permit the solid to settle and the supernatant is then removed via syringe. DMF (8 ml) is then added, followed by bromomethyl acetate (1.00 mL, 10.3 mmol). The reaction mixture is then stirred for 2 hr at room temperature. The suspension is then left standing for 1 hour to permit the solid to settle. Next a separate flask is charged with 5-(2-chloropyrimidin-4-yloxy)-1H-indole (450 mg, 1.83 mmol), prepared as described in Example 73-A, DMF (3 mL) is then added to the 5-(2-chloropyrimidin-4-yloxy)-1H-indole followed by Pd(dppf)Cl2.CH2Cl2 (230 mg, 0.28 mmol). To this solution is added a portion of the supernatant (6 mL), from the flask containing the organozincate, via syringe. The reaction is heated at 50° C. for 16 h then cooled to room temperature and diluted with DCM and saturated aqueous NH1Cl. The layers are separated and the aqueous layer is extracted 2 additional times with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:17][CH2:18][CH2:19][O:20]CC2C=CC=CC=2)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:5]=1
Reactant: COC(=O)c1cc(OCCCOCc2ccccc2)cc(N2CCCC2=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OCCCO)cc(N2CCCC2=O)c1
Reaction time: 48 h
Yield: 69 %

Procedure:
3-(3-Benzyloxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D38) in MeOH (15 ml) was hydrogenolysed initially with 10% Pd on charcoal (50% wet, 0.25 g, 0.25 equiv w/w) at atmospheric pressure for 24 hrs and then a further 0.25 g of 10% Pd on charcoal (50% wet, 0.25 g, 0.25 equiv w/w) was added and the mixture hydrogenolysed at 50 psi for a further 48 hrs. The mixture was filtered through Celite and concentrated in vacuo. Purification by flash chromatography on silica gel (AcOEt/iso-hexane: 1/1) gave 3-(3-hydroxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B15) (260 mg, 69% over 2 steps). [M+H]+=294.0
Reaction SMILES: Cl[C:2]1[CH:20]=CC(C(OC2CNC2)C2C=CC(Cl)=CC=2)=C[CH:3]=1.[N-]=C=O.Cl[C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27]([O:35][CH:36]1[CH2:39][N:38]([C:40]([NH:42][C:43]([CH3:46])(C)[CH3:44])=[O:41])[CH2:37]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]([O:35][CH:36]2[CH2:39][N:38]([C:40]([NH:42][CH:43]3[CH2:44][CH2:20][CH2:2][CH2:3][CH2:46]3)=[O:41])[CH2:37]2)[C:26]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][CH:25]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Agent: [N-]=C=O
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.S(Cl)([Cl:13])(=O)=O>ClC1C=CC=CC=1>[Cl:13][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc2sncc2c1
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Yield: 95.8 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 27.0 g (0.2 mol) of 1,2-benzisothiazole was added under nitrogen atmosphere. 32.4 g (0.22 mol) Of sulfuryl chloride was added dropwise thereto while stirring at a temperature of from 70° to 80° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the reaction mixture was subjected to distilling off of the solvent and then to distillation under reduced pressure to give 32.5 g of 3-chloro-1,2-benzisothiazole (boiling point: 116° to 118° C./5 mm Hg, melting point: 38° to 40° C.). The yield was 96% to the 1,2-benzisothiazole.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Yield: 65.6 %

Procedure:
To a solution of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (3.04 g, 13 mmol) in CH2Cl2 (50 mL) were added morpholine (1.74 g, 20 mmol) and Et3N (2.63 g, 26 mmol). The reaction was refluxed overnight, and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (2.05 g, 65%).