Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([C:43]2[C:44](C)=[C:45](OS(C)(=O)=O)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:45]2[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[N:48]=[C:43]([C:37]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:35]([Cl:34])[CH:36]=3)[CH:44]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(OS(C)(=O)=O)c2C)cc1Cl
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 89 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and tert-butyl 1-piperazine-carboxylate were reacted to yield the title compound as a yellow oil (yield: 89.0%).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[Cl:4].[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][Si:3]([Cl:4])([CH3:6])[CH3:5]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](C)(Cl)CCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](C)(Cl)C[Si](Cl)(Cl)Cl
Yield: 60 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.27 g (1.5 mmol) of tetrabutylphosphonium chloride, 2.15 g (15.0 mmol) of (chloromethyl)dimethylchlorosilane, and 6.10 g (45.0 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 2.18 g of 1,1,1,3-tetrachloro-3-methyl-1,3-disilabutane (yield; 60%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][OH:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[O:44]=[C:45]1[CH:50]([N:51]2[C:59](=[O:60])[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][C:57]=3O)[C:52]2=[O:62])[CH2:49][CH2:48][C:47](=[O:63])[NH:46]1>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:25][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[C:52](=[O:62])[N:51]([CH:50]1[CH2:49][CH2:48][C:47](=[O:63])[NH:46][C:45]1=[O:44])[C:59]2=[O:60]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of polymer-supported triphenylphosphine (1.46 g, ˜4.4 mmol) and 3,4-dichlorobenzyl alcohol (0.65 g, 3.6 mmol) was stirred in THF (10 mL) at 0° C. Keeping the reaction mixture at 0° C., a solution of diisopropylazodicarboxylate (0.87 mL, 4.4 mmol) in THF (2.1 mL) was added dropwise. 2-(2,6-Dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (1.00 g, 3.60 mmol) was then added as a solid, the reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was evaporated under vacuum and the residue was chromatographed using a methanol-CH2Cl2 gradient, eluting the product at 95:5 CH2Cl2-methanol. This material was dissolved in ethyl acetate (150 mL) and water (100 mL) was added. The organic phase was then washed with 10% dilute aqueous sodium carbonate (2×50 mL) and water (3×50 mL). The solvent was removed under vacuum and the resulting solid was triturated with ether, filtered and dried to provide the title compound as a white solid (0.41 g, 26% yield); mp 245-247° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.50 (99.78%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.45-2.62 (m, 2H), 2.82-2.96 (m, 1H), 5.12 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 5.38 (s, 2H), 7.49-7.51 (m, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.81-7.88 (m, 2H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 48.8, 68.5, 115.9, 116.8, 120.1, 127.3, 129.0, 130.5, 130.8, 131.2, 133.3, 137.1, 137.5, 155.1, 165.3, 166.8, 169.9, 172.8; Anal. Calcd for C20H14N2O5Cl2+0.3 H2O: C, 54.76; H, 3.35; N, 6.39. Found: C, 54.48; H, 3.07; N, 6.29.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-:12].[Na+]>OO>[CH:9]1[CH:10]=[C:2]([C:1]([OH:6])=[O:11])[C:3]([C:4]([O:12][O:12][C:4]([C:3]2[C:2]([C:1]([OH:6])=[O:11])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[O:5])=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: O=C(O)c1ccccc1C(=O)OOC(=O)c1ccccc1C(=O)O
Reaction time: 0.42 h

Procedure:
Diphthaloyl peroxide was prepared by adding finely powdered phthalic anhydride (7.2g) gradually over a period of five minutes to a solution of hydrogen peroxide (0.46% by weight, 90 cm3) maintained at a temperature of between 1° to 3° C by the use of a cooling jacket, and the pH of 9 plus or minus 0.2 by dropwise addition of sodium hydroxide sufficient to counteract the generation of acidity as the reaction proceeded. The solution was stirred constantly, so that the proportion of the finely powdered phthalic anhydride which did not go into solution, remained in suspension, and the temperature and pH were controlled for a further 25 minutes, by which time substantially all the hydrogen peroxide had been consumed. The suspension was filtered into sulphuric acid (10% by weight, 30 cm3) and substantially all the diphthaloyl peroxide precipitated out. The solid which had been filtered off was washed with water and then dried to recover phthalic anhydride (3.03g). The acidified filtrate was centrifuged and the precipitate, separated thereby, was washed with water (40 cm3) and dried giving diphthaloyl peroxide (3.l g). An iodometric assay of the crude product showed that it contained 89.1% of active material, and negligible amount of monoperoxyphthalic acid, giving a reaction yield of 59.4%, based on consumption of phthalic anhydride.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([Br:17])[N:9]=1)([CH3:6])[CH3:5].[Sn].Cl>O>[Br:17][C:10]1[CH:11]=[CH:12][C:13]2[NH:14][C:3](=[O:2])[C:4]([CH3:6])([CH3:5])[O:7][C:8]=2[N:9]=1
Reactant: COC(=O)C(C)(C)Oc1nc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: O
Product: CC1(C)Oc2nc(Br)ccc2NC1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 640 mg 2-(6-Bromo-3-nitro-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester and 542 mg tin powder were added dropwise 10 ml concentrated hydrochlorid acid upon cooling in an ice bath so that the reaction temperature did not exceed 40° C. The ice bath was then removed and the reaction mixture stirred at 85° C. for one hour. To the cooled reaction mixture was added 100 ml water. The precipitate was collected and dissolved in 300 ml ethyl acetate dried over MgSO4 then the ethyl acetate was removed in vacuo to obtain 335 mg 6-Bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7](O)(=[O:15])[CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH3:14].O.[OH-].[Na+]>C1COCC1>[CH2:7]([OH:15])[CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCC/C=C/CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC/C=C/CCO
Temperature: 25 °C
Yield: 76.4 %

Procedure:
LiAlH4 (13.5 mL, 13.5 mmol, 1 M/THF) was added to an ice cold solution of (E)-oct-3-enoic acid (7-1, 1.86 g, 13.1 mmol) in THF (48 mL). The reaction was allowed to warm to room temperature and after 2 h, was cooled in an ice bath and 50 mL H2O was added slowly. NaOH (3 M, 50 mL) and H2O (50 mL) were added and the resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (100 mL) and was then dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (1.283 g, 76%).
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[C:30]([CH3:39])[CH:29]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:39])[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Reactant: Cc1cc(F)ccc1CC(C)(C)N
Agent: Cl
Product: Cc1cc(F)ccc1CC(C)(C)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Prepared analogously to the method for Example 8(d) from 0.95 g (2.66 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.43 g (2.37 mmol) of 2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamine. Yield: 0.75 g (55%, hydrochloride); melting point 233° C.-236° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C(N(CC)CC)C.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](Cl)=[C:20]([N+:26]([O-:28])=[O:27])[C:21]([Cl:25])=[N:22]2)=[CH:17][CH:16]=1.O>CN(C=O)C>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[C:20]([N+:26]([O-:28])=[O:27])[C:21]([Cl:25])=[N:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1c(Cl)nc2cc(Br)ccc2c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
1-Amino-2-methylpropan-2-ol (575 mg, 6.45 mmol) and triethylamine (889 mg, 8.79 mmol) were added to a solution of 7-bromo-2,4-dichloro-3-nitroquinoline (1.9 g, 5.9 mmol) in DMF (25 mL), and the reaction was stirred at room temperature for two hours and poured into water (750 mL). A precipitate formed and was isolated by filtration, washed with water (500 mL), and dried under vacuum for two hours to provide 1.94 g of 1-[(7-bromo-2-chloro-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])=[N:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([Br:1])[C:3]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH3:14])=[N:4]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1[nH]nc(OC[C@H](C)NC(=O)OC(C)(C)C)c1Br
Product: COC(=O)c1c(Br)c(OC[C@H](C)NC(=O)OC(C)(C)C)nn1Cc1ccccc1

Procedure:
Using methyl 4-bromo-3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate and benzyl bromide, and in the same manner as in Example 1, step A, the title compound was obtained.
Reaction SMILES: S(=O)(=O)(O)O.N.[C:7]1([O:17][CH3:18])[C:8](=[CH:10][CH:11]=[C:12]([CH:16]=1)[CH2:13][CH:14]=[CH2:15])[OH:9].C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.C[O:35]S([O-])(=O)=O>CCCCCCCC.O>[CH2:15]([OH:35])/[CH:14]=[CH:13]/[C:12]1[CH:11]=[CH:10][C:8]([OH:9])=[C:7]([O:17][CH3:18])[CH:16]=1
Reactant: COS(=O)(=O)[O-]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCCCC
Product: COc1cc(/C=C/CO)ccc1O
Reaction time: 1.62 h

Procedure:
A dilute sulfuric acid solution or aqueous ammonia was dropwise added to the foregoing reaction solution for enzyme-activity determination from which the buffer is omitted (i.e., a solution comprising 50 μl of a 200 mM solution of eugenol in n-octane, 200 μl of a 50 mM aqueous solution of phenazine methosulfate and 675 μl of deionized water) to adjust the pH thereof from 5 to 7 and the resulting mixture is stirred at a temperature ranging from 25 to 55° C. for 15 to 180 minutes. After the completion of the reaction, the coniferyl alcohol is extracted from the reaction solution with an organic solvent such as ethyl acetate, chloroform, methylene chloride or ethyl ether, followed by purification thereof by a means such as silica gel chromatography, reverse phase liquid chromatography or vacuum distillation, optional discoloration with active carbon and vacuum drying to give colorless coniferyl alcohol powder.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>C(#N)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 49.6 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol), valeryl chloride (0.16 mL, 1.4 mmol), and pyridine (0.30 mL, 3.7 mmol) in acetonitrile (15 mL) provided N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)pentanamide (0.17 g). MS (ESI) m/z 286([M+H]+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O.[CH3:23][N:24](C)[CH:25]=O.C(N(CC)C(C)C)(C)C.CNC>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([N:24]([CH3:25])[CH3:23])=[O:14]
Reactant: CC(C)(C)OC(=O)NC(Cc1nc2ccccc2s1)C(=O)O
Reactant: CN(C)C=O
Agent: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)C(Cc1nc2ccccc2s1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 80 %

Procedure:
The 3-(benzo[d]thiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (0.15 g, 0.465 mmol) was combined with N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.21 g, 0.558 mmol), N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (120 μl, 0.92 mmol) and the 2 M dimethylamine in THF (1.0 mL). The reaction was stirred for 2 h., partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as a semisolid. The product was purified by Flash chromatography on a silica gel column eluting hexane:ethyl acetate gradient to give tert-butyl 3-(benzo[d]thiazol-2-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.13 g, 80%). Analytical LCMS (M+H)+: m/z=350.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>>[N+:17]([C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2ncccc2c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.45 mol of 6-methylquinoline were added to 1 l of concentrated sulfuric acid, and 2.94 mol of 65% strength nitric acid were added dropwise at from 0 to 10° C. The mixture was stirred for one hour, poured onto ice, adjusted to pH 2.5 using aqueous sodium hydroxide solution, filtered off with suction, washed with water and dried over magnesium sulfate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][C@H:28]([CH3:30])[O:27][C@H:26]([CH3:31])[CH2:25]2)=[CH:20][C:19]=1[C:32]1[CH:36]=[CH:35][O:34][C:33]=1[CH3:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:30][C@H:28]1[O:27][C@@H:26]([CH3:31])[CH2:25][N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[C:19]([C:32]3[CH:36]=[CH:35][O:34][C:33]=3[CH3:37])[CH:20]=2)[CH2:29]1
Reactant: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2-c2ccoc2C)ccn1
Temperature: 100 °C

Procedure:
2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (313 mg, 1.428 mmol) was added to a solution of cis-4-[4-bromo-3-(2-methyl-3-furanyl)phenyl]-2,6-dimethylmorpholine (500 mg, 1.428 mmol) in a mixture of 1,4-dioxane (6 mL), water (1.000 mL) and sodium carbonate (303 mg, 2.86 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (165 mg, 0.143 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. overnight. Crude LCMS showed starting material and desired product so 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.5 equivalents), tetrakis(triphenylphosphine)palladium(0) (0.05 equivalents) and sodium carbonate (1.0 equivalent) were added and the reaction mixture was stirred and heated at 100° C. in the microwave for a further 1 hour. Crude LCMS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure. This solid was dissolved in 1:1 MeCN:DMSO (3×0.9 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (169 mg, 0.443 mmol, 31.0% yield).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:22])[CH2:4][O:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CC(C)=O>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH:29]([NH:32][CH2:2][CH:3]([CH3:22])[CH2:4][O:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: CC(CCl)COC1c2ccccc2C(=O)N1c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Product: CC(CNC(C)C)COC1c2ccccc2C(=O)N1c1ccccc1
Temperature: 2 °C

Procedure:
A solution of 3-(3-chloro-2-methylpropoxy)-2-phenyl-isoindolin-1-one (24.7 g.) in isopropylamine (250 cc.) is heated in an autoclave at 120° C. for 24 hours. After cooling, the reaction mixture is concentrated to dryness under reduced pressure and the residue is then taken up in a 5N aqueous solution of sodium hydroxide (30 cc.) water (200 cc.) and diethyl ether (200 cc.). The ether solution is washed three times with distilled water (total 150 cc.) and is extracted four times with a 2N aqueous solution of methanesulphonic acid (total 200 cc.). The acid solution is washed three times with diethyl ether (total 150 cc.) and is then rendered alkaline by adding 10N sodium hydroxide solution (50 cc.). The oil which separates out is extracted four times with diethyl ether (total 200 cc.). The organic extracts are combined, washed five times with distilled water (total 250 cc.), dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained (22.2 g.) is dissolved in acetone (130 cc.). A solution of oxalic acid (6.2 g.) in acetone (30 cc.) is added to the solution obtained. After cooling for 3 hours at 2° C., the product which has crystallised is filtered off and washed twice with acetone (total 20 cc.) and then with diethyl ether (30 cc.). After drying, 3-(3-isopropylamino-2-methylpropoxy)-2-phenyl-isoindolin-1-one hydrogen oxalate (26.6 g.), which melts at 150° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[CH2:8]([O:10][C:11]([C:13]#[C:14][C:15](OCC)=[O:16])=[O:12])[CH3:9]>C(O)C>[CH2:8]([O:10][C:11]([C:13]1[N:6]2[CH:5]=[C:4]([CH3:7])[S:3][C:2]2=[N:1][C:15](=[O:16])[CH:14]=1)=[O:12])[CH3:9]
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(C)cn12
Reaction time: 72 h

Procedure:
A mixture of 3.4 g 2-amino-5-methylthiazole, 70 ml of ethanol and 5.1 g of acetylene dicarboxylic acid diethyl ester is left standing for 3 days. The solution is evaporated to dryness and the residue is triturated with ethyl acetate, crystallization occurring. The product is filtered off under suction, washed with ether and dried. The 2-methyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained in a yield of 4.5 g (63% of the theoretical) melts at 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[C:4]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][NH:17]2)[CH:3]=1.CCN(CC)CC.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34]([N:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([OH:13])[CH:9]=1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Oc1cc(COc2ccc(Cl)cc2C2NCCc3ccccc32)on1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1OCc1cc(O)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of (±)-5-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxymethyl]-isoxazol-3-ol (49 mg, 0.138 mmol, 1.0 eq.) and NEt3 (58 μL, 0.414 mmol, 3.0 eq.) in DCM (3.8 mL), benzyl chloroformate (23 μL, 0.152 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (3.8 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. The residue, redissolved in DMF, was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[N+:9]([CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2)([O-:11])=[O:10].[NH4+].[OH-]>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([CH2:13][CH2:12][N+:9]([O-:11])=[O:10])[CH:15]=3)[NH:19][CH:18]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])CCc1ccc2[nH]ccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(CC[N+](=O)[O-])cc23)CC1
Temperature: 100 °C
Yield: 46.4 %

Procedure:
N-Methyl-4-piperidone (Aldrich, 4.2 g) was added to a solution of the product from step (c) (2.3 g) in glac. acetic acid (35 ml) at 100° C. The resulting solution was heated at 100° C. for 1 hour, cooled and poured into a mixture of 0.88 NH4OH (61 ml) and ice (61 g). The resulting solid was filtered off, dried and recrystallised from ethanol to give the desired product as a white solid (1.6 g).