Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]=3)[CH:9]=2)[N:4]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:3]=1.[C:41]1([C:47]2[CH:51]=[C:50]([CH2:52][N:53]3[CH2:58][CH2:57][CH:56]([CH2:59][NH2:60])[CH2:55][CH2:54]3)[O:49][N:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:41]1([C:47]2[CH:51]=[C:50]([CH2:52][N:53]3[CH2:54][CH2:55][CH:56]([CH2:59][NH:60][C:2]4[C:10]5[C:5](=[CH:6][CH:7]=[C:8]([C:11]6[N:15]=[CH:14][N:13]([C:16]([C:29]7[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=7)([C:23]7[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=7)[C:17]7[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=7)[N:12]=6)[CH:9]=5)[N:4]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][O:36]5)[N:3]=4)[CH2:57][CH2:58]3)[O:49][N:48]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(CN3CCC(CNc4nn(C5CCCCO5)c5ccc(-c6ncn(C(c7ccccc7)(c7ccccc7)c7ccccc7)n6)cc45)CC3)on2)cc1
Temperature: 100 °C

Procedure:
3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(1-trityl-1H-1,2,4-triazol-3-yl)-1H-indazole (0.25 g, prepared according to the reported preparation in US 2004/0127536), the compound prepared in Example 9 (0.29 g), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.040 g), and sodium tert-butoxide (0.20 g) were suspended in toluene (6 mL) and purged with argon. Tris(dibenzylideneacetone)dipalladium(0) (0.019 g) was added and the system was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (0.13 g) having the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]1([Mg]Br)[CH2:45][CH2:44]1.C(OCC)(=O)C>O1CCCC1>[CH:43]1([CH:36]([OH:37])[CH2:35][O:34][C@H:31]2[CH2:30][CH2:29][C@H:28]([N:18]3[C:17](=[O:42])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]4[N:25]=[CH:26][CH:27]=[C:19]34)[CH2:33][CH2:32]2)[CH2:45][CH2:44]1
Reactant: Br[Mg]C1CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ccnn12
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.57 g) in tetrahydrofuran (6 mL) was added dropwise cyclopropylmagnesium bromide (0.5M tetrahydrofuran solution, 4 mL) at 0° C., and the mixture was stirred for 1.5 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL), sodium borohydride (0.04 g) was added, and the mixture was stirred for 18 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.45 g, 81%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:26][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)cc1-c1ccccc1
Reaction time: 24 h
Yield: 47 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (296 mg, 0.81 mmol) in 2-propanol (2.5 mL) and 3 N aq. NaOH (1 mL) is treated with epichlorohydrine (150 mg, 1.63 mmol) and the mixture is stirred at it for 24 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated and the residue is purified by CC on silica gel eluting with hepaten:EA 4:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (160 mg) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=421.22, 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (m, 2H), 3.99 (dd, J=2.9, 11.1 Hz, 1H), 3.72 (dd, J=5.8, 11.1 Hz, 1H), 3.38-3.31 (m, 1H), 3.19-3.11 (m, 2H), 2.98-2.85 (m, 5H), 2.72-2.67 (m, 1H), 2.26 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:39][C:10]2([CH2:17][N:16]3[C:18]4[CH:19]=[C:20]([C:31]([O:33][CH3:34])=[O:32])[CH:21]=[CH:22][C:23]=4[C:24]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:15]3[C:14]3[CH:35]=[CH:36][CH:37]=[CH:38][C:13]=3[O:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.[ClH:40]>CO.CCOC(C)=O.[Pd]>[CH:25]1([C:24]2[C:23]3[CH:22]=[CH:21][C:20]([C:31]([O:33][CH3:34])=[O:32])=[CH:19][C:18]=3[N:16]3[C:15]=2[C:14]2[CH:35]=[CH:36][CH:37]=[CH:38][C:13]=2[O:12][CH2:11][C:10]2([CH2:9][NH:8][CH2:39]2)[CH2:17]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1.[ClH:40]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)CN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(CNC1)COc1ccccc1-3

Procedure:
A 0.07M solution of methyl 1-benzyl-14′-cyclohexylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate in MeOH and EtOAc (2:1) was stirred in the presence of 10% Pd/C and 3M HCl under H2-atmosphere for 3 days. The reaction mixture was filtered on CELITE and co-evaporated with toluene, pentane and Et2O until a solid was obtained; this solid was washed with Et2O and dried to afford the title compound as its HCl salt (46%). MS (ES+) m/z 431 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20](=[O:34])[C:21]([CH3:33])([CH3:32])[O:22][C:23]=4[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[N:10]=2)[N:7]=1.C(NCC)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[N:10]1[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:34])[C:21]([CH3:32])([CH3:33])[O:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: [H][H]
Reactant: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCNCC
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(OCc4cn5ncccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Palladium hydroxide (36 mg) was added to a solution of 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 0.37 mmol) and diethyl amine (28 mg, 0.37) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was exchanged for hydrogen and was stirred at RT for 2 h (the reaction was monitored by TLC). The compound was filtered through a bed of Celite® bed washing with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 96.7%,) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=442.3. HPLC: (97.4%, Condition-A).
Reaction SMILES: [Na+].[CH3:2][CH:3]([CH3:9])[C:4](=O)[C:5]([O-:7])=[O:6].[NH2:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12].C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH:3]([CH3:9])[CH3:2])([OH:7])=[O:6]
Reactant: CC(C)C(=O)C(=O)[O-]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 73.2 %

Procedure:
A mixture of 3-methyl-2-oxobutyric acid sodium salt (1.46 g) and L-alanyl-L-proline (0.40 g) was treated with sodium cyanoborohydride (0.41 g) as described above. Crude N-(1-carboxy-2-methylpropyl)-L-alanyl-L-proline (0.45 g) was obtained by elution from ion-exchange resin. The product melted at 131°-142°. The nmr spectrum shows complex absorption in the 4.6 to 3.3 region, a broad multiplet centered at 2.2 and doublets at 1.65 and 1.1 ppm.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:2]2[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Br[Mg]c1ccccc1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1

Procedure:
One mole of cyanuric chloride was treated with one mole of phenylmagnesium bromide in Step I to form 6-phenyl-2,4-dichloro-s-triazine. This reaction is described in detail in a paper by Hirt, et al., Helvetica Chimica Acta 33, pages 1365-9 (1950). In Step II, the product of the reaction of Step I (0.025 mole) was dissolved in chloroform (35 ml) and stirred in an oil bath at 50° C. To this solution was added dropwise with stirring a solution of sodium hydroxide (0.05 mole), 3-ethynylphenol (0.05 mole), and water (25 ml) during one hour. The reaction was continued overnight and yielded an organic phase which was subsequently separated and dried over sodium sulfate. Removal of solvent under reduced pressure gave a solid product 6-phenyl-2,4-bis(3-ethynylphenoxy)-s-triazine, mp 139°-144° C., which thermally cured at 260° C. to a heat stable polymer.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][N:9]=[C:8](O)[N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.P(Cl)(Cl)([Cl:23])=O>>[S:1]1[C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][N:9]=[C:8]([Cl:23])[N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: Oc1ncc(C(F)(F)F)c(-c2cc3ccccc3s2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cnc(Cl)nc1-c1cc2ccccc2s1
Temperature: 100 °C

Procedure:
4-(Benzo[b]thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-ol (0.28 g, 0.94 mmol) was treated with phosphorous oxychloride (6 mL) and the mixture was heated to 100° C. overnight. The volatiles were removed in vacuo and residual phosphorous oxycloride was azeotroped with toluene. The resulting residue was dissolved in chloroform, washed successively with cold water, saturated aqueous solution of sodium bicarbonate, water again and brine. The organic solution was dried with sodium sulfate and passed through a plug of silica gel. The filtrate was concentrated to yield a yellow solid (0.2 g). MS (M+H)+ 315.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][N:8]([CH3:20])[CH2:9][CH2:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>O.CO>[CH3:7][N:8]([CH3:20])[CH2:9][CH2:10][S:11]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:2]
Reactant: CN(C)CCSc1ccc(C=O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)CCS(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
Sodium periodate (512 mg, 2.39 mmol) was dissolved in water (10 ml) and cooled to 0° C. 4-(2-Dimethylaminoethylthio)benzaldehyde (0.5 g, 2.39 mmol), prepared as described in Reference Example 2, was then added in methanol (2 ml) and the reaction mixture stirred at room temperature and then later warmed to 35° C. After 7 hours the reaction mixture was basified using sodium carbonate and exhaustively extracted with dichloromethane, dried over magnesium sulphate and the solvent removed in vacuo to yield the title compound as an oil in a yield of 53%.
Reaction SMILES: I[CH3:2].[CH:3]1([N:6]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:9][N:8]=[C:7]2[SH:17])[CH2:5][CH2:4]1>C(O)C.[OH-].[Na+]>[CH:3]1([N:6]2[C:7]([S:17][CH3:2])=[N:8][N:9]=[C:10]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: Sc1nnc(-c2ccncc2)n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccncc2)n1C1CC1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of iodomethane (0.457 mL, 7.33 mmol) in ethanol (3 mL) was added to a solution of 4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (1 g, 4.58 mmol) in 1M sodium hydroxide (10 mL) at room temperature. After stirring overnight, the reaction mixture was extracted with dichloromethane and then the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the titled compound (729.1 mg, 69%, beige solid). 1H NMR (CDCl3) δ (ppm): 8.77 (d, 2H), 7.75 (m 2H), 3.23 (m, 1H), 2.82 (s, 3H), 1.17 (m, 2H), 0.80 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCCN1c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N2CCCC2=O)c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A suspension of 1-(3-nitrophenyl)pyrrolidin-2-one (3.0 g, 15 mmol) in ethanol (50 ml) was heated until complete solution was obtained. The solution was cooled to ambient temperature then treated with 10% palladium on charcoal (150 mg) and hydrogenated at 50 psi until hydrogen uptake ceased (ca. 2 hours). The mixture was filtered through a glass microfibre filter paper (Whatman GF/A) and evaporated to dryness to give 1-(3-aminophenyl)pyrrolidin-2-one as a pale green oil (2.6 g, 100%) which was used without purification.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5]([CH2:7][O:8][N:9]=[C:10]([C:16](=O)[CH2:17]Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6].[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:25][C:23]1[S:24][CH:17]=[C:16]([C:10](=[N:9][O:8][CH2:7][C:5]([O:4][CH2:3][C:2]([Cl:21])([Cl:20])[Cl:1])=[O:6])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:22]=1
Reactant: CCOC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c1csc(N)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A mixture of ethyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-4-chloro-3-oxobutyrate (20 g), thiourea (3.9 g) and sodium acetate (4.2 g) in ethanol (50 ml) and water (50 ml) was stirred at 40° C. for 5 hours. After removal of the solvent from the reaction mixture, the residue was triturated with diisopropyl ether. The precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetate (syn isomer) (10.6 g), mp 138°-141° C.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH2:36]C(OCC)=O)[C:22](=[O:35])[CH2:23][N:24]2C(=O)C3=CC=CC=C3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>ClCCl.CO>[Cl:1][C:2]1[C:20]([N:21]2[CH2:36][C:25](=[O:34])[NH:24][CH2:23][C:22]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CCOC(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: CN
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N4CC(=O)NCC4=O)c3Cl)c2n1
Reaction time: 24 h
Yield: 50 %

Procedure:
To the solution of 8-[2,6-dichloro-3-[N-ethoxycarbonylmethyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane/methanol (20/1, V/V) and by crystallizing from isopropyl ether to give 8-[2,6-dichloro-3-(2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystals. mp: 211-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].Cl[CH2:20][C:21](Cl)=[O:22]>CC(CC(C)C)=O.O>[I:13][C:10]1[C:11]2[O:12][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(N)c(O)c(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: COC(=O)c1cc(I)c2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To an ice-cold, stirred solution of Methyl 3-amino-4-hydroxy-5-iodobenzoate (2.3 g) and sodium bicarbonate (1.5 g) in 1:1 isobutyl methyl ketone/water (80 mL) was added chloroacetyl chloride (1.1 g), and the reaction mixture was stirred for 1 h. The mixture was warmed to room temperature and heated at reflux for 18 h. After overnight, a beige solid formed. The mixture was filtered, and washed with water and hexanes to give 2.4 g of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 10.98, 7.89, 7.47, 4.79, 3.82.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([CH:15]2[CH2:17][CH2:16]2)([N:12]=[C:13]=[O:14])[CH2:10]I)[CH:3]=1.C(N(CC)CC)C.C([OH:29])CCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]2([CH:15]3[CH2:17][CH2:16]3)[CH2:10][O:14][C:13](=[O:29])[NH:12]2)[CH:3]=1
Reactant: O=C=NC(CI)(c1cc(Br)ccc1F)C1CC1
Reactant: CCCCO
Solvent: CCN(CC)CC
Product: O=C1NC(c2cc(Br)ccc2F)(C2CC2)CO1
Reaction time: 8 h

Procedure:
A solution of the crude (RS)-4-bromo-2-(1-cyclopropyl-2-iodo-1-isocyanato-ethyl)-1-fluoro-benzene (6.40 g, 16 mmol) in tent-butanol (200 ml) was treated at 23° C. with triethylamine (2.16 ml, 16 mmol) and the mixture was stirred overnight at reflux. For the workup, the reaction mixture was evaporated at reduced pressure to yield the crude title compound as a yellow oil which was directly used in the next step. Mass (calculated) C12H11BrFNO2 [300.126]; (found) [M+H]+=300, [M+2-H]+=302.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19](=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].[Cl:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl.[OH-].[Na+]>O>[Cl:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][O:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH:19]=[O:27]
Reactant: ClC/C=C\CCl
Reactant: O=Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccccc1OC/C=C\CCl

Procedure:
To 1.2 lt of refluxing water, 1 ml of 40% aqueous tetrabutylammonium hydroxide, 125 ml of salicylaldehyde and 150 ml of cis-1,4-dichloro-2-butene are added while vigorously stirring, followed by the dropwise addition of the solution of 42 g of sodium hydroxide in 200 ml of water at such a rate that the pH of the mixture is kept between 7 and 8. Thereafter the mixture is refluxed until the pH is about 7, cooled and extracted with methylene chloride. The extract is washed with 5% aqueous sodium hydroxide, dried, evaporated, the residue distilled and the fraction boiling at 137°-140°/0.1 mmHg collected, to yield the 2-(4-chloro-cis-2-butenyloxy)-benzaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O>[CH:3]([S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)=[CH2:2]
Reactant: COc1ccc(-c2nc(SCCBr)sc2-c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1

Procedure:
0.8 g of 2-(2-bromoethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are dissolved in 20 ml of toluene. 2 ml of a 30% strength solution of tetrabutylammonium hydroxide in water are added and the mixture is heated under reflux for 2 hours while stirring vigorously. The mixture is then allowed to cool, the organic phase is separated off, washed twice with 10 ml of water each time, dried over sodium sulphate and concentrated to dryness by evaporation. The crude product is purified by chromatography over a silica gel column with toluene/ethyl acetate (10:1) as eluant. The fractions that according to the thin layer chromatogram contain 2-vinylthio-4,5-bis-(p-methoxyphenyl)-thiazole are concentrated by evaporation and dried to constant weight. 2-Vinylthio-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4]>Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
(2S,4S)-4-Benzyloxycarbonylaminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (10.4 g, 28 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane. The solution was stirred at room temperature for 3 hours and then evaporated. The residue was partitioned between EtOAc (200 mL) and 1M NaOH (100 mL), the layers separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, and evaporated to afford the title compound (5.4 g, 19 mmol) as a white solid, which was used without further purification. MS m/z: [M+H]+ calcd for C14H18N2O4, 278.3. found 279.2.