Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccc(F)cc3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 4-fluorophenyl isocyanate to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: C(N(CC)CC)C.C[O:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)=[O:11].[NH2:21][C:22]1[CH:23]=[C:24]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1)=[O:26]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:21][C:22]2[CH:23]=[C:24]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=2)=[O:26])=[O:17])=[CH:14][CH:13]=1)([OH:9])=[O:11]
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(C(=O)O)cc1

Procedure:
Triethylamine (0.26 ml) was added to a stirred mixture of 4-methoxycarbonylbenzoyl chloride (0.221 g), 4-dimethylaminopyridine (0.01 g), 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.2 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with methylene chloride and washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulphate and evaporated. The residue was triturated under isohexane. The resultant solid was isolated and dried under vacuum at 55° C. to give the required starting material as a solid (0.286 g); NMR Spectrum: (CDCl3) 2.4 (s, 3H), 2.98 (s, 6H), 3.98 (s, 3H), 6.54 (m, 1H), 6.92 (d, 1H), 7.2 (m, 3H), 7.35 (d, 1H), 7.71 (d, 1H), 7.92 (s, 1H), 7.98 (d, 2H), 8.18 (d, 2H), 8.35 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[F:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]([CH3:14])[CH3:13])[NH:10][C:4]=2[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(F)c(F)c(F)cc2[nH]1
Yield: 56.9 %

Procedure:
3,4,5-Trifluoro-1,2-phenylenediamine (6.0 g, 31.2 mmol), isopropyl isothiocyanate (3.6 g, 35.6 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (17.0 g, 40.1 mmol) and pyridine (225 mL) were used according to general procedure I. The title compound was recrystallized from 1,4-dioxane to provide a white solid (4.07 g, 57%); m.p. 182-184° C.; 1H NMR (DMSO-d6) δ: 10.97 (br s, 1H, NH), 7.01 (m, 1H, Ar—H), 6.80 (br s, 1H, NH), 3.91 (m, 1H, CH), 1.20 (d, J=6.4 Hz, 6H, overlapping CH3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:24][OH:25])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCC[N+](CCC)(CCC)CCC.[O-]I(=O)(=O)=O>C(Cl)Cl>[C:20]([O:19][C:17]([N:24]1[C@H:4]2[CH2:5][CH2:6][C@:1]([CH2:7][CH2:8][O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH:2]=[CH:3]2)[O:25]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1=CCCC(CCOCc2ccccc2)=C1
Reactant: CC(C)(C)OC(=O)NO
Agent: CCC[N+](CCC)(CCC)CCC
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1O[C@@]2(CCOCc3ccccc3)C=C[C@@H]1CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2-Cyclohexa-1,3-dienyl-ethoxymethyl)-benzene (9) (6 g, 28 mmol) is dissolved in 280 ml of dry methylene chloride and cooled down to 0° C. After addition of molecular sieves (6 g, UOP Type 4A) and N—BOC-hydroxylamine (5.6 g, 42 mmol) in small portions, tetrapropylammonium(meta)periodate (10.8 g, 28 mmol) is added slowly in small portions the mixture was stirred for 1 h. Then the mixture is diluted with CH2C12 and cooled to −10° C. 2M Na2S2O5 solution is added slowly (exothermic!). The mixture is washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), silicagel).
Reaction SMILES: O=[C:2]1[O:3][CH2:4][CH2:5]/[C:6]/1=[CH:7]/[O-:8].[Na+].[NH2:10][C:11]([NH2:13])=[O:12]>C(O)C>[OH:3][CH2:4][CH2:5][C:6]1[C:7]([OH:8])=[N:10][C:11]([OH:12])=[N:13][CH:2]=1
Reactant: NC(N)=O
Reactant: O=C1OCC/C1=C/[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1cnc(O)nc1O
Yield: 18.6 %

Procedure:
Sodium (Z)-(2-oxodihydrofuran-3(2H)-ylidene)methanolate (1.36 g, 10 mmole) was added to a solution of 600 mg. (10 mmole) of urea in 50 ml. of absolute ethanol, and the reaction mixture was boiled under reflux for 5 h with stirring. Concentration under vacuum gave a residue, which was crystallized from ethanol to yield 5-(2-hydroxyethyl)pyrimidine-2,4-diol (290 mg, 18.5%). LC-MS (m/z)=157 [M+H]+
Reaction SMILES: [Cl-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Reactant: COC(=O)CS
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To sodium chloride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added methyl thioglycolate (160 ul) dropwise at 0° C. After 30 minutes added 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) as a solution in DMF (1.5 ml) and the reaction mixture was warmed up to room temperature over 5 hours. Aqueous work-up and purification on silica yielded 4-methoxycarbonylmethylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[O:6][CH2:5][CH2:4][O:3]1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CCOC(=O)CCC1(C)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CCC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.8 %

Procedure:
A solution of ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate (68.9 g, 366 mmol) in methanol (73 mL) was cooled to approximately 0° C. A warm solution of sodium hydroxide (14.63 g, 366 mmol) in water (73 mL) was added dropwise over a period of three hours. The reaction was then allowed to warm to room temperature and stirred for 17 hours. The methanol was removed under reduced pressure, and the resulting aqueous solution was diluted with water (400 mL) and washed with ethyl acetate (150 mL). The aqueous solution was then cooled to approximately 0° C. and adjusted to pH 2 with the addition of sulfuric acid (180 mL of 1 M). The resulting mixture was extracted with ethyl acetate (2×150 mL), and the combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 38.6 g of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid as a light yellow oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]([CH3:33])[C:11]([C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([OH:31])[C:14]=1[OH:32])=[O:12].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:31][C:15]1[C:14]([OH:32])=[C:13]([C:11](=[O:12])[N:10]([CH3:33])[CH3:9])[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OCc2ccccc2)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
Benzyl bromide (3.94 mL, 33.2 mmol) was added to a stirred suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (10.5 g, 30.1 mmol), potassium iodide (5.50 g, 33.2 mmol) and K2CO3 (4.58 g, 33.2 mmol) in DMF (100 mL). The reaction was allowed to stir at 80° C. for 24 h. The reaction mixture was poured into water (200 mL), washed with Et2O (2×200 mL), and the combined organic layers were washed with 1M HCl (aq.) (400 mL), brine (2×400 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g, 0-50% EtOAc in toluene) to afford ethyl 3-(benzyloxy)-5-(dimethylcarbamoyl)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (41) (4.36 g, 33%) as a pale yellow solid: m/z 439 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.53-7.47 (m, 2H), 7.42-7.29 (m, 3H), 7.08-7.01 (m, 2H), 6.90-6.84 (m, 2H), 5.09 (s, 2H), 3.96 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.82 (br s, 6H), 0.97 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([CH:15]=[CH2:16])[C:8]=1[O:17][CH3:18].[C:19](=[O:21])=[O:20].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:18][O:17][C:8]1[C:9]([CH:15]=[CH2:16])=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: C=Cc1c(SC)ccc(Br)c1OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1c(SC)ccc(C(=O)O)c1OC
Temperature: -100 °C
Reaction time: 0.33 h

Procedure:
At −100° C., n-BuLi (25 ml, 15% strength in n-hexane, 4.1 mmol) was added to a solution of 1-bromo-2-methoxy-4-methylsulfanyl-3-vinylbenzene (7 g, 31.3 mmol) in THF (300 ml), and the mixture was stirred at −100° C. for 20 min. At −100° C., CO2 was then introduced (exothermic reaction up to −60° C.). At -80 to −90° C., the mixture was then stirred for another 1 h, and NaOH (100 ml) was added dropwise at −40° C. The solution was stirred into EtOAc (400 ml), and the mixture was extracted 3× with 5% strength NaOH and acidified to a pH=1 using 10% strength HCl. The H2O phase was extracted with EtOAc (300 ml), and the combined organic phases were dried over MgSO4 and concentrated.
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.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:17]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CCCCCCCCCc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCCCCc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
At 0°-3° C., 9.6 g of phthalic anhydride are added to a solution of 18 g of ethyl 10-phenyldecanoate in 100 ml of 1,2-dichloroethane, after which 26 g of aluminium chloride are added in portions over a period of 1 hour. After stirring for 20 hours at room temperature, the mixture is poured onto ice/2N hydrochloric acid and extracted with methylene chloride. Washing of the organic phase with saturated sodium chloride solution, drying and evaporation gives 25.1 g of 2-[4'-(9"-ethoxycarbonylnonyl)benzoyl]benzoic acid as a waxy solid which can be used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:27])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:18]([O:20]C)=[O:19])[N:10]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:27])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:18]([OH:20])=[O:19])[N:10]=1
Reactant: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Oc4ccc(F)cc4F)ccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-[2-(2,4-difluorophenoxy)-6-oxo-6H-pyrido[1,2-b]pyridazin-5-yl]-4-methoxybenzoate (750 mg) dissolved in dioxane (10 mL) was added 1 N NaOH (10 mL). The reaction stirred at room temperature for 3 hrs until completion by LCMS analysis. The reaction was diluted with H2O, washed with ether, and acidified to pH 4.5. The solid precipitate was collected and dried to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: Cc1ccc(C2CNCCN2)o1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(C)o4)C3)cc21
Yield: 27.6 %

Procedure:
A mixture of 4.98 g of 2-(5-methyl-2-furanyl)piperazine and 2.69 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was refluxed for 48 hours and then evaporated. The residue was chromatographed on silica gel eluting with chloroform:methanol:water (9.5:0.5:0.02), giving 1.1 g of the desired product, mp 186°-188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28].Cl>[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][OH:29])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Reactant: C#CCCCO
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C#CCCCO)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To 3.73 g (12.5 mmol) 5-Bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 25 ml piperidine 722 mg (0.63 mmol) tetrakis-(triphenylphosphine)-palladium and 120 mg (0.625 mmol) CuI were added. The solution was purged with argon and was heated to 80° C. over a period of 45 min, during which 0.9 ml (9.4 mmol) 4-pentynol were added. Additional 0.9 ml (9.4 mmol) 4-pentynol were added and the mixture was stirred for 2 h, poured into ice water and 2M HCl was added. The inorganic phase was extracted with ether, the combined organic phases were washed with water and dried over Na2SO4. Purification on silica gel with hexane/EtOAc 4:1 to 2:1 yielded 3.0 g (79%) 5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as light brown solid, MS: 302 (MH+). (See also: Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:15][NH2:16]>CO>[CH2:6]([O:5][CH2:4][C:3]([NH:15][NH2:16])=[O:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)COCc1ccccc1
Yield: 99.7 %

Procedure:
A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine hydrate (65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with benzene. The solvent was evaporated and the crude product was further dried under high vacuum (6 h) to give 71 (2.75 g), as a light yellow waxy material, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[S:10][C:3]=12.CN(C=O)C.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH2:24]([O:23][C:21]([C:20]1[S:13][C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:12][C:26]=1[CH3:28])=[O:22])[CH3:25]
Reactant: NC(=S)c1cc2nccc(Cl)c2s1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2cc3nccc(Cl)c3s2)nc1C
Temperature: 80 °C
Yield: 53.8 %

Procedure:
19.5 g (85.6 mmol) of 7-chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide was added to 160 mL of a 1:1 DMF:THF solution mixture and cooled to 0° C. To this solution was slowly added 17.7 mL (128 mmol) of ethyl 2-chloroacetoacetate. After addition, the reaction was heated to 80° C. for sixteen hours. The reaction was cooled to room temperature and extracted with dichloromethane and water. The organic layer was separated and dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography to afford 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (15.6 g) in 54% yield. C14H11ClN2O2S2: APCI m/z 339.1/341.0 (pos.); 1H NMR (CDCl3): δ 8.68 (d, 1H , J=5.4 Hz), 8.24 (s, 1H), 7.51 (d, 1H, J=5.4 Hz), 4.36 (q, 2H, J=7.1 Hz), 2.77 (s, 3H), 1.38 (t, 3H, J=7.1 Hz) ppm.
Reaction SMILES: [NH:1]([C:3]([NH:5][CH2:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:14])[CH2:9][C@H:8]1[F:24])=[S:4])[NH2:2].[CH:25](OCC)(OCC)OCC.Cl>C(O)C>[F:24][C@H:8]1[C@@H:7]([CH2:6][NH:5][C:3]2[S:4][CH:25]=[N:2][N:1]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:14])[CH2:9]1
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CNC(=S)NN)[C@H](F)C2)cc1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCO
Product: Cc1ccc(COC(=O)N2CC[C@H](CNc3nncs3)[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (±)-cis 4-methylbenzyl 4-{[(hydrazinocarbonothioyl) amino]methyl}-3-fluoropiperidine-1-carboxylate (180 mg, 0.51 mmol) in ethanol (10 mL) was treated with triethyl orthoformate (151 mg, 1.02 mmol) and concentrated HCl (0.01 mL) and stirred at room temperature, under nitrogen, for 18 h. After all solids had dissolved, the reaction mixture was heated to reflux for 1.5 hour, cooled to room temperature and the volatiles evaporated. The residue was partitioned between ethyl acetate and dilute sodium bicarbonate solution, the organic layer washed with brine, dried over sodium sulfate and solvent evaporated. The crude product was purified by gradient elution on silica gel (50% ethyl acetate: hexane to 20% methanol: ethyl acetate) to give the title compound as a white solid. The (−)-enantiomer was separated and the hydrochloride salt formed as described in Examples 1 and 2 Step 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][S:31]([C:29]2[S:30][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[CH:27][CH:28]=2)(=[O:32])=[O:33])[CH2:10][CH2:11]1
Reactant: NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
The product of Example 3, Step (d) (0.3 g) was dissolved in pyridine (1 ml) and CH2Cl2 (4 ml). 5-Pyridin-2-yl-thiophene-2-sulfonyl chloride (0.317 g) [dissolved in CH2Cl2 (4 ml)] was then added and the reaction left to stir for 1 hr. The reaction mixture was poured onto flash silica and the silica flushed with 5% MeOH/94% CH2Cl2/1% aq NH3 as eluent. Evaporation of solvent and purification using reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.120 g).
Reaction SMILES: [CH2:1]([C:3]([CH3:10])([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][OH:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][N:19]1[C:4](=[O:5])[C:3]([CH2:1][CH3:2])([CH3:10])[C:7](=[O:8])[O:20]1
Reactant: ONCc1ccccc1Cl
Reactant: CCC(C)(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(C)C(=O)ON(Cc2ccccc2Cl)C1=O
Yield: 68.1 %

Procedure:
This compound was prepared in the manner of Example IV, using 8.2 grams (0.045 mole) of 2-ethyl-2-methylmalonyl dichloride, 7.1 grams (0.045 mole) of N-(2-chlorophenylmethyl)hydroxylamine and 16 ml of pyridine in 184 ml of methylene chloride. After purification on a silica gel column, 8.2 grams of 2-[(2-chlorophenyl)methyl]-4-ethyl-4-methylisoxazolidine-3,5-dione were obtained as an oil. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][C:8]([Cl:17])=[N:7][C:6]=2[N:18]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>CN(C=O)C>[Cl:17][C:8]1[N:9]=[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:4][C:3]([CH2:2][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])=[N:18][C:6]=2[N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(2-(bromomethyl)-5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 57 in DMF was added K2CO3, and phthalimide. The resulting solution stirred 20 h at room temperature. The reaction was concentrated in vacuo and diluted with water (10 mL). The heterogeneous mixture was filtered to afford 2-((5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methyl)isoindoline-1,3-dione 58.