Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]1[C:17]([O:19][CH3:20])=[O:18])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:30].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[OH:30][CH2:3][CH2:2][CH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH:5]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl 3-methyl 4-allylpiperidine-1,3-dicarboxylate [WO2002/072572] (715 mg, 2.53 mmol) in tetrahydrofuran (5 mL) at 0° C. was treated with a solution of 9-BBN in tetrahydrofuran (0.5M, 10.2 mL, 5.1 mmol). After one hour the reaction mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was cooled to 0° C. and treated with water (3 mL), NaOH (3N, 6 mL) and hydrogen peroxide (30% solution, 6 mL). The reaction was allowed to warm to room temperature and stir for one hour. The reaction was diluted with ethyl acetate and water. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated at reduced. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave the product as a colorless oil as a mixture of diastereomers (460 mg, 60%).
Reaction SMILES: CN(C=O)C.[N:6]([C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH3:20])=[N:14]2)=[N+:7]=[N-:8].N1C=CN=C1.[Si:26](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[N:6]([C:9]1[CH:18]=[CH:17][C:16]([O:19][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH3:20])=[N:14]2)=[N+:7]=[N-:8]
Reactant: Cc1ccc2c(N=[N+]=[N-])ccc(O)c2n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(N=[N+]=[N-])ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1917.5 %

Procedure:
A 100-mL flask was successively loaded with dry DMF (10 mL), 13 (200 mg, 1 mmol), imidazole (68.08 mg, 1 mmol), and tert-butyldiphenylsilyl chloride (302 mg, 1.1 mmol). The solution was stirred at room temperature for 10 h, diluted with ethyl acetate (500 mL), washed with aqueous HCl (0.1 M, 50 mL), brine (100 mL), water (100 mL), dried over Na2SO4 and evaporated under reduced pressure to afford 8.41 g (96%) of protected product as a colorless oil (428 mg, 98%). 1H NMR (500 MHz, CDCl3) δ ppm: 1.19 (s, 9H), 2.33 (s, 3H), 6.98 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.38-7.26 (m, 6H), 7.81-7.79 (m, 4H), 8.11 (d, J=8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ ppm: 20.1, 24.3, 26.8, 113.5, 116.7, 120.6, 121.8, 127.3, 128.4, 129.2, 130.6, 134.3, 135.1, 140.9, 148.9, 157.9. HRMS (ESI): calc'd for C26H26N4OSi [M+H]+: 438.1876, found: 438.1879.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1

Procedure:
To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of 4-bromo toluene (1.17 mole) in 650 ml. dry tetrahydrofuran; the reaction is started and the remainder of the bromo toluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 11/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5° C. The solution is stirred for an additional 11/2 hours at 0° C. and then at room temperature for 18 hours. The mixture is then cooled to 0° C. and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution, and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 80° to 84° C./0.7 mm, nC21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886 mole) N-bromosuccinimide, 4.0 g. (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°-132° C/0.7 mm, nD22 1.5546-V.P.C. 96% monobromo 4% -dibromo).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH2:8])[C:5]([OH:7])=[O:6])[CH3:2].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[CH2:8])[C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: C=C(OCC)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a solution of 2-ethoxyacrylic acid B-43a (1 g, 8.61 mmol) in DMF (10 mL) under a nitrogen atmosphere was added (bromomethyl)benzene (1.620 g, 9.47 mmol) followed by potassium carbonate (1.309 g, 9.47 mmol) and stirred for 12 h at 25° C. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×100 mL). The combined organic layer was washed with water (3×50 mL) followed by brine solution (50 mL) and dried over anhyd. Na2SO4. It was filtered and concentrated under reduced pressure. The crude was purified by Combiflash (Silica gel, 12 g, Redisep, EtOAc/petroleum ether, 10:90) to obtain benzyl 2-ethoxyacrylate B-43b (550 mg, 2.67 mmol, 31.0% yield) as a colorless liquid. 1H NMR (CDCl3, 6=7.26 ppm, 400 MHz): δ 7.39-7.31 (m, 5H), 5.36 (d, J=2.8 Hz, 1H), 5.25 (s, 2H), 4.61 (d, J=2.4 Hz, 1H), 3.82 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:18][O:19]C)[CH:15]=2)[CH:10]=[C:9]1[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[N:23][C:22]=1[O:33][CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].Cl[Si](C)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]=[O:19])[CH:15]=2)[CH:10]=[C:9]1[C:21]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)[N:24]=[N:23][C:22]=1[O:33][CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC=Cc1ccc2cc(-c3cc(-c4ccncc4)nnc3OC)n(C(=O)OC(C)(C)C)c2c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CC=O)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.6 %

Procedure:
180 mg 6-(2-methoxyvinyl)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester are dissolved in 10 mL acetonitrile. Then 196 mg potassium iodide and 125 μL chlorotrimethylsilane are added. The reaction mixture is stirred for 2 hours at rt. The solvent is removed in vacuo and the obtained solid is dissolved in dichloromethane/water. The aqueous phase is extracted five times with dichloromethane, the combined org. phases are dried (MgSO4) and the solvent removed in vacuo. 200 mg crude product are obtained as a mixture of 6-(2-Oxoethyl)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 6-(2-oxoethyl)-2-(3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-yl)indole-1-carboxylic acid tert-butyl ester. The mixture is directly used in the next step.
Reaction SMILES: [I-].[Na+].[C:3]1([S:9][CH2:10][CH2:11]Cl)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Li+].[C:15]([NH:23][CH:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.O.CN1CCCC1=O>[C:15]([NH:23][C:24]([CH2:11][CH2:10][S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(NC(=O)c1ccccc1)C(=O)OCC
Reactant: ClCCSc1ccccc1
Agent: [I-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CCSc1ccccc1)(NC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
A solution comprised of sodium iodide (7.9 g, 52.7 mmol) and 2-chloroethyl phenyl sulfide (4.7 g, 27.2 mmol) in acetone (40 mL) was refluxed for 15 hours. The reaction mixture was cooled, diluted with ice water and extracted with ethyl acetate. The extract was concentrated and the residue was combined with N-methylpyrrolidone (20 mL), lithium hydroxide (1.6 g, 67 mmol) and diethyl 2-benzoylaminomalonate (5 g, 18 mmol). The mixture was stirred at ambient temperature of 15 hours and then poured into cold water. The product was extracted with ethyl acetate and purified by silica gel chromatography to provide diethyl 2-benzoylamino-2-(2-phenylsulfanylethyl)malonate (1.316 g, 3.2 mmol).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].Cl>O.C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:10][C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: NCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)NCc1cccc(Cl)c1
Reaction time: 72 h

Procedure:
3.22 g of sodium cyanate was added to a solution of 5.50 ml of 3-chlorobenzylamine in 40 ml of water and 40 ml of THF followed by dropwise addition of 48.6 ml of 1N HCl. After 3 days, the mixture was evaporated to dryness, the residue extracted with hot THF and the filtrate again evaporated to dryness. The residue was suspended in 180 ml of diethyl ether and the solid collected to give the title compound (7.91 g) as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[S:6][C:7]([Cl:32])=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:14](=[O:31])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)(=[O:4])=[O:3].NS(C1C=C(Br)C=CC=1NC(C1C(=O)N(CC2C=CC=CC=2)C2C(C=1O)=CC=CN=2)=O)(=O)=O>>[CH2:24]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][N:17]=2)[C:22]([OH:23])=[C:13]([C:11]2[NH:10][C:9]3[CH:8]=[C:7]([Cl:32])[S:6][C:5]=3[S:2](=[O:4])(=[O:3])[N:1]=2)[C:14]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1sc(Cl)cc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Agent: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: O=c1c(C2=NS(=O)(=O)c3sc(Cl)cc3N2)c(O)c2cccnc2n1Cc1ccccc1

Procedure:
The title compound is prepared according to the procedure of Example 84D substituting the product of Example 174B for the product of Example 84C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)s3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCO)CC4)s3)ccc21

Procedure:
The preparation was carried out as already described starting from 125 mg (0.35 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-thiadiazol-2-yl]piperidine and 76 μl (0.53 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[CH2:12][C:13](=O)[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:10][CH:12]=[C:13]([CH3:14])[C:8]=2[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc2ccc(C(C)C)cc12
Yield: 67.3 %

Procedure:
A mixture of 4-isopropyl-thiophenol (5.0 g, 32.8 mmol), chloroacetone (7.0 mL, 88 mmol) and K2CO3 (6.4 g, 46.3 mmol) in acetone (100 mL) was refluxed over night. More K2CO3 (2 g, 14.5 mmol) and chloroacetone (3.5 mL, 43 mmol) were added and the reaction mixture was heated for another 5 h. The reaction mixture was filtered and the solvent was evaporated. The crude product was mixed with polyphosphoric acid (15 g) and chlorobenzene (100 mL) and the reaction mixture was heated at reflux for 5 h. (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was diluted with CH2Cl2 and washed with water. The combined organic phases were dried and the solvent was evaporated. The crude product was purified on silica using heptane as eluent, giving 4.2 g of the title compound as a colourless oil (67% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, 6 H) 2.47 (d, 3 H) 3.02-3.16 (m, 1 H) 7.08 (s, 1 H) 7.27-7.30 (m, 1 H) 7.58 (d, 1 H) 7.80 (d, 1 H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14]>>[Br:6][C@H:7]([CH2:11][CH3:12])[C:8]([O:10][CH2:13][CH3:14])=[O:9]
Reactant: CC[C@@H](Br)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](Br)CC
Temperature: 25 °C

Procedure:
0.45 mL of sulfuric acid was added to ethanol (70 mL) solution of 7.0 g of (R)-2-bromobutyric acid at room temperature, and refluxed for 3 hours. The reaction mixture was cooled to room temperature, and poured into ice water (140 mL). The solution was extracted 3 times with ethyl acetate. The combined extract was sequentially washed with saturated sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and 7.47 g of the subject compound was prepared as colorless oil. Optical purity 96% ee (HPLC)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])=[O:28])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)cc(S(=O)c2c(C(C)C)nc(C)n2C)c1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
In methylene chloride (10 ml) was dissolved 150 mg (0.55 mmol) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1,2-dimethyl-1H-imidazole, followed by addition of 177 mg (0.82 mmol) of 80% metachloroperbenzoic acid under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture, an aqueous solution of sodium thiosulfate and then, an aqueous sodium hydrogen carbonate solution was added, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue purified by silica gel chromatography (ethyl acetate), and recrystallized from n-hexane to give 100 mg of Compound I-104 (yield 63%). mp 100-101° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][C@H:20]([CH3:22])[O:19][C@H:18]([CH3:23])[CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.[ClH:25]>CO>[ClH:25].[CH3:22][C@H:20]1[O:19][C@@H:18]([CH3:23])[CH2:17][N:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:21]1
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(N2C[C@@H](C)O[C@@H](C)C2)c1
Agent: Cl
Solvent: CO
Product: C[C@@H]1CN(c2cccc([C@H](C)N)c2)C[C@H](C)O1

Procedure:
A solution of {1-[3-(cis-2,6-dimethylmorpholin-4-yl)phenyl]-ethyl}carbamic acid tert-butyl ester (2.12 g, 6.35 mmol), and hydrochloric acid (1.0M solution in diethyl ether) (15.9 mmol, 2.5eq) in methanol (5 ml) was stirred at room temperature overnight. Concentrated under vacuum and 2 g of hydrochloric acid salt of (S)-1-[3-(cis-2,6-dimethylmorpholin-4-yl)phenyl]-ethylamine was obtained as yellow solid (quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][C:15]1([OH:25])[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1>C1COCC1.O.CC(O)=O>[OH:25][C:15]1([CH2:14][CH2:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: COc1ccc2nccc(CCC3(O)CCC4(CC3)OCCO4)c2n1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nccc(CCC3(O)CCC(=O)CC3)c2n1

Procedure:
A solution of 8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]-1,4-dioxa-spiro[4.5]decan-8-ol (960 mg, 2.79 mmol) in THF/H2O/AcOH (2:2:3, 22 ml) was stirred overnight at 65° C. The reaction mixture was concentrated and purified by chromatography on silica gel (EtOAc).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9](/[C:10](=[N:15]/[OH:16])/[NH2:11])=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccc(C2OCCO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(=N\O)c1ccc(C2OCCO2)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of 4-(1,3-dioxolan-2-yl)benzonitrile (16.4 g, 93.6 mmol), hydroxylamine hydrochloride (9.76 g, 140 mmol) and sodium bicarbonate (15.7 g, 187 mmol) in MeOH (100 mL) was heated to reflux for 4 hr. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated to provide solids that were collected by filtration and washed with cold methanol to provide (Z)-4-(1,3-dioxolan-2-yl)-N′-hydroxybenzimidamide (16 g, 76.8 mmol). The compound had an HPLC retention time=0.38 min. —CHROMOLITH® SpeedROD 4.6×30 mm. flow=5 mL/min (2 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=209.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30].CCN(C(C)C)C(C)C>C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Cl)c([N+](=O)[O-])c4)cc3)sc2c1
Yield: 96.8 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.50 g, 1.95 mmol), 4-chloro-3-nitrobenzoyl chloride (0.43 g, 1.95 mmol) and Hunig's base (0.28 g, 2.15 mmol) in dry THF (20 ml) to give the title compound (0.83 g, 97%) as a yellow solid after work-up.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](=[O:26])[NH:38][S:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[CH3:28])(=[O:36])=[O:37])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(C(=O)O)cs4)ccc3o2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1csc(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Temperature: 0 °C
Yield: 65 %

Procedure:
A solution of 4-tert-butyl-2-{5-[(4-carboxythiazol-2-yl)methyl]benzofuran-2-yl}thiazole (0.20 g), 2-methylbenzenesulfonamide (0.10 g), 4-dimethylaminopyridine (0.12 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g) in N,N-dimethylformamide (6 ml) was stirred at ambient temperature for 2 days. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure. The residue was crystallized from diethyl ether and filtered to give 4-tert-butyl-2-{5-{{4-[N-(2-methylphenylsulfonyl)carbamoyl]thiazol-2-yl}methyl}-benzofuran-2-yl}thiazole (0.18 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[C:7]([NH:10][C:11](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:9])[CH3:8].Cl>CO.O>[C:7]([NH:10][C:11](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:12]([O:14][CH3:1])=[O:13])(=[O:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=C(NC(C)=O)C(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)NC(C)=O

Procedure:
This compound was prepared from the product of Example 2 by treatment with sodium carbonate in methanol by a modification of the procedure of Saxena et al (supra). Alternatively, it could be made by esterification of α-acetylamino-3,4-dimethoxycinnamic acid. Thus, 9.62 g of the acid was heated under reflux for 19 hours in 100 mL of methanol containing 1 mL of concentrated hydrochloric acid. After diluting with 500 mL of water, the solution was basified with a 10% aqueous solution of sodium carbonate to a pH of 8-9. The resultant solids were collected by filtration, washed with 3×50 mL of water and dried at the pump. The crude product was further purified by column chromatography on silica gel, eluting with a gradient of methylene chloride/methanol (99:1 thru 96:2). After stripping the solvent from the appropriate fractions, and drying at the pump 2.07 g (21%) of the title compound were obtained; 1HNMR (CDCL3) 7.42 (s, 1H), 7.10 (d, J= 8.5 Hz, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.17 (s, 3H); MP 198°-200° C. Anal. calcd for C14H17NO5 : C, 60.2; H, 6.14; N, 5.02. Found: C, 60.42; H, 5.78; N, 4.53.