Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2].ClS([N:21]=[C:22]=O)(=O)=O>ClCCCl.C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:22]#[N:21])[C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)cc1OCC
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C#N)c(OC)cc1OCC
Temperature: 50 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a stirring solution of 2-ethoxy-4-methoxy-benzoic acid ethyl ester (1.5 g, 6.7 mmol) in 1,2-dichloroethane (2 mL) was added chlorosulfonyl isocyanate (0.923 mL, 10.6 mmol, in 1 mL of 1,2-dichloroethane) in several portions. The reaction was stirred at 50° C. overnight. Reaction was diluted with methylene chloride (2 mL) and water (1 mL), and extracted. The organic layer was washed with brine and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 900 mg (54% yield) of 5-cyano-2-ethoxy-4-methoxy-benzoic acid ethyl ester. LC-MS: 236.2 [(M+H—CH3)+].
Reaction SMILES: [CH:1]([C:17]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=1[OH:19])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2].S(Cl)([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][C:21]1[CH:20]=[C:18]([OH:19])[C:17]([CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2])=[CH:23][C:22]=1[OH:24]
Reactant: CCCCCCCCCCCCCCC(C)c1cc(O)ccc1O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(C)c1cc(O)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
33.5 g (0.1 mol)of 2-sec-hexadecylhydroquinone was dissolved in 300 ml of methylene chloride and to a resulting solution was added dropwise 8.1 ml (0.1 mol) of sulfuryl chloride with stirring at room temperature over a period of 30 minutes. After stirring for 6 hours at room temperature, the reaction mixture was allowed to stand overnight and extracted with ethyl acetate. The extract was washed three times with a 5% aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (solvent: chloroform) to obtain 27 g of the desired 2-chloro-5-sec-hexadecylhydroquinone as the light from oily product. The structure thereof was confirmed by NMR and mass spectra.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15](Cl)[N:14]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([O:23][CH3:22])[CH:29]=2)[N:14]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Product: COc1cc(-c2cc(=O)[nH]c(CC(=O)N3CCc4c(F)cccc43)n2)ccn1
Yield: 60.7 %

Procedure:
The product is prepared by following the procedure described in example 12b using 100 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one and 160 mg of 2-methoxypyridine-4-boronic acid pinacol ester. 75 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methoxypyridin-4-yl)-3H-pyrimidin-4-one are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH2:12](S)[CH3:13]>C(OCC)C>[CH2:12]([O:6][C:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)=[O:7])[CH3:13]
Reactant: CCS
Reactant: CC1(C(=O)O)CC1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
100 gm of 1-methylcyclopropanoic acid was added to 150 ml of diethyl ether. The system was cooled to 0°-5° C. and 119 gm of thionyl chloride was added dropwise over a period of time. After addition, the system was heated at reflux for 8 hours. The system was then cooled to 0°-5° C. and 62 gm of ethanethiol was added dropwise. The system was heated at reflux for 6 hours and then stirred at room temperature for 72 hours. The diethyl ether was removed by stripping to give the 1-methylcyclopropanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46](I)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:46]3[CH:47]=[C:42]4[N:41]=[C:40]([CH2:39][CH2:38][C:34]5[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][N:35]=5)[NH:49][C:43]4=[N:44][CH:45]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: Cc1ccc(N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(c6ccc(C)cc6C)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 47.5 %

Procedure:
A mixture of 0.614 g of 1-(4-bromo-benzene-sulfonyl)-4-(2,4-dimethylphenyl)-piperazine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 8 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 7 hours. To the resulting mixture 10 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 10 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 23 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-20:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.27 g of the title compound as a solid of m.p. 208-209° C. The mass spectrum shows the molecular peak MH+ at 583.5 Da.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=O)[NH2:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(C(N)=O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)cc(C#N)c1
Temperature: 100 °C
Yield: 96.4 %

Procedure:
To methyl 3-bromo-5-carbamoyl-benzoate (2.8 g, 10.8 mmol, 1.0 eq) was added POCl3 (30 mL) and the reaction heated at 100° C. overnight. The POCl3 was removed under reduced pressure, water was added and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to afford a crude residue which was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give methyl 3-bromo-5-cyano-benzoate (2.5 g, 96%). This material was dissolved in THF (30 mL) and LiOH.H2O (1.7 g, 41.6 mmol, 1.54 eq) and H2O (10 mL) were added. The mixture was stirred at room temperature overnight. The THF was removed under reduced pressure and the aqueous phase acidified with diluted HCl and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2: MeOH, 50:1) to give the title compound as a white solid (2 g, 85%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C[N:12]1CCOCC1.C(OC(Cl)=O)C(C)C.N.O1CCOCC1.C[O-].[Na+]>COCCOC.CO>[SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:12])=[O:6]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: C[O-]
Agent: N
Solvent: COCCOC
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cccc(S)c1
Yield: 50.4 %

Procedure:
To a solution of 3-mercaptobenzoic acid (1.00 g, 6.49 mmol) in DME (ethyleneglycol-dimethylether, ˜15 ml) was added N-methylmorpholine (1.5 ml, 13.6 mmol) and isobutylchloroformate (1.77 ml, 13.6 mmol) under a flow of nitrogen. The clear solution quickly became a cloudy mixture and the temperature started to rise. After stirring for half an hour the reaction was filtered and then treated with 0.5M NH3 in dioxane (27 ml, 13.5 mmol). The reaction was treated with sodium methoxide in methanol, then quenched with 2N HCl until pH=4 and then concentrated in vacuo to a white paste. This was partitioned between CHCl3 and H2O (3×100 ml) and the organic layer dried (MgSO4) and concentrated in vacuo to a white solid (1.6 g). This was dissolved in H2O, basified (2N NaOH, pH=10) and the aqueous washed with CHCl3. The aqueous was acidified (2N HCl, pH=2) then extracted with CHCl3 (2×50 ml). The organic extracts were dried (MgSO4) then concentrated in vacuo to give 3-mercaptobenzamide as a white solid (501 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=CC=C[CH:3]=1.[C:15](O)(=O)C(C)(C)C>>[C:9]1([C:1]([C:2]([CH3:3])([CH3:7])[CH3:15])=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)O
Product: CC(C)(C)C(=O)c1ccccc1

Procedure:
This invention will be useful in reactions like: benzophenone and pivalic acid to obtain t-butyl phenyl ketone; 1,3-dichloroacetone and pivalic acid to obtain monochloropinacolone; and cyclopentanone and acetic acid to obtain 2,7-octanedione.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH2:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][OH:82].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:82][CH2:81][CH2:80][O:79][CH2:78][CH2:77][O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][CH2:66][CH2:65][O:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][NH:58][C:38](=[O:40])[CH2:37][CH2:36][S:35][CH2:34][C:33]1[CH:32]=[C:31]([CH:43]=[CH:42][CH:41]=1)[C:29]([NH:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:1])([F:48])[F:47])[CH:4]=1)=[O:9])=[O:30]
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: NCCOCCOCCOCCOCCOCCOCCOCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 6.8 %

Procedure:
A solution of 50 mg of 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoic acid 1.1, 57 mg of diisopropylethylamine, 27 mg of 23-amino-3,6,9,12,15,18,21-heptaoxatricosan-1-ol, 18 mg of EDCI, and 19 mg of HOBt in 2 mL of DMF was stirred for 24 h. The product was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 5.1 mg of product. MS (ES, m/z): 1028 [M+H]+
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:40]=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 88 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 3-methoxy-phenylboronic acid (2.3 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (425 mg, 0.6 mmol) in 1,4-dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15.4 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×40 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 10:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.3 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.50 (d, 1H, J=4.8 Hz), 7.90 (d, 1H, J=4.8 Hz), 7.67 (d, 2H, J=7.5 Hz), 7.42 (t, 1H, J=7.5 Hz), 7.27-7.18 (m, 3H), 6.82 ((t, 2H, J=9.0 Hz), 6.65 (s, 1H), 6.55-6.46 (m, 2H), 6.18-6.15 (d, 1H, J=10.2 Hz), 3.67 (s, 3H), 2.69-2.66 (m, 1H), 1.15 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30](I)[CH3:31]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:30][CH3:31]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCI
Product: CCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and ethyl iodide, white powdery N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: CS(C)=O.[CH2:5]([OH:8])[CH2:6][OH:7].CC([O-])(C)C.[K+].Cl[C:16]1[CH:25]=[C:24]2[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]2[CH:26]2[CH2:28][CH2:27]2)=[CH:18][C:17]=1[F:33]>O>[CH:26]1([N:23]2[C:24]3[C:19](=[CH:18][C:17]([F:33])=[C:16]([O:7][CH2:6][CH2:5][OH:8])[CH:25]=3)[C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22]2)[CH2:27][CH2:28]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(OCCO)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a mixture of DMSO (5 ml) and ethyleneglycol (6 ml), KOtBu (1.6 g, 14.23 mmol) was added portionwise over 10 min, and then heated to 90° C. To the mixture, 7chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105° C. and the mixture was stirred for 6 h. Water (30 ml) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2:1 mixture of Intermediate 26A and Intermediate 26B (1.0 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[N:19]1([C:25]2[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:26]=1)=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: Nc1cccc(N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1I
Temperature: 80 °C
Yield: 67.5 %

Procedure:
3-Iodo4-methylbenzoyl chloride (Intermediate 1) (19.5 g, 69.6 mmol) was added portion-wise to a mixture of triethylamine (48 ml, 350 mmol) and 3-(4-morpholinyl)benzenamine (Intermediate 3) (12.6 g, 70.6 mmol) in dimethyl formamide (150 ml) and the mixture was heated at 80° C. for 16 hours. The solvent was removed in vacuo and the residue taken up in chloroform (200 ml). The organic layer was washed with water (2×100 ml), 2M sodium hydroxide solution (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The resulting yellow solid was titurated with diethyl ether and collected by filtration to yield the desired product as an off-white solid (20.0 g, 47.0 mmol). The product was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[C:11](Cl)(=O)[CH3:12]>>[CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCC(=O)O)C(=O)O
Reactant: CC(=O)Cl
Product: C=C(CCC(=O)OCC)C(=O)O

Procedure:
A mixture of 2-methyleneglutaric acid [Ber. 34, 427 (1901)] (40 g.) and acetyl chloride (80 ml.) is heated on the steam bath for 1.5 hours. The excess acetyl chloride is removed in vacuo (75°) and the residue is evaporated from toluene twice. Finally, the residue is dissolved in ethanol and heated on the steam bath for one hour. The reaction mixture is concentrated to dryness to yield 2-methylene-4-(ethoxycarbonyl)butyric acid.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][CH:8]([NH:20][C:21](=[O:47])[C@H:22]([CH3:46])[NH:23][C:24](=[O:45])[C@H:25]([CH:42]([CH3:44])[CH3:43])[NH:26][C:27](=[O:41])[C@H:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31])[C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.CO.[OH-].[Na+].Cl>O>[C:30]([NH:29][C@H:28]([C:27]([NH:26][C@H:25]([C:24]([NH:23][C@H:22]([C:21]([NH:20][CH:8]([C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:6]([OH:48])=[O:5])=[O:47])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CCCc1ccccc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)O)C(=O)CCCc1ccccc1)C(C)C
Yield: 72.8 %

Procedure:
N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-7-phenyl heptanoic acid t-butyl ester (12 mg) was stirred with MeOH (0.5 mL), water(0.2 mL), and 2N NaOH (0.1 mL) overnight. The mixture was acidified with 2N HCl and was extracted with EtOAc (3×5 mL). The solvent was evaporated and the product was recrystilized from acetone/hexane to provide the title compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
125 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(3,4-dichlorophenyl)piperazine (60 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:12])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Br)cc(F)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 4-bromo-2-fluoro 6-nitrophenol(1 g, 4.2 mmol) and tin (II) chloride (4.78 g, 21.2 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(710 mg, 82%). 1H NMR (CD3OD): δ 6.51-6.40 (m, 2H).
Reaction SMILES: CC([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=O.Cl>CO>[CH3:29][O:28][C:10]1[CH:9]=[C:8]2[CH2:7][CH2:6][C@H:5]([NH2:4])[C:21]3[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=3)=[O:19])[C:13]2=[C:12]([O:24][CH3:25])[C:11]=1[O:26][CH3:27]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](N)CC2
Yield: 50.4 %

Procedure:
The reaction mixture of thiocolchicine (705 mg, 1.7 mmol), methanol (20 ml) and 2N hydrochloride (20 ml) was refluxed for 24 h. After cooling, the mixture was concentrated in vacuo. After water layer was acidified with sodium hydroxide solution to pH 10, it was extracted with chloroform. Organic layer was washed with water and brine, dried over MgSO4. After removal of the solvent, the residue was separated by column chromatography (eluent: ethyl acetate and ethanol) to give 320 mg N-deacetylthiocolchicine, mp 168-170° C.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][O:4]1)[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C>[CH3:9][C:8]1([CH3:10])[O:7][CH2:6][CH2:5][O:4][C:3]1=[N:1][O:2][C:13](=[O:14])[NH:12][CH3:11]
Reactant: CN=C=O
Reactant: CC1(C)OCCOC1=NO
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1OCCOC1(C)C
Reaction time: 16 h

Procedure:
To a solution of 16.8 g of crude 2-oximino-3,3-dimethyl-1,4-dioxane and 2 drops of triethylamine was added 17 ml of methyl isocyanate. The reaction mixture was left at ambient temperature for 16 hours. The reaction mixture was concentrated and filtered to yield 4.0 g of 3,3-dimethyl-2-[O-(methylcarbamoyl)oximino]-1,4-dioxane, m.p. 144°-146° C. (m/e 202).