Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[CH:41][C:42]([O:45][C:46]([F:49])([F:47])[F:48])=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(F)(F)F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(F)(F)F)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.54 g), sodium hydrogen carbonate (2.23 g) and dimethyl sulfoxide (11 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-6-oxo-4-propyl-1-[4-(trifluoromethoxy)phenyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.12 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.43 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.40 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.04 g, 83%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:70])[C:59]2[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:60]=2[C:66]([F:69])([F:68])[F:67])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[F:65][C:63]1[CH:62]=[CH:61][C:60]([C:66]([F:68])([F:67])[F:69])=[C:59]([CH:64]=1)[C:58]([N:55]1[CH2:56][CH2:57][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:23]([C:20]2[CH:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH3:10])[NH:22][N:21]=2)=[O:25])[CH2:53][CH2:54]1)=[O:70]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: COc1ccccc1-c1cc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cc(C(=O)NCC(=O)N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41 %

Procedure:
DIPEA (166 mg, 0.22 mL, 1.28 mmol) was added to a stirred solution of 5-(2-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid (70 mg, 0.32 mmol) in DMF (2 mL). HOBT (55 mg, 0.4 mmol) and EDCI (77 mg, 0.4 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-5-fluoro-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (119 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 70 mg (40.9% yield) of 5-(2-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 94.72%. 1H NMR (DMSO-d6): δ 13.45 (s, 1H), 8.0 (m, 1H), 7.88 (m, 1H), 7.7 (d, 1H), 7.46 (m, 2H), 7.4 (m, 1H), 7.1 (d, 1H), 7.0 (m, 2H), 4.32 (d, 2H), 3.86 (s, 3H), 3.64 (m, 1H), 3.5 (m, 3H), 3.4 (m, 1H), 3.1 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C:18](O)=[O:19])[N:13]=[CH:12]1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:18](=[O:19])[CH2:17][CH2:16][C:14]2[N:13]=[CH:12][NH:11][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)CCc1c[nH]cn1
Product: O=C(CCc1c[nH]cn1)NCCCc1ccccc1

Procedure:
The preparation is carried out as in Example 1 with 3-phenylpropanamine and 3-(1H-imidazol-4-yl)propanoic acid, the acid being here added after the reaction of the amine component with N,N'-carbonyldiimidazole. The title compound is extracted from water with diethyl ether, purified by chromatography and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [NH2:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]1[C:11]([NH2:13])=[O:12].C(Cl)(=O)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[NH:1]1[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]=2[C:11](=[O:12])[NH:13][C:15]1=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)C1Oc2ccccc2C1N
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)c2oc3ccccc3c2[nH]1
Temperature: 115 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a stirred solution of 3-amino-2,3-dihydrobenzofuran-2-carboxamide (82.2 mg, 0.461 mmol, 1.0 eq.) in anhydrous toluene (8 mL) under an inert atmosphere was added oxalyl chloride (70.2 mg, 553 μmol, 1.2 eq.) in a dropwise manner. The resulting mixture was heated to reflux (115° C.) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was concentrated to half of its volume and filtered to give a colorless solid (41.5 mg, 45%).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[F:19][C:18]1[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccnc1OCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(COc2ncccc2F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 2-(4-bromo-benzyloxy)-3-fluoro-pyridine (2.03 g, 7.20 mmol) described in Manufacturing Example 149-1-1 was added n-Butyl lithium (5.04 mL, 1.6 M hexane solution, 7.92 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78° C. Then, N,N-dimethylformamide (725 μL, 9.36 mmol) was added to the reaction mixture at −78° C., which was stirred for 1 hour and 10 minutes while the temperature was raised to room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (887 mg, 53%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:28])=CC=1.N1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O1C=CCCC1.C(OCC)(=O)C>[O:28]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Reactant: c1ccncc1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@@H]3[C@@H]1CCC2=O

Procedure:
A suspension of 2.0 g of 3-hydroxy-8a-estra-1,3,5(10)-trien-17-one in 20 ml of tetrahydrofuran and 2.0 ml of dihydropyran is stirred with 15 mg of para-toluenesulfonic acid for 24 hours at room temperature. Then, 0.3 ml of pyridine is added, diluted with ethyl acetate, washed with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 2.2 g of 3-tetrahydropyranyloxy-8a-estra-1,3,5(10)-trien-17-one is obtained as colorless crystals with a melting point of 153-155° C., [α]D22 =+47.5° (c=0.53% in pyridine).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Br[C:37]1[S:47][C:40]2=[N:41][C:42](=[O:46])[CH:43]=[C:44]([CH3:45])[N:39]2[N:38]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:47][C:40]4=[N:41][C:42](=[O:46])[CH:43]=[C:44]([CH3:45])[N:39]4[N:38]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: Cc1cc(=O)nc2sc(Br)nn12
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(=O)nc2sc(N3CCN(S(=O)(=O)c4ccc(OC(F)(F)F)cc4)[C@@H](C(=O)NCc4ccc(OC(F)(F)F)cc4)C3)nn12
Temperature: 100 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a mixed solution of the compound (0.038 g) obtained in Example 783, the compound (0.023 g) obtained in Step 3 and ethanol (1.0 ml) was added N,N-diisopropylethylamine (0.019 ml) at room temperature. After stirring at 100° C. for 3 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:9) to give the title compound (0.032 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][CH2:3][CH:4]([CH3:7])[CH3:5])[CH:5]=[O:6])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCI
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCOc1ccc(C=O)cc1OCCC(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 50 ml of N,N-dimethylformamide are suspended 5.0 g of 3,4-dihydroxybenzaldehyde, 15.5 g of potassium carbonate and 14 ml of isopentyl iodide. The mixture is stirred at 60° C. for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 9.4 g of 3,4-diisopentyloxybenzaldehyde as a light yellow oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[CH3:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[C:26]([CH3:32])[CH:27]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(N)ccc1F
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1ccc(F)c(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 4-fluoro-3-methylaniline. After completion, the reaction mixture was extracted with HCl and washed with a saturated NaHCO3 solution. The organic was dried (Na2SO4), filtered and concentrated. The product was used without further purification. tR: 1.37 min (LC-MS 2); ESI-MS: 508.1/510.1 [M+H]+ (LC-MS 2).
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[NH2:61][CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([S:70]([NH2:73])(=[O:72])=[O:71])=[CH:66][CH:65]=1>>[NH2:73][S:70]([C:67]1[CH:66]=[CH:65][C:64]([CH2:63][CH2:62][NH:61][S:53]([C:33]2[C:32]3[C:36](=[CH:37][CH:38]=[C:30]([Br:29])[CH:31]=3)[NH:35][C:34]=2[C:48]([NH2:7])=[O:50])(=[O:54])=[O:55])=[CH:69][CH:68]=1)(=[O:71])=[O:72]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)NCCc1ccc(S(N)(=O)=O)cc1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with 4-(aminoethyl)benzene-sulfonamide hydrochloride, the title compound was obtained. HRMS (ES) exact mass calculated for C17H18BrN4O5S2 (M+H+): 500.9897. Found 500.9927.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]=[O:19].[NH2:20]C1C=CC=CC=1>O1CCOCC1.C(OCC)C>[O:19]1[C:18]2[CH:2]=[CH:3][CH:4]=[CH:5][C:8]=2[CH2:11][CH2:16][NH:20]1.[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Nc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCNO2
Temperature: 25 °C

Procedure:
34.2 g (0.15 mole) of bisphenol-A and 48.6 g (0.6 mole) of aqueous formaldehyde (37%) were added into a 4-neck reactor equipped with a stirrer, temperature controller, and condenser, and then 100 ml of 1,4-dioxane was added as a solvent. The mixture was stirred at room temperature, and to the resulting solution 27.9 g aniline in 30 ml 1,4-dioxane was dripped at a rate of one drop per second while stirring. Upon completion of the dripping the solution was heated and reacted under refluxing for 10 hours. The reaction mixture was dried in a rotary evaporator under vacuum to obtain a yellowish solid. The yellowish solid was dissolved in ethyl ether and washed with 3N aqueous NaOH three times, followed by 1 N aqueous HCl solution several times and pure water several times, before removing the solvent in vacuo. The dried solid was ground to obtain bisphenol-A dihydrobenzoxazine powder, which is yellowish white. m.p. 110° C. EA: Calcd.: C: 80.50%; H: 6.49%; N: 6.00%. Found: C: 80.00%; H: 6.56%; N: 6.08%.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[Cl:6][C:7]([Cl:13])([Cl:12])[C:8](=[NH:11])OC>C1(C)C=CC=CC=1>[Cl:6][C:7]([Cl:13])([Cl:12])[C:8]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[NH:11]
Reactant: CC(=O)NN
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)NNC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5.0 g (0.07 mole) acetylhydrazine and 20 ml (28.5 g, 0.16 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The resulting solid was recrystallized from toluene to yield 7.3 g. Addition of petroleum ether to the filtrate gave another 1.5 g. The total yield was 8.8 g (59%; mp 130°-132° C.). An analytical sample (mp 131°-132° C.) was prepared by recrystallization from toluene. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9]=[C:8]([C:10]3[N:14]=[CH:13][S:12][CH:11]=3)[NH:7][C:5]=2[CH:6]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][Cl:26])=[O:23].[K+].[Br-]>C(Cl)(Cl)Cl>[Cl:26][CH2:25][O:24][C:22]([N:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=[C:8]1[C:10]1[N:14]=[CH:13][S:12][CH:11]=1)=[O:23]
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: O=C(Cl)OCCl
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCCl)n1c(-c2cscn2)nc2ccccc21

Procedure:
To a suspension of 15.0 g of thiabendazole in 300 ml of chloroform, 6 g of pyridine was added and the suspension cooled in an ice bath. Chloromethyl chloroformate (10.6 g) was added to the reaction mixture dropwise during 10 minutes with stirring. A clear solution was formed which was kept stirred at room temperature for 16 hours. After washing the chloroform solution with water, it was dried over Na2SO4 and evaporated to a light yellow solid weighing 20.4 g. It was crystallized from EtOAc-CHCl3. Obtained in two crops were 15.07 g of compound, m.p. 143°-144° NMR (CDCl3) δ5.9 (2H, s, OCH2Cl), 7.2-8.2 (5H, m, aromatic), 8.93 (1H, d, J=3 Hz, aromatic). IR (KBr) ν3095, 1780, 1460, 1374, 1340, 1194, 1140, 1078 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:14]=[CH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCN(c2cccc(C(=O)O)c2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CCC1CCCN(c2cccc(C(=O)O)c2)C1

Procedure:
10% Palladium on activated carbon (5 mg) was added to 3-[3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethenyl]piperidin-1-yl]benzoic acid (35.0 mg, 0.0797 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for hours in a hydrogen atmosphere. Subsequently, the mixture was filtered through Celite and the solvent was evaporated to give 35.1 mg (quant.) of the desired compound as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccc2)cn1)c1ccccc1
Yield: 67.2 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (0.64 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and filtered over a short pad of silica. Evaporation of the solvent in vacuo yielded the title compound (0.70 g, 68% yield) as a thick oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[BH4-].[Na+].[C:26](=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH2:17][CH2:18][N:19]([CH3:26])[CH2:20][CH:21]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(=O)N1CCc2cc(SCc3ccncc3)c(I)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(SCC3=CCN(C)CC3)c(I)cc21
Temperature: 0 °C

Procedure:
1-Acetyl-2,3-dihydro-6-iodo-5-(pyridin-4-ylmethylthio)-1H-indole (D50) (0.390 g, 0.951 mmol) was dissolved in dry DMF (5 ml) and was treated with methyl iodide (0.089 ml, 1.430 mmol) with stirring. After 24 hours the reaction mixture was evaporated under reduced pressure and was triturated with ethyl acetate (~20 ml). The resultant brown solid was then filtered off, washed with diethyl ether and dried in vacuo (0.513 g). The solid was then redissolved in a mixture of ethanol (20 ml) and water (10 ml) and was cooled to 0° C. Sodium borohydride (0.069 g, 1.824 mmol) was then added. After 0.5 h a further amount of sodium borohydride (0.035 g, 0.912 mmol) was added. The reaction mixture was then allowed to warm to room temperature. After 1.5 hours the reaction mixture was treated with sodium bicarbonate solution (~15 ml) and was partitioned between dichloromethane and water. The aqueous layer was then extracted with dichloromethane (1X) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a yellow solid which was purified by silica-gel chromatography (5% MeOH/CH2Cl2 as eluant) to give the title compound as an off white solid (0.208 g, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
To a solution 4-bromobenzoyl chloride (25 g, 114 mmoles) in THF at 0° C. (200 mL) was added triethylamine (63.5 Ml, 456 mmoles) dropwise followed by diisopropylamine (32.5 mL, 228 mmol). The solution was allowed to stir overnight. The next day the reaction mixture was acidified with 1 N HCl and extracted with CH2Cl2. The organic layer was basified with sat. NaHCO3 wash and dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex. to 100% EtOAc provided the desired product as a yellow solid. 1H NMR (600 MHz, CD3OD) δ 7.60 (d, 2H), 7.23 (d, 2H), 3.30 (br s, 1H), 3.29 (br s, 1H), 1.5, (br s, 6H), 1.22 (br s, 6H). LRMS (ESI) calc'd for (C13H19BrNO) [M+H]+, 284.1; found 284.1.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].N#N.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:1]([O:5][CH2:6][CH3:7])(=[O:4])/[CH:2]=[CH:3]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3]
Reactant: C=CC(=O)OCC
Reactant: c1ccccc1
Agent: N#N
Product: CCOC(=O)/C=C/c1ccccc1
Product: CCOC(=O)CC
Temperature: 180 °C
Reaction time: 48 h
Yield: 26 %
Yield: 22 %

Procedure:
A solution containing 8 ml of benzene, 0.02 mmol of [η6-C6H6—Ru(H2O)3](F3CSO3)2 and 5 mmol of ethyl acrylate in a Fisher-Porter glass reactor was pressurized with 1 atm CO and 7.1 atm of inert gas (e.g., Argon or N2) and heated to 180° C. with stirring for 48 hours. GC analysis revealed formation of 1.1 mmol (E)-ethyl cinnamate (22% yield, 55 TON) and 1.3 mmol ethyl propanoate (26% yield, 65 TON).