Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)[OH:38].[NH4+].[Cl-]>C1COCC1.C(N(CC)CC)C>[OH:38][C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=1)=[O:24]
Reactant: OC(c1ccc2ccccc2c1)(c1ccc2ccccc2c1)[C@@H]1CCCN1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)N2CCC[C@H]2C(O)(c2ccc3ccccc3c2)c2ccc3ccccc3c2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of mesyl chloride (0.1 ml) in 1 ml of dry THF is added dropwise under argon over a period of 15 minutes to a cooled (−20° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (0.38 g) and triethylamine (0.52 ml) in 10 ml of dry THF. The obtained reaction mixture is stirred for 60 min at −20° C. then treated with a solution of (S)-dinaphthalen-2-ylpyrrolidin-2-ylmethanol (0.46 g) in 5 ml of dry THF and further stirred at −20° C. for 2 h. The reaction mixture is then allowed to warm to room temperature, and stirring is continued overnight. The reaction mixture is then poured into 40 ml of saturated NH4Cl solution and extracted with 4×40 ml of diethyl ether and 20 ml of dichloromethane. The combined organic extracts are washed with saturated NaCl solution (2×80 ml), dried over MgSO4, filtered and evaporated to give a brownish residue. This was purified by chromatography over a short silica column (CH2Cl2 / Et2O : 19 / 1 ) to give acrylic acid (S)-6-[4-[2-(hydroxydinaphthalen-2-ylmethyl)pyrrolidine-1-carbonyl]phenoxy]hexyl ester as a white crystalline material. Yield 0.51 g.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:25]1[CH:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc(-c2ccnc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: CNC1CCC(N(Cc2cc(-c3ccnc(F)c3)ccc2OC)C(=O)c2sc3cccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4-fluoro-benzo[b]thiophene-2-carboxylic acid [5-(2-fluoro-pyridin-4-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(2-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 49%.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[H-].[Na+]>C1COCC1>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4](=[O:21])[NH:32][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 18.9 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide (309 mg, 1 mmol) and toluene-4-sulfonamide (171 mg, 1 mmol) were dissolved in 2 mL of THF. To this was added 40 mg of NaH (60% dispersion in mineral oil) and the resulting mixture stirred overnight. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and solvent removed to yield an oily solid. The product was triturated with MeOH to yield 80 mg solid (19% yield). HRMS (M−H) calcd for C19H18FN2O6S: 412.0870. Found: 421.0876. Anal calcd for C19H19FN2O6S: C, 54.02; H, 4.53; N, 6.63. Found: C, 54.07; H, 4.51; N, 6.51. 1H NMR (500 MHz, CDCl3) δ: 2.44 (s, 3), 3.64 (s, 3), 4.76 (s, 2), 6.45 (s, 1), 7.03 (m, 2), 7.25 (m, 2), 7.35 (d, 2, J=8), 8.00 (d, 2, J=8), 9.11 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 21.68, 48.21, 63.07, 92.21, 115.67, 115.84, 128.70, 129.64, 130.18, 131.01, 135.14, 145.55, 158.85, 159.30, 161.60, 163.56, 170.87.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH:8]([CH3:16])[CH2:7]1)=O)C.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.CC(O)=O>[Br:24][C:14]1[S:15][C:9]2[CH:8]([CH3:16])[CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: CCOC(=O)N1CCc2ccsc2C(C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1CNCCc2cc(Br)sc21
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The product of step f) was dissolved in 2 mL of 1:1 CHCl3/HOAc and treated with NBS (62 mg, 0.35 mmol). After stirring for 10 minutes, the reaction was concentrated to dryness and filtered through a pad of silica gel, eluting with EtOAc. The eluent was concentrated and the residue was treated with 2 mL each EtOH and 40% aqueous KOH. After heating for 14 hours at 100° C., the reaction was diluted with water and extracted 2× into DCM. The title compound was purified by preparative HPLC-MS. The two enantiomers were separated using a Chiralpak® AD-RH® 20×250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase) to give enantiomer 1 (rt=11.6 minutes) and enantiomer 2 (rt=13.6 minutes) of the title compound. 1H NMR (CD3OD) δ 6.92 (s, 1H), 3.48-3.34 (m, 3H), 3.17-2.99 (m, 4H), 1.44 (d, J=7.2 Hz, 3H); MS: ESI (positive): 246, 248 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:17][C:13]=2[C:12]([CH3:37])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:18]([C:16]1[N:15]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:35][NH2:36])=[CH:27][CH:28]=2)[C:14]2[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([CH3:37])[C:13]=2[N:17]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc2c(C)ccc(OCc3ccccc3)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2CN)cc1

Procedure:
3.3 g (7.1 mmol) of 4'-[(7-benzyloxy-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl are dissolved in 100 ml of methanol and hydrogenated at ambient temperature in the presence of 0.5 g of palladium (10% on carbon) at 5 bar of hydrogen. After 3 hours the catalyst is filtered off. 20 ml of 20% strength ammonia in methanol is added to the filtrate and the mixture is hydrogenated again at 70° C. in the presence of 0.5 g of Raney nickel at 5 bar of hydrogen. After 4 hours of the catalyst is filtered off under suction and the filtrate is evaporated to dryness in vacuum. The crude crystalline product is suspended in ether, filtered under suction, washed using ether and dried in vacuum.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:4]1([C:5]([OH:6])=[C:7]([N+:20]([O-:22])=[O:21])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O

Procedure:
U.S. Pat. No. 2,945,890 to Allan shows a method of preparing 2,4-dinitroresorcinol using a sulfuric acid/nitric acid nitrating solution. Apparently, however, styphnic acid (2,4,6-trinitroresorcinol), an undesirable and explosive side product, is also produced in fairly substantial quantities.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][CH:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:68][C:65]1[CH:64]=[CH:63][C:62]([CH:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=2)=[CH:67][CH:66]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc(C(N)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (275 mg, 1.33 mmol) and Et3N (404 mg, 4 mmol) in MeCN (6 ml) was added HATU (558 mg, 1.47 mmol). The mixture was stirred for 5 min at room temperature and then compound 17-e (450 mg, 1.47 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (CH2Cl2:CH3OH=50/1) to provide the product, 17-f, (180 mg, 27%).
Reaction SMILES: [CH:1]1([C:4]([CH:22]2[CH2:24][CH2:23]2)([OH:21])[CH2:5][N:6](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:3][CH2:2]1.[H][H]>CO.[OH-].[OH-].[Pd+2].C>[NH2:6][CH2:5][C:4]([CH:22]1[CH2:24][CH2:23]1)([CH:1]1[CH2:3][CH2:2]1)[OH:21]
Reactant: [H][H]
Reactant: OC(CN(Cc1ccccc1)Cc1ccccc1)(C1CC1)C1CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCC(O)(C1CC1)C1CC1
Yield: 81.4 %

Procedure:
To a solution of 0.28 g 1,1-dicyclopropyl-2-dibenzylamino-ethanol (0.00087 mol) in 10 ml methanol was added 0.060 g Pd(OH)2/charcoal (Fluka 7663; 20%) and the mixture was hydrogenated under 8 bar hydrogen pressure at 60° C. for 2 hours. The catalyst was removed by filtration and the mother liquor was concentrated and the residue was purified by chromatography on silicagel with MeCl2/MeOH/NH3 90:10:1 to yield 0.10 g (81% yield) of the title compound as colorless oil. 1H-NMR (CDCl3 300 MHz, δ ppm) 0.28-0.45 (m, 8H); 0.71-0.78 (m, 2H); 2.77 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:19])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C(Cl)Cl>[Cl:22][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:19])[CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1

Procedure:
A mixture of 25 g (91 mmol) of 2-(4-chlorophenyl)-6-fluoro-4-hydroxyquinoline and 50 ml of phosphorus oxychloride was stirred and heated under reflux for 2 hr. It was then cooled, poured onto ice and diluted with 500 ml of methylene chloride. This mixture was then made alkaline with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted with 2×200 ml of methylene chloride. The organic extracts were combined, washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was collected and washed with hexane to give 22.2 g of product as a brownish solid, mp 169°-172°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:6])[CH3:2]>C1COCC1.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(N)cc1
Reaction time: 24 h

Procedure:
A mixture of 2 (6.7 g, 1 mmol) in THF (100 ml) and EtOH (100 ml) is slowly added 10% Pd/C (680 mg) at room temperature. The reaction mixture is hydrogenated for 24 h with H2 balloon at room temperature. The mixture is filtered through celite pad and washed with EtOH. The filtrate is concentrated in vacuo.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.[H][H]>[C].[Pd].CCO>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[O:1])[CH:10]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CNCCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg) was mixed with EtOH (7 ml), and 10% palladium carbon (70 mg) was added thereto under argon atmosphere to change the atmosphere to hydrogen atmosphere, followed by stirring at room temperature overnight. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure to obtain 1-(pyridin-3-ylmethyl)piperazin-2-one (190 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([N:28]=[C:29]=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH:21]([NH:28][C:29]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:10][CH2:11]1)=[O:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.5 g, 2.7 mmol) in dry CH2Cl2 (12 ml) was added diphenylmethyl isocyanate (0.56 ml, 2.7 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using CH2Cl2:CH3OH (10:1) gives the desired product in 82% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([O:19][CH2:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]OS(C)(=O)=O)=[CH:29][CH:28]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([O:19][CH2:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH2:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][S:23]([CH3:22])(=[O:24])=[O:25])=[CH:32][CH:31]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C(C)(C)C)c1)OCC
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C(C)(C)C)c1)OCC
Yield: 22.1 %

Procedure:
Ethyl 3-(3-tert-butyl-4-hydroxyphenyl)-2-ethoxypropanoate (0.15 g, 0.44 mmole) and 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate (0.26 g, 0.89 mmole) were dissolved in 2-butanone (4 ml). Polyethyleneglycol 400 (0.05 g) and anhydrous potassium carbonate (0.092 g, 0.67 mmole) were added the mixture. After stirring at reflux for 16 hours it was checked using HPLC whether all the starting material was consumed. The mixture was washed with water dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using actonitrile(40-80%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.048 g (22% yield) of the desired product
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:17][C:18](=[O:32])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:12]=[CH:13][C:14]=1[CH2:15]Cl>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:17][C:18](=[O:32])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:12]=[CH:13][C:14]=1[CH2:15][N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1CCNCC1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCl)c(Cl)c1
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
0.24 mL (2.000 mmol) 4-methylpiperidine was added to a solution of 0.206 g (0.500 mmol) N-(3-chloro-4-chloromethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32b) in 5 mL abs. THF and the mixture was refluxed for 2 h. The reaction mixture was poured onto ice water, the precipitate was filtered off, washed with water and dried in a HV.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29](=[O:40])[CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:23]1.N1CCCCC1>C(O)C>[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29](=[O:40])[CH2:30][C:31]2[C:32]([CH3:39])=[C:33](/[CH:37]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:34][C:35]=2[CH3:36])[CH2:23]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 4-[2-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (184 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with acetone to give the titled compound as a pale orange-red solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 3-trifluoromethylbenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 341 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:31][CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:31][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[O:10])[S:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cc(Br)c(Br)s1
Yield: 71.8 %

Procedure:
To a solution of 2.55 g (8.91 mmol) of 4,5-dibromothiophene-2-carboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 2.79 g of the desired compound (yield: 71.8%, colorless powder).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[N:18]2)/[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[N:18]3)=[N:12][N:11]=[C:9]12)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCn1/c(=N/NC(=O)CCCn2cc(-c3ccccc3)cn2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCn3cc(-c4ccccc4)cn3)nnc12
Temperature: 25 °C
Yield: 66 %

Procedure:
A mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(4-phenyl-1H-pyrazol-1-yl)butanohydrazide (369 mg, 0.823 mmols) in toluene (20 ml) was refluxed for 2 hours. After cooling to room temperature, the solid formed was filtered, washed with EtOAc/Hexane (1:9) and dried to give the desired product (234 mg, 66% yield) as off pink solid. LCMS calculated for C23H27N8O (M+H): 431.2. found: 431.1.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:47]=[CH:48][CH:49]=1)[CH2:37][S:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O.CO>C(COC)OC>[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:47]=[CH:48][CH:49]=1)[CH2:37][S:38][C:39]1[CH:40]=[C:41]([CH2:42][C:16]#[N:17])[CH:44]=[CH:45][CH:46]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C=O)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(CC#N)c2)c1
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a mixture of potassium t-butoxide (0.38 g) and dimethoxyethane (10 mL) was added a solution of toluenesulfonylmethylisocyanide (0.33 g) in dimethoxyethane (5 mL) at −78° C. and the mixture was stirred for 10 min. A solution (10 mL) of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde (0.70 g) in dimethoxyethane was added to the reaction mixture and the mixture was stirred for 30 min at −78° C. Methanol (25 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetonitrile as an oil (0.295 g, yield 41%) from a fraction eluted with acetone-hexane (1:5, v/v).