Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.N1C=CN=N1.[K].CS(C)=O.BrCC(C#N)(C1C=CC(Cl)=CC=1)CCC1C=CC=C([C:46]([F:49])([F:48])[F:47])C=1>CCOCC.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([C:46]([F:49])([F:48])[F:47])[CH:24]=2)([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CC(CBr)(CCc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: N#CC(CCc1ccccc1)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [K]
Agent: c1c[nH]nn1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CS(C)=O
Product: N#CC(CCc1cccc(C(F)(F)F)c1)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
A 500 ml 1 neck round bottom flask was charged with 10.7 gms of potassium triazole (0.10 mole, 4.0 eq.), 75 ml of DMSO and 1-bromo-2-cyano-2-(4-chlorophenyl)-4-(3-trifluoromethylphenyl)butane (10.4 gms, 0.025 mole, 1.0 eq.). The reaction was heated at 80° C. overnight and then quenched by adding 1 liter of H2O and extracted three times with 200 ml of ether. The combined ether extracts were washed with water and brine, then dried and rotovaped to give a crude product which was slurried in ether:hexane (1:1). A solid formed which was washed with hexane and gave 5.0 gms of a light yellow solid having a melting point of 118°-121° C. (47% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=[CH:5]2.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(C(=O)O)cccc2c1
Product: Cc1ccc2c(C(=O)Cl)cccc2c1

Procedure:
6-Methyl-1-naphthoic acid (6 g; J. Amer. Chem. Soc., 1941, 63, 1857) was added to thionyl chloride (50 ml) and the mixture was heated to reflux for 30 minutes. The solution was evaporated to give 6-methyl-1-naphthoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][C:31]=1[Cl:36].NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][C:31]=2[Cl:36])[CH:4]=1)=[O:8])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol) in tetrahydrofuran (2.78 ml) and methanol (2.78 ml) at 25° C. was added hydrazine (0.17 ml, 5.55 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (190 mg, 0.389 mmol, 70.0% yield) as a yellow solid: LCMS (ES) m/z=415, 417 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (br. s., 1H) 8.06 (s, 4H) 7.74 (s, 1H) 4.25 (dd, J=8.84, 4.29 Hz, 1H) 3.77 (s, 3H) 2.87-2.93 (m, 2H) 1.71-1.79 (m, 1H) 1.64 (d, J=9.85 Hz, 3H) 1.54 (br. s., 1H) 1.48 (br. s., 1H) 1.37 (dd, J=13.26, 4.93 Hz, 1H) 1.14 (br. s., 1H) 1.17 (d, J=7.33 Hz, 2H) 0.93 (d, J=10.86 Hz, 1H) 0.82-0.89 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:8](=O)[C:9]([CH3:12])([CH3:11])[CH3:10]>CO>[CH3:8][C:9]([CH3:12])([CH3:11])[CH:10]=[N:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)C=O
Reactant: NCC1CCNC1
Solvent: CO
Product: CC(C)(C)C=NCC1CCNC1
Reaction time: 1 h

Procedure:
2.0 g (20 mmol) of 3-aminomethyl-pyrrolidine are initially introduced into 10 ml of methanol, and 1.8 g (22 mmol) of 97% strength pivalaldehyde are added dropwise at room temperature, after which the internal temperature rises to 30° C. The mixture is subsequently stirred for 1 hour and then concentrated, and the residue is distilled through a Vigreux column. Yield: 2.8 g (80% of theory) of 97% pure product;
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH2:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C.CP(C)C.[F:39][C:40]1([F:55])[C:45](O)(O)[CH2:44][CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:41]1.[B][B][B][B][B][B][B][B][B][B].C([O-])(O)=O.[Na+]>C1COCC1.CO>[C:51]([O:50][C:48]([N:42]1[CH2:43][CH2:44][CH:45]([NH:19][C:17]2[N:18]=[C:11]3[C:10]([C:3]4[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=4[F:1])=[CH:15][CH:14]=[CH:13][N:12]3[N:16]=2)[C:40]([F:55])([F:39])[CH2:41]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3F)cccn2n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(O)C(F)(F)C1
Agent: CP(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)c(F)c4F)cccn3n2)C(F)(F)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a suspension of 8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c, 200 mg, 757 μmol) and hexachloroethane (215 mg, 908 mmol) under argon in dry THF (10 mL) was added triethylamine (230 mg, 317 μL, 2.27 mmol) followed by trimethylphosphine (1 M in THF, 908 μl, 908 μmol). The reaction mixture was stirred at room temperature for 0.5 hous, then tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (see example 247e, 230 mg, 908 μmol) was added and the mixture was heated to 150° C. in the microwave for 30 minutes. A solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (1 mL) was added to the reaction mixture, then stirred at room temperature for 12 hours. Again a solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (5 mL) was added and heated to 70° C. for 18 hours. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester, was isolated, which was again dissolved in dry MeOH (3 mL). Decaborane (21.6 mg, 23.0 μL, 177 μmol) was added and heated to 70° C. for 30 minutes. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) to yield title compound as white foam (300 mg, 82%). MS ISP (m/e): 484.3/428.1/384.2 (13/100/41) [(M+H)+/(M−tBu)+/(M−Boc)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:31][C:32](=[NH:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:32]([NH:44][O:26][C:25]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:29][CH:28]=1)=[O:27])(=[NH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCC(=N)NO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCCC(=N)NOC(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.8 %

Procedure:
To a solution of 4-({(tert-butoxycarbonyl)[4-(trifluoromethyl)benzyl]amino}methyl)-benzoic acid (102 mg, 0.25 mmol), N-hydroxydodecanimidamide (70 mg, 0.33 mmol) and DMAP (3 mg, 0.03 mmol) in anhydrous DCM (15 mL) was added EDC (62 mg, 0.33 mmol) and the resulting reaction mixture was stirred at RT for 14 h. Evaporation of the solvents gave an oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 80/20) to give the title compound as a colorless oil (36 mg, 24%). 1H NMR (CDCl3, 300 MHz) δ 8.01 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.40-7.20 (m, 4H), 4.88 (br s, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 2.36 (t, J=8.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.49 (s, 9H), 1.45-1.16 (m, 16H), 0.89 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 5.42 min (HPLC purity: 96.1%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.[O:19]1[C@@:36]2([CH3:37])[C@@H:20]1[CH2:21][C@@H:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][O:25][C@@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[C@H:23]12>CCCCCC.C(OCC)(=O)C>[CH2:7]([O:30][C:28]([C:27]1[C@H:22]2[CH2:21][C@@H:20]3[O:19][C@:36]3([CH3:37])[C@@H:23]2[C@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[O:25][CH:26]=1)=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCI
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCOC(=O)C1=CO[C@@H](OC(=O)NC)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
124 mg of potassium carbonate and 0.10 ml of n-hexyliodide were added to a dimethylformamide solution containing 200 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid described in Example 1 followed by heating and stirring for 1 hour at 70° C. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid n-hexylester (210 mg, yield: 80%). The physicochemical properties of this compound are described in Table 1, Compound No. 5.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:3]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:33]([NH:40][C:41](=[O:49])[NH:42][C@H:43]([CH3:48])[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:14]([N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:45](=[O:46])[CH2:44][CH:43]([NH:42][C:41]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:49])[CH3:48])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:26][CH:27]=1)=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CN(Cc1ccccc1)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 ml) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 ml) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 661 (M+H), 683 (M+Na)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:21]2[N:17]([CH3:16])[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)Cc1cccn1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C#N)cc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5.0 g. (0.03 mole) of p-cyanobenzoyl chloride in 60 ml. of methylene chloride is added to a suspension of 40 g. of aluminum chloride in 30 ml. methylene chloride. The resulting mixture is added dropwise to a chilled solution of 5.0 g. (0.03 mole) of ethyl 1-methylpyrrole-2-acetate in 15 ml. of methylene chloride. The resulting mixture is stirred at room temperature for 20 minutes, and then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated, washed successively with N,N-dimethylaminopropylamine, 3N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo. The resulting solid, which separates from the oily residue on standing, is recrystallized from methanol to give pure ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate, m.p. 117-120° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].Cl[Si:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH:25]([F:27])[F:26])=[C:19]([F:28])[CH:18]=2)[CH2:9][CH2:8]1>C1COCC1>[F:28][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH:10]2[CH2:11][CH2:12][Si:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]2)[CH:22]=[C:21]([F:23])[C:20]=1[O:24][CH:25]([F:27])[F:26]
Reactant: CCC[Mg]Br
Reactant: Fc1cc(CCCCC2CC[Si](Cl)(c3ccccc3)CC2)cc(F)c1OC(F)F
Solvent: C1CCOC1
Product: CCC[Si]1(c2ccccc2)CCC(CCCCc2cc(F)c(OC(F)F)c(F)c2)CC1

Procedure:
50 ml (0.13 mols) of a THF solution of 2.5M of propylmagnesium bromide was dropped in a mixed solution of 44.5 g (0.1 mol) of 1-chloro-1-phenyl-4-(4-(3,5-difluoro-4-difluoromethoxyphenyl)butyl)-1-silacyclohexane and 300 ml of THF. After ordinary after-treatments, 4-(4-(3,5-difluoro-4-difluoromethoxyphenyl)butyl)-1-phenyl-1-propyl-1-silacyclohexane was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[OH:19])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:6].[CH3:20]O>>[CH3:20][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([OH:19])=[C:2]([OH:1])[CH:3]=2)[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1cccc(C(=O)c2ccc(O)c(O)c2)c1
Product: COC(=O)c1cccc(C(=O)c2ccc(O)c(O)c2)c1
Reaction time: 8 h

Procedure:
A solution of 2.9g of 3-(3,4-dihydroxybenzoyl)-benzoic acid in 100 ml of methanol is mixed with 7g of Amberlyst 15® and refluxed with stirring for 8 hours. The reaction mixture is filtered on diatomaceous earth, the filtrate concentrated by evaporation, taken up in ethyl acetate and shaken out with 10% sodium bicarbonate solution. The organic phase is dried on sodium sulfate and concentrated by evaporation. 1.4g of 3-(3,4-dihydroxybenzoyl)-benzoic acid methyl ester is obtained as oily crude product. 272 mg of this crude product is dissolved in 2.5 ml of dimethylformamide, mixed with 269 mg of (1E)-6-bromo-l-(4-methoxyphenyl)-1-hexene and 185 mg of lithium carbonate and the mixture is heated for 18 hours to 50°-60° C. with stirring. The reaction mixture is filtered, washed with dichloromethane, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate=98/2. 230 mg of 3-[3-hydroxy- 4-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]benzoyl]-benzoic acid methyl ester is obtained as oil.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:35]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)([F:35])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Product: Cc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), using compound 11.2 HCl salt instead of compound 1.5. m/z (ES+) 458 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.66 (d, 2H), 7.51 (d, 3H), 7.38 (s, 1H), 4.72 (d, 1H), 4.30 (br s, 1H), 3.46 (br s, 1H), 3.16 (dd, 1H), 3.04-2.78 (m, 2H), 2.38 and 2.36 (2 singlets, amide rotamers, ArCH3, 3H), 2.35-2.27 (m, 3H), 2.22-1.82 (m, 6H), 1.81-1.56 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)O1>>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([C:2]3[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: Oc1cc(F)cc(Br)c1
Product: Oc1cc(F)cc(-c2ccc3scnc3c2)c1

Procedure:
Compound 3-(benzo[d]thiazol-5-yl)-5-fluorophenol (W190) was prepared using the general procedure for Suzuki coupling reaction between 3-bromo-5-fluorophenol (57 mg, 0.3 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (78 mg, 0.3 mmol), as a white solid (60 mg, 81%). 1H NMR (400 MHz, acetone-d6) δ 9.30 (s, 1 H), 9.02 (brs, 1 H), 8.30 (d, J=1.6 Hz, 1 H), 8.19 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=8.4, 2.0 Hz, 1 H), 7.07 (t, J=1.6 Hz, 1 H), 7.02 (dt, J=10.0, 2.0 Hz, 1 H), 6.64 (dt, J=10.4, 2.4 Hz, 1 H); MS (ESI) m/z 275 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])[NH2:21])[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1>[C:24]1([S:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:21])[NH2:22])[CH:15]=4)[C:8]3=[O:23])[CH2:3][CH2:2]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with phenylsulfonyl chloride in tetrahydrofuran with triethylamine followed by amidine formation as described above; HRMS (M+H)+ calc. 454.191287, found 454.191418.
Reaction SMILES: CN1C=CN=C1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[CH3:12][O:13][CH2:14][CH2:15][OH:16].O>ClCCl>[CH3:7][S:8]([O:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9]
Reactant: COCCO
Reactant: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
1-Methylimidazole (50 g) and methanesulfonyl chloride (66 g) were mixed in dichloromethane in a 500 mL two-bulb flask. After adding ethylene glycol monomethyl ether (42 g) dropwise at 10° C., the mixture was stirred at room temperature for 4 hours. After the reaction was completed, water was added. After stirring for 10 minutes, the solvent layer in which the product was dissolved was separated from the aqueous layer in which the byproduct was dissolved. The product was yielded by removing the solvent at room temperature using an evaporator (yield: 98%), and the byproduct 1-methylimidazolium chloride was recovered as 1-methylimidazole using 40 wt % NaOH aqueous solution and used again (yield: 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(Cl)(Cl)Cl>[C:26]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH2:17][CH3:18])[CH:11]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1cc(O)cc(C)c1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a mixture of 6.3 g of 4-benzyloxy-3-ethyl-5-methylphenol, 3.2 g of triethylamine and 50 ml of chloroform was added dropwise 4.0 g of benzoyl chloride, while stirring at 0° C. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added 100 ml of 10% hydrochloric acid, and the mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was successively washed 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, which afforded 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate (93% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].Cl[C:22]([O:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH3:25])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: COC(=O)Cl
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OC)C2=O)cc1

Procedure:
The title compound 26a was prepared from compound 76 (101 mg, 0.25 mmol), methyl chloroformate (21 μL, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 98.2% (86 mg) yield as a yellow solid.