Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
4-Phenoxybenzoic acid (214 mg, 1.0 mmol), 1-hydroxybenzotriazole (203 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg, 1.5 mmol) and triethylamine (0.7 mL, 5 mmol) were dissolved in dichloromethane (15 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (190 mg, 1.0 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methane=40:1) to give the product as a white solid (120 mg, 34%). LRMS (M+H+) m/z: calcd 348.15. found 348. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.28 (m, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.40 (t, J=7.2 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 5.84 (s, 1H), 4.27 (d, J=7.5 Hz, J=3.6, 2H), 2.15 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]([OH:12])=O)[N:5]=1)([O-:3])=[O:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]([CH3:37])[CH3:36])[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]([CH3:37])[CH3:36])[CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c([N+](=O)[O-])n3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (5-Nitro-1H-[1,2,4]triazol-3-yl)-acetic acid and 3 (S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 3.10 min, [M+1]+ 495. Potency class C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([S-:22])[CH2:20][CH3:21].[Na+]>CC(S)CC>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:22][CH:19]([CH2:20][CH3:21])[CH3:18])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCC(C)[S-]
Agent: CCC(C)S
Agent: [Na+]
Product: CCC(C)SC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium 2-butanethiolate in 2-butanethiol there is obtained 2-butyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate which is purified by flash chromatography on silica gel using n-hexane/ethyl acetate (1:1) as the eluent, 1H-NMR(CDCl3): 1.05 (t, CH2CH3), 1.42 (d, CH--CH3), 1.46-1.93 (m, CH2CH3), 2.81-3.37 (m, 1H), 4.41 (s, 4H), 5.1 (broad s, NH), 7.37-7.70 (8H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:5][CH2:6][CH3:7]>C(Cl)Cl>[CH2:4]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:3])=[O:20])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1c[nH]c2cc(C(=O)O)ccc2c1=O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: CCCCc1c[nH]c2cc(C(=O)OC)ccc2c1=O

Procedure:
Diazomethane was added to a solution in methylene chloride of the product of Step D until a persistent yellow color was obtained. The excess diazomethane was destroyed with acetic acid and the medium was evaporated t dryness to obtain the expected product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24].[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26].CCN(CC)CC>C1COCC1.[Cu]I>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[C:30][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24])[CH3:26]
Reactant: Cc1c(Br)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C#CC(OCC)OCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1nc(C(=O)N(C)C)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.1 %

Procedure:
6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.10 g, 0.247 mmol), propargylaldehyde diethyl acetal (0.48 mg, 0.370 mmol), copper(I) iodide (0.001 mg, 0.005 mmol) and Et3N (1 ml) in THF (1 ml) were placed in a glass tube for microwave synthesis. The mixture was degassed with argon and Pd(Cl2) (PPh3)2 (0.007 g) was added. The tube was sealed and heated with stirring at 60° C. (150 W) in a microwave heater for 20 minutes. The mixture was diluted with EtOAc (5 ml) and filtered. The solution was concentrated in vacuo and was then purified on silica to give the title compound (28 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[NH:6]2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:14])([F:15])[F:16])[N:6]2[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1Cl
Product: Cc1noc(C)c1-c1nc(Cn2c(C(F)(F)F)cc3c(Cl)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 5.93 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H); MS (ES) m/z 422 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: COc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Sc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
3-Bromobenzenecarboxylic acid (402 mg, 2 mmol), i-Pr2NEt (700 μL, 4 mmol) and dry 1,4-dioxane (8 mL) were put into a round-bottomed flask, and the round-bottomed flask with the resulting mixture therein was purged repeated three times with nitrogen gas. Next, Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol) and 4-methoxythiophenol (246 μL, 2 mmol) were added to it, and this was purged repeatedly twice with nitrogen gas, and then heated under reflux for 6 hours. Next, the completion of the reaction was confirmed through high-performance liquid chromatography, then this was cooled to room temperature, and made to have a pH of 3 to 4 with acetic acid. The insoluble matter was removed through filtration, and the filtrate was concentrated. The resulting concentrate liquid was isolated and purified through flash column chromatography (developer: hexane/ethyl acetate=10/1) with silica gel serving as a carrier, thereby giving 432 mg (yield: 83%) of 3-(4-methoxyphenyl)sulfanylbenzenecarboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:13][C:14]([F:19])([F:18])[C@@H:15]([NH2:17])[CH3:16]>N1C=CC=CC=1.C(OCC)(=O)C>[F:13][C:14]([F:19])([F:18])[C@@H:15]([NH:17][S:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH3:16]
Reactant: C[C@H](N)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
2-chloropyridine-5-sulfonyl chloride (12 g, 56.6 mmol) was added to a solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (7.8 g, 51.2 mmol) in pyridine (15 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes and diluted with ethyl acetate (200 ml) and washed with 3 N aq. HCl (2×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The solid was triturated with hexane (2×40 mL) and filtered to provide (S)-6-chloro-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as an off-white solid (11.84 g, 75%). 1H NMR (500 MHz, CDCl3): δ0.81 (1H, d, J=2.4 Hz), 8.18 (1H, dd, J=2.5 Hz, 2.6 Hz), 7.51 (1H, d, J=8.8 Hz), 4.92 (1H, br s), 4.08 (1H, m), 1.45 (3H, d, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(C#N)c2ccc(F)cc2)nc1
Yield: 66.1 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-5-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. and the mixture was heated to reflux for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 2-(α-cyano-4-fluorobenzyl)-5-methylpyridine (4.35 g) as yellow oil.
Reaction SMILES: C=CC1C=CC=CC=1.[CH2:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19]CCO)[CH2:10]CC.[NH2-].[Na+]>C1COCC1>[CH2:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH3:10]
Reactant: CCCCOCCOCCOCCO
Agent: [NH2-]
Agent: [Na+]
Solvent: C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCOCCOCCO
Yield: 50 %

Procedure:
Polymerization of styrene with the system NaNH2 and triethylene glycol monobutyl ether. Polymerization is allowed to proceed from 8.32 g (8·10-22 mole) of styrene in in 30 cc THF in the presence of 0.98 g (25·10-3 mole) of sodium amide and 1.71 g (8.3·10-3 mole) of triethylene glycol monobutyl ether. The reaction mixture which is obtained prior to the addition of the monomer has a yellow color which is more pronounced than that obtained with diethylene glycol monoethyl ether, contrary to the results which have been obtained with glycol monomethyl ether. At the end of four hours, a polymer is obtained in 50% yield, with Mn=8500.
Reaction SMILES: [Cl:1]Cl.[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26](SC(C)(C)C)[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26]([Cl:1])[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CN=[N+]=[N-]
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CN=[N+]=[N-])C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: -60 °C
Reaction time: 2 h

Procedure:
286 μl of a solution containing 1.14 g/10 ml of chlorine in carbon tetrachloride are added to a solution of 110 mg of p-nitrobenzyl 5-azido-2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 9 ml of methylene chloride at -60° C., and the mixture is subsequently stirred for 2 hours at -60° C. The reaction solution is evaporated in a rotary evaporator to give 119 mg of a yellow oil. IR spectrum in CH2Cl2 : 2930, 2860, 2105, 1780, 1755, 1720, 1610, 1530, 1350, 1190 cm-1.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1Cc1ccccc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of phosphorus tribromide (2.1 mL, 6.0 g, 22.1 mM) in 30 mL of carbon tetrachloride was slowly added dropwise to solution of 2-benzylbenzyl alcohol (1.98 g, 10 mM) in 70 mL of carbon tetrachloride at 0° C. The mixture was stirred at 0° C. for 2 hours, then at room temperature for 2 hours. The solvent was removed in vacuo and the residue diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 2.6 g (99%) of 2-benzylbenzyl bromide as a yellow solid. 1H NMR (DMSO-d6) δ 7.5-7.0 (m, 9H), 4.7 (s, 2H), and 4.15 (s, 2H). IR (CHCl3, cm−1) 3065, 1601, 1495, and 1453. MS (FD) m/e 260, 262.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].[I-:12].[Na+]>CC(CC)=O>[I:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1nccn1CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1nccn1CCI
Yield: 82.9 %

Procedure:
163.4 g of 1-(2-chloroethyl)-2-nitroimidazole and 200.4 g of sodium iodide were heated under reflux for 4.5 hours in a 1 liter of ethyl methyl ketone. After cooling, the mixture was filtered, the solvent was evaporated off, the residue was partitioned between 2 liters of dichloromethane and 1 liter of water and the organic phase was washed twice with 1 liter of water each time and evaporated. Crystallization from 1 liter of of isopropanol yielded 206 g 1-(2-iodoethyl)-2-nitroimidazole, m.p. 79°-82° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2C(C)(C)C)cc1

Procedure:
118 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(2,3-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:6]=1[Cl:7].[Mg+2].[Cl-].[Cl-].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([OH:18])([C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[C:6]=1[Cl:7]
Reactant: Cc1nc(Cl)c(Cl)n1CCCCN1CCC(=O)CC1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCN(CCCCn3c(C)nc(Cl)c3Cl)CC2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g (3.3 mmol) of 4,5-dichloro-2-methyl-1-[4-(4-oxo-1-piperidyl)butyl]-1H-imidazole in 10 ml of anhydrous tetrahydrofuran is added to a suspension of 1.08 g (11.4 mmol) of MgCl2 in 15 ml of anhydrous THF at -40° C. and under a nitrogen atmosphere. The mixture is stirred for 5 minutes and then, at -40° C., 6.8 ml of a 1.0M solution of 4-methylphenylmagnesium bromide are added. The resulting suspension is stirred for 15 minutes at -40° C. and for 3 hours at room temperature. An aqueous ammonium chloride solution is then added and the tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with chloroform. The chloroform phase is washed with water, dried with anhydrous sodium sulfate and evaporated to dryness, a crude product being obtained which is purified by chromatography on silica gel, giving 1.02 g (2.6 mmol) of 4,5-dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidyl]butyl}-2-methyl-1H-imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([CH2:18][C:19](=O)[CH3:20])[C:15]([CH3:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:20][C:19]1[N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[C:15]([CH3:17])=[CH:14][CH:18]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 77.3 %

Procedure:
A mixture of 4-nitrobenzenesulfonamide (30.3 g, 0.15 mol), acetonylacetone (34.2 g, 0.30 mol) and 4-toluenesulfonic acid (3.0 g, catalyst) in 200 mL of toluene was heated at reflux under nitrogen using a Dean-Stark trap for 18 hours. The reaction was cooled and filtered through silica gel (700 g), eluting with mixtures of ethyl acetate and hexane. Removal of solvent in vacuo gave a crude brown solid. The crude product in ethyl acetate was treated with activated charcoal, and recrystallized from ethyl acetate and hexane to afford 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (32.5 g, 77%) as a light yellow solid: mp (DSC): 101–103° C. Anal. Calc'd. for C12H12N2O4S: C, 51.42; H, 4.32; N, 9.99; S, 11.44. Found: C, 51.62; H, 4.18; N, 9.96; S, 11.31.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH:12]([C:14]1[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=O.[OH-].[K+]>CCO>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])/[CH:10]=[CH:12]/[C:14]2[CH:15]=[CH:16][C:17](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 1-(4-hydroxymethyl-phenyl)-ethanone (1 g, 6.67 mmol), 4-formylcinnamic acid (1.17 g, 6.67 mmol) and 1.7 M KOH (5.89 ml) in EtOH (60 ml) was stirred at room temperature overnight. The resulting precipitate was filtered and washed with EtOH to give 1.39 g of (E)-3-{4-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid as its potassium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[CH3:14][C:15]([O:18][C:19](=[O:40])[N:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:17])[CH3:16].CCCCCC.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:15]([O:18][C:19](=[O:40])/[N:20]=[C:8](/[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:13])\[CH:9]([F:11])[F:10])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/N=C(/c1cc(Br)ccc1F)C(F)F
Temperature: 100 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
A suspension of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (16.0 g, 63.2 mmol) and N-(triphenylphosphoranylidene)-carbamic acid 1,1-dimethylethyl ester (CAS 68014-21-1) (26.3 g, 69.6 mmol) in 12 ml toluene was stirred at 100° C. for 2 days. The suspension became clear. After being cooled down somewhat, hexane was added till crystallization of triphenylphosphine oxide started. The mixture was filtered and the filtrate was purified by chromatography on silica gel with hexane/TBME 1-5% to give 11.37 g of the title compound as a yellow liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([CH2:32][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:8]=3)[CH2:3][CH2:2]2)=[CH:31][C:26]=1[C:25]([OH:36])=[O:24]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccsc1
Product: COc1ccc(CN2CCC(c3cn(Cc4ccsc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.1 g (0.38 mmol) of 3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 0.13 g (0.48 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. The crude mixture was purified by HPLC-MS using a C-18 column, and 0.002 g (94% of purity) of the expected acid were isolated.