Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26]>CO>[Cl-:17].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: CO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)cc1Cl
Product: [Cl-]
Yield: 119.5 %

Procedure:
A mixture of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylamine (2.0 g), α,2,4-trichlorotoluene (3.0 g) and methanol (10 cc) was refluxed for 5 hours, and the solvent of the reaction mixture was distilled off under reduced pressure. The residue was dissolved in a small amount of benzene and thereto was added a large amount of ether. The precipitated oil was gathered by decantation and dissolved in a small amount of benzene and thereto was further added a large amount of ether. The solvent was distilled off to give colorless oil (4.5 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(2,4-dichlorobenzyl)ammonium chloride.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:32]=[CH:31][C:14]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[N:26]([CH:27]([CH3:29])[CH3:28])[C:25]([CH3:30])=[N:24][CH:23]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:33]1[CH2:36][CH2:35][CH2:34]1>CCOC(C)=O>[ClH:1].[N:33]1([CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:32]=[CH:31][C:14]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[C:25]([CH3:30])=[N:24][CH:23]=5)[CH:19]=[CH:18][N:17]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)=[O:4])[CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CCl)CC4)cc3)n2)n1C(C)C
Reactant: C1CNC1
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CN5CCC5)CC4)cc3)n2)n1C(C)C
Product: Cl

Procedure:
2-{4-[4-(Chloroacetyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 24; 0.34 g, 0.75 mmol) and azetidine (2 ml) was stirred for 24 hours at ambient temperature. The solution was diluted with EtOAc (20 ml), washed with aqueous saturated sodium bicarbonate solution (10 ml) and aqueous saturated sodium chloride solution (10 ml), then dried and evaporated at reduced pressure. The residue was purified by chromatography on a 40 g silica column, eluted with a 3% MeOH-ammonia/DCM to 5% MeOH-ammonia/DCM gradient, to give the amine, which was converted to the hydrochloride salt by dissolving in EtOAc (3 ml) and treating with a 1.0 molar solution of ethereal-HCl (0.75 ml). The solid was triturated with ether (20 ml) and filtered to give the title compound (24 mg, 7%). NMR: 9.77 (s, 1H), 8.58 (d, 1H), 8.20 (s, 1H), 7.61 (d, 2H), 7.35-7.24 (m, 2H), 7.13 (d, 1H), 5.64-5.55 (m, 1H), 4.65 (brs, 1H), 4.44 (d, 2H), 4.23-4.11 (m, 2H), 4.09-3.96 (m, 2H), 3.81-3.71 (m, 2H), 3.69-3.59 (m, 2H), 3.42-3.31 (m, 2H), 3.30-3.17 (m, 2H), 2.48-2.24 (m, 2H), 2.81 (s, 3H), 1.48 (d, 6H); m/z 475.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24].B(F)(F)F.CCOCC>C(O)(=O)C.CCOCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][C:6]3([S:25][CH2:21][CH2:22][CH2:23][S:24]3)[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reactant: SCCCS
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC2(CC1(C)C)SCCCS2
Reaction time: 8 h

Procedure:
To a solution of 4a (7.75 g, 26.7 mmol) and 1,3-propanedithiol (3.03g, 28.1 mmol) in 50 mL acetic acid was added boron trifluoride etherate (7.98g, 56.2 mmol). The solution was stirred overnight, diluted with ether, washed with H2O saturated NaHCO3, and brine and dried (MgSO4). Removal of the volatile in vacuo provided a residue which was crystallized from hexane, wt 8.0 g, mp 100°-01° C. Anal. C20H25OF2S2 : Theory C: 63.12; H:6.62; S:16.85. Found C: 63.45; H:6.58; S: 16.44.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:18])[C@@H:11]([NH2:17])[CH2:12][O:13][CH2:14][CH2:15]Cl>CO>[CH3:8][O:9][C:10]([C@@H:11]1[CH2:12][O:13][CH2:14][CH2:15][NH:17]1)=[O:18]
Reactant: COC(=O)[C@@H](N)COCCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H]1COCCN1

Procedure:
Triethylamine (1.2 mL) was added to the above-obtained (2S)-2-amino-3-(2-chloroethoxy)propanoic acid methyl ester (726 mg) in methanol (10 mL), and the resultant mixture was refluxed under heat for 3 hours, and then cooled in air. The reaction solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and insoluble matter was removed by filtration. The solvent of the filtrate was removed under reduced pressure, to thereby give the title compound as an oily product (467 mg, 80%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][O:23][CH2:24][CH:25]([NH2:27])[CH3:26].Cl>C(O)C>[CH3:22][O:23][CH2:24][CH:25]([NH:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH3:26]
Reactant: COCC(C)N
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: COCC(C)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 33.6 %

Procedure:
A mixture of 200 mg (0.63 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 0.27 ml (2.51 mmol) of 2-methoxy-1-methyl-ethylamine and 3 ml ethanol is heated at 150° C. in a closed vial in a microwave reactor for 15 minutes. After cooling to room temperature, 1M aqueous hydrochloric acid is added until a pH value of 5-6 is reached. The resulting suspension is filtered, the residue washed with water and dried at 60° C. Crystallization from ether-hexane gives 82 mg (34%) of the title compound as red crystals, m.p. 103-111° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[C:26]([C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])=[CH:3][CH:4]=2)[CH:10]=1)=[O:28])([CH3:24])[CH3:25])#[N:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (2.5 g, 6.71 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.34 g, 7.05 mmol) under ice-cooling, and the mixture was stirred with heating at 80° C. for 2 days. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.48 g, 99%) as a colorless powder. The compound was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C(Cl)Cl>[CH2:28]([NH:30][C:31]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:32])[CH3:29]
Reactant: CCN=C=O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: ClCCl
Product: CCNC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (73 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with ethyl isocyanate (19 μL, 0.24 mmol) and stirred for 1 h, then evaporated and the residue purified by silica gel flash chromatography with 50% then 75% EtOAc/hexane as eluant to afford the title compound as a foam (60 mg, 69%) 1H NMR (CDCl3) 7.35-7.22 (m, 5H), 6.78 (d, J=8.8, 1H), 6.49 (br s, 1H), 6.40 (br d, J=7.5, 1H), 4.73-4.70 (m, 1H), 4.27-4.13 (m, 2H), 3.93 (br d, J=12.5, 1H), 3.79 (s, 3H), 3.43-3.00 (m, 7H), 2.75-2.67 (m, 2H), 1.96-1.91 (m, 2H), 1.90-1.79 (m, 3H), 1.64-1.59 (m, 2H), 1.04 (t, J=7.2, 3H). LC/MS (Method A) 6.86 min, [M+1]+ 438.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: CCCCCCCCCCCC(O)CC(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymyristic acid (5.00 g) and triethylamine (2.85 g) in DMF (50 ml) was added benzyl bromide (2.43 ml) and the mixture was stirred at room temperature overnight. After the solvent was removed in vacuo, to the residue were added ethyl acetate and water. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After the ethyl acetate was removed in vacuo, purification was carried out by a silica gel column chromatography (silica gel 30 g, chloroform:methanol=100:0-10) to afford 3.69 g of benzyl 3-hydroxymyristate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.S(Cl)([Cl:16])=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([Cl:16])=[O:8])[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Cl)c1

Procedure:
Isophthalic acid mono methyl ester (200 mg, 1.10 mmol) was heated at reflux for 15 min in the mixture of thionyl chloride (2 ml) and DMF (cat.). The solvent was evaporated in vacuo, the residue was dissolved in DCM (5mi) and the solvent was evaporated to afford 3-chlorocarbonyl-benzoic acid methyl ester. To a solution of the product of step b above (435 mg, 1.00 mmol) and triethylamine (280 μl, 2.00 mmol) in DCM (10 ml) was added a solution of the previously prepared 3-chlorocarbonyl-benzoic acid methyl ester in DCM (2 ml). The reaction mixture was stirred at room temperature for 1h. It was washed with 5% aqueous potassium hydrogen sulfate (10 ml) and water (10 ml), dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/ethyl acetate 4:1) to afford the product as a white solid (310mg, 52%). 1H NMR (300 MHz, CDCl3) 8.53 (1H, s), 8.18 (2H, m), 8.07 (1H, d), 7.51 (1H, t), 7.30-7.21 (4H, m), 3.95 (3H, s), 2.91 (2H, m), 2.20 (3H, s), 1.94 (3H, br s), 1.66 (6H, m), 1.5 (6H, s), 1.38 (2H, m), 1.21 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.BrN1C(=O)CCC1=O.[SH:31][CH2:32][CH2:33][CH2:34][SH:35].[OH-].[Na+]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:35][CH2:34][CH2:33][CH2:32][S:31]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Reactant: SCCCS
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To the solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-formyl-1H-pyrazole-3-carbonitrile (0.5 g, 1.4 mmol) in dichloromethane (10 mL) was added N-bromosuccinimide (0.075 g, 0.2 mmol) followed by the addition of 1,3-dimercaptopropane (0.19 g, 1.8 mmol). The resulting solution was stirred at room temperature for eight hours. It was then worked-up by the addition of 2 N sodium hydroxide. The layers were separated and the organic layer was dried (Na2SO4) and concentrated. The resulting solid was further purified via silica gel column eluting with heptane:ethyl acetate (1:1) to afford a white solid (0.2 g, 33%). 19F-NMR: −64.231.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]([F:30])([F:29])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26](O)=[O:27])=[CH:16][CH:15]=1>>[N:1]1([CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[NH:11][C:26]([C:17]2[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:14]([C:13]([F:29])([F:30])[F:12])=[CH:15][CH:16]=2)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccccc1
Product: O=C(NC1CCCC1N1CCCC1)c1ccc(C(F)(F)F)cc1-c1ccccc1

Procedure:
The title compound, off-white oil, MS: m/e=403.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 5-trifluoromethyl-biphenyl-2-carboxylic acid (intermediate AI).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].[CH:25]1([CH2:28][N:29]2[CH:33]=[C:32](I)[CH:31]=[N:30]2)[CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH:25]4[CH2:27][CH2:26]4)[CH:33]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: Ic1cnn(CC2CC2)c1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC4CC4)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 1-cyclopropylmethyl-4-iodo-1H-pyrazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:36])(=[O:35])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=2)[C@H:10]([OH:37])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][C@@H:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[OH:37])=[CH:20][CH:19]=2)(=[O:36])=[O:35])=[CH:29][CH:30]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
To a solution of (+/−)trans-4-{4-[(4-chloro-benzyl)-isobutyl-sulfamoyl]-phenoxy}-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (222 mg, 402 μmol) in DCM (8 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2 M NH3 in MeOH to give N-(4-chloro-benzyl)-4-((+/−)trans-3-hydroxy-piperidin-4-yloxy)-N-isobutyl-benzenesulfonamide (202 mg, 447 μmol). LCMS (m/z, Method A) ES+ 453 [M+1]+.
Reaction SMILES: CBr.[C:3]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:28]([C:30]1[C:31]([CH3:38])=[CH:32][C:33]([NH2:37])=[N:34][C:35]=1[CH3:36])=O>C1COCC1>[CH3:38][C:31]1[C:30]([CH:28]=[CH2:3])=[C:35]([CH3:36])[N:34]=[C:33]([NH2:37])[CH:32]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(N)nc(C)c1C=O
Agent: CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(C)cc(N)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round bottomed flask was added a magnetic stirrer bar, 500 mg (1.2 mmol) of triphenylphosphonium methyl bromide and 137 mg (1.22 mmol) of potassium t-butoxide. The flask is stoppered with a rubber septum, flushed with nitrogen and 5 mL of dry THF was added to the mixture. After stirring at room temperature for 1 h, the solution was cooled to -60° C. and a solution of 170 mg (1.0 mmol) of 5-formyl4,6-dimethyl-2-aminopyridine in 2 mL of THF was added. After stirring for 30 minutes, the solution was warmed to 25° C. and stirred for 1 h. The solvent was removed in vacuo and and the title compound purified by silica gel column chromatography eluted with (methylene chloride/methanol (95:5).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[CH2:19][CH3:20])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[C:26]([CH3:33])[CH:25]=1>>[Br-:21].[NH2:1][C:2]1[N:6]([CH2:22][S:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[C:26]([CH3:33])[CH:25]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[CH2:19][CH3:20])[C:4]=2[N+:3]=1[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[C:26]([CH3:33])[CH:25]=1
Reactant: CCc1c(OC)cccc1-c1cccc2nc(N)[nH]c12
Reactant: CCCc1ccc(SCBr)cc1C
Product: CCCc1ccc(SCn2c(N)[n+](CSc3ccc(CCC)c(C)c3)c3c(-c4cccc(OC)c4CC)cccc32)cc1C
Product: [Br-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-4-(2-ethyl-3-methoxyphenyl)benzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3-methyl-4-propylphenyl bromomethyl sulfide, the title compound is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:47]=[CH:46][C:29]2[C:30](=[O:45])[C:31]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=3)([CH3:34])[CH2:32][O:33][C:28]=2[CH:27]=1.O>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:30]1([OH:45])[C:29]2[CH:46]=[CH:47][C:26]([O:25][CH2:24][O:23][CH3:22])=[CH:27][C:28]=2[O:33][CH2:32][C:31]1([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=1)[CH3:34])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C#CCCCCCCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
8-(t-Butyldimethylsilyloxy)oct-1-yne (0.6 g, 2.5 mmol) was dissolved in dry tetrahydrofuran (8 ml) under argon atmosphere and then cooled to -78° C. 2.5M n-BuLi (0.94 ml, 2.35 mmol) was slowly added dropwise thereto and then the mixture was stirred for 30 minutes. To the mixture was added dropwise 7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran-4-one (300 mg, 0.84 mmol) dissolved in dry tetrahydrofuran (4 ml), and then the reaction mixture was slowly warmed to room temperature. After 3 hours, water was added to the reaction mixture. The reaction solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 500 mg (yield: ~100%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[NH:12][CH2:11][CH2:10][N:9]=2)=[CH:5][CH:6]=1.[H-].[Na+].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Cl>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[CH2:10][CH2:11][N:12]=[C:8]1[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc(CC2=NCCN2)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CCN=C2Cc2ccccc2)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Tolazoline (16 g, 0.1 mol) in dimethylformamide (40 ml) was added dropwise to a suspension of sodium hydride (80% dispersion in mineral oil, 3 g, 0.1 mol) in dimethylformamide (40 ml) under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes and at 65° C. for an additional 30 minutes, a solution of 2,4-dichlorobenzyl chloride (19.5 g, 0.1 mol) in dimethylformamide was added dropwise to the reaction mixture over a period of 2.5 hours. The mixture was heated to 80°-90° C. for 5 hours, cooled and concentrated under reduced pressure. Water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic phase was separated, washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure yielding a residue which was chromatographed on silica gel eluting with ammonia/methanol/ethyl acetate (3:12:85) to yield as a colorless oil, 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-phenylmethylimidazole (16 g). Treatment of the oil with ethereal hydrogen chloride yielded the hydrochloride salt of 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-phenylmethyl imidazole m.p. 185°-189° C. (Found C, 56.75; H, 4.91; N, 7.71. C17H17Cl3N2.1/4H2O requires C, 56.70; H, 5.58; N, 7.77) having the formula ##STR22##
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.C([O:18][C:19]1[CH2:23][CH2:22][C:21](=O)[CH:20]=1)C.Cl>CCOCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:21]2[CH2:22][CH2:23][C:19](=[O:18])[CH:20]=2)=[C:3]([F:10])[CH:4]=1
Reactant: CCOC1=CC(=O)CC1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1C=C(c2cc(F)c(Br)cc2F)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A solution of 27.2 g (0.1 mole) of 1,4-dibromo-2,5-difluorobenzene in 200 ml of ether was blanketed with argon and cooled to -78° C. To this mixture was added 42 ml of n-butyl lithium (2.4 M; 0.10 mole) dropwise via an addition funnel. The solution was stirred at -78° C. for 15 minutes, then allowed to warm to -45° C. To the anion was added 13 ml of 3-ethoxy-2-cyclopentenone (0.10 mole); the solution was kept at -45° for 30 minutes and was then warmed slowly to room temperature. The mixture was poured into 250 ml of 1 N hydrochloric acid, stirred for 30 minutes, and extracted with ethyl acetate; the organic phases were combined, washed with water, dried over magnesium sulfate, and concentrated. The crude product was purified via silica gel chromatography using an 80:20 chloroform ethyl acetate mixture to give 14.2 g of the desired product; mp 129°-131° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:8][OH:9])[Cl:7].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CCOCC>[CH3:10][S:11]([O:9][N:8]=[C:6]([Cl:7])[CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)C1CCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A 500 mL round-bottomed flask was charged with tetrahydrofuran-2-carbonyl chloride oxime (2.6 g, 17.4 mmol), methanesulfonyl chloride (1.4 mL, 17.4 mmol), and Et2O (200 mL). Triethylamine (2.4 mL, 17.4 mmol) was added dropwise over 1 minute and stirred at ambient temperature for 10 minutes. The solids were filtered and the filtrate was concentrated. The residue was purified on silica gel (100% CH2Cl2) to afford the title compound (2.1 g, 53.07% yield).