Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.[CH3:27][O:28][C:29]([C:31]1[N:32]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:33]=[C:34](I)[CH:35]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:27][O:28][C:29]([C:31]1[N:32]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH:33]=[C:34]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]=2[O:8][CH3:7])[CH:35]=1)=[O:30]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)cn1S(=O)(=O)c1ccc(C)cc1
Yield: 48.3 %

Procedure:
To a solution of 15 mL of 1,4-dioxane and 5 mL of water was added 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (2.05 g, 5.5 mmol) followed by 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (2.03 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (144 mg, 0.125 mmol). Upon completion of the addition, the reaction mixture was reacted at 80° C. for 30 minutes under microwave. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was diluted with 20 mL of water. After mixing well, the mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-1-(p-tolylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, yield 48%) as a grey solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[CH:39][CH:38]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1-c1ccc(N)nc1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.21 mmol) were added 70 mg (0.32 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, 19 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and 317 μl of a 2M aqueous solution of sodium carbonate in dioxane. The mixture was stirred under argon atmosphere at 80° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified first by flash chromatography (0% to 15% MeOH/DCM) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 28 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([NH:8][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][C:2]4[CH:7]=[N:6][CH:5]=[CH:4][N:3]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[N:10]1
Reactant: Clc1cnccn1
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4cnccn4)cc23)n1

Procedure:
The compound of Example 109 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloropyrazine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxyquinazoline.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.2 g (0.1 mol) of 4-hydroxybenzaldehyde, 16.6 g (0.12 mol) of potassium carbonate and 100 ml of N,N-dimethylformamide were put in a three-neck 300 ml-flask equipped with a thermometer and a stirrer and heated up to 60° C. To this mixture was dropwise added 25.0 g (0.2 mol) of 2-bromoethanol. The internal temperature rose up to 80° C. due to the reaction heat. Afterwards, the reaction system was heated and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The residue was subjected to silica gel column chromatography (using an eluent of ethyl acetate/n-hexane of 1/1) to obtain the intended 4-(2-hydroxyethoxy)benzaldehyde as an oily product. The yield of the product was 5.8 g (34.9%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8]C(C#N)=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-:13].[Na+].[CH2:15]([OH:17])[CH3:16]>>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:16]([C:15]([OH:13])=[O:17])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CCO
Reactant: [OH-]
Reactant: COc1cc(N)c(F)cc1C#N
Agent: [Na+]
Product: COc1cc(N)c(F)cc1C(=O)O
Temperature: 110 °C
Yield: 80 %

Procedure:
To a solution of 4-amino-5-fluoro-2-methoxybenzonitrile (intermediate 88; 5.3 g, 0.03 mol) in ethanol (20 mL) was added sodium hydroxide 8M (27.9 mL, 0.22 mol), the mixture was placed in a sealed vessel and heated to 110° C. for 20 hours. The solvent was removed under reduced pressure and the crude obtained was partitioned between water and ether. The aqueous layer was acidified by hydrochloric acid 6N until pH 4 and the crude was extracted with ethyl acetate, dried, filtered and evaporated under reduced pressure giving the title compound as a yellow solid (80%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[C:9](O)[CH:10]=[CH:11][CH:12]=1.C1(C(=CC=CC=1)O)[OH:20]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[OH:20]
Reactant: Oc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: Oc1ccccc1O
Product: Oc1ccccc1Oc1cccc(C(F)(F)F)c1

Procedure:
Then, 1-chloro-4-(1,1,1,2,2-pentafluoroethylsulfonyl)benzene was prepared as follows: ##STR19## 64 g of 1-chloro-4-(1,1,1,2,2-pentafluoroethylthio)benzene and 250 mL of glacial acetic acid were placed into a flask and stirred to form a mixture. While stirring, 250 mL of a 30% H2O2 /water solution was added dropwise. After this addition, the mixture was stirred for four hours at reflux and allowed to cool to room temperature. GC analysis showed reaction was complete. The resulting solids ("first product solids") were filtered off and rinsed with water. The filtrate was poured into 500 ml of water, stirred, and extracted with 300 mL of methylene chloride to form an aqueous phase and a methylene chloride product phase. The methylene chloride product phase was separated, dried by passing it through sodium sulfate, and low boilers were distilled off. The resulting product phase was combined with the first product solids and distilled at 80°-85° C. and 1.0 mm Hg to produce a total of 62 g of white solids having a melting point of 37°-38° C. The white solids were confirmed by GC-MS analysis as 1-chloro-4-(1,1,1,2,2-pentafluoroethylsulfonyl)benzene. ##STR20## 2-(3-trifluoromethylphenoxy)phenol was prepared by a procedure identical to the one described above for preparing 3-(3-trifluoromethylphenoxy)phenol, with the exception that catechol (Aldrich Chemical Company) is used in place of resorcinol.
Reaction SMILES: [I-].C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=O)C.I[C:15]1[CH:20]=[CH:19][CH:18]=CC=1.Br[C:22]1C=CC=C[N:23]=1>>[CH3:18][C:19]1[CH:20]=[CH:15][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:23][CH:22]=1
Reactant: Ic1ccccc1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Reactant: Brc1ccccn1
Agent: [I-]
Product: Cc1ccc(-c2ccccc2)nc1

Procedure:
Following the procedure of Preparation 2(a), except substituting 5-methyl-2-pyridinylzinc bromide for 4-(ethoxycarbonyl)phenylzinc iodide and iodobenzene for 2-bromopyridine. afforded the title compound.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22]C[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.[CH3:34]C#N>>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:34][CH2:31][O:30][C:28]([C:27]3[CH:32]=[CH:33][CH:24]=[CH:25][CH:26]=3)=[O:29])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC#N
Product: O=C(OCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2)c1ccccc1
Product: [Br-]
Yield: 7 %

Procedure:
Following the general procedure outlined in Example 1, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (32.2 mg, 0.115 mmol) and methyl 4-(bromomethyl)benzoate (0.03 mL, 0.19 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (4 mg, 7%). EI-MS m/z 428 (M+) Rt (1.69 min).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])[CH3:10].[Br:33]Br.CCOCC>C(O)(=O)C>[BrH:33].[C:9]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:25])[CH2:22][CH2:23]2)=[C:16]([Br:33])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(N2CCC(N(C)Cc3ccccc3)CC2)cc1
Reactant: BrBr
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Br
Product: CC(=O)c1ccc(N2CCC(N(C)Cc3ccccc3)CC2)c(Br)c1
Reaction time: 4 h
Yield: 183.7 %

Procedure:
2.5 g (7.9 mmol)of the product from Example 17 were dissolved in 50 ml of glacial acetic acid and, at room temperature, 1.26 g (7.9 mmol) of bromine dissolved in 10 ml of glacial acetic acid were added dropwise. The mixture was stirred for 4 hours, after which ether was added, whereupon crystals slowly separated out. The crystals were filtered off and washed with ether. 3.5 g of 1-(4-acetyl-2-bromophenyl)-4-(N-benzyl-N-methylamino)piperidine hydrobromide were obtained. Melting point 201°-202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[NH2:11].[CH3:21][N:22]([CH3:27])[C:23](=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>C1COCC1>[NH2:11][C:7]1[C:6]2[C:10](=[C:2](/[CH:25]=[CH:24]/[C:23]([N:22]([CH3:27])[CH3:21])=[O:26])[CH:3]=[CH:4][C:5]=2[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[NH:9][N:8]=1
Reactant: Nc1n[nH]c2c(Br)ccc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: C=CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)/C=C/c1ccc(-c2ccc([N+](=O)[O-])cc2)c2c(N)n[nH]c12

Procedure:
A mixture of Example 84B (165 mg), N,N-dimethylacrylamide (0.102 mL), triethylamine (0.207 mL), and Pd(o-tol3P)2Cl2 (30 mg) in THF (2 mL) in a sealed tube was heated in a Smith Synthesizer microwave oven (at 300 W) to 150° C. and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide 163 mg of the desired product. MS (ESI(+)) m/e 352 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(=O)(O)[O-].[K+].Br[C:20]1[CH:21]=[CH:22][C:23]2[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][C:24]=2[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:20]2[CH:21]=[CH:22][C:23]3[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][C:24]=3[CH:37]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Temperature: 90 °C
Yield: 63.1 %

Procedure:
To a solution of 4-(methoxycarbonyl)phenylboronic acid (6.0 g, 33 mmol), potassium bicarbonate (9.1 g, 92 mmol), 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (10 g, 31 mmol) and DIPEA (16 mL, 92 mmol) in dioxane (27 mL) and water (3 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (1.3 g, 1.8 mmol). The biphasic mixture was then heated at 90° C. for 2 h then partitioned with ethyl acetate and 1M hydrochloric acid. The organic layer was washed with 1M sodium hydroxide solution then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate in hexanes) to provide 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (7.5 g, 64% yield) as a pale yellow solid. MS (EI) for C26H23FN6O3: 384 (MH+).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Na].[S:9]([CH2:13][CH2:14]O)([OH:12])(=[O:11])=[O:10]>>[OH:4][CH2:3][CH2:2][N:1]([CH:13]([S:9]([OH:12])(=[O:11])=[O:10])[CH3:14])[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: O=S(=O)(O)CCO
Agent: [Na]
Product: CC(N(CCO)CCO)S(=O)(=O)O
Temperature: 93.33333333333333 °C
Yield: 100 %

Procedure:
In a preferred embodiment, diethanol amine is charged to the reaction vessel in a substantially equal molar quantity to a 54 percent aqueous solution the sodium salt of isethionic acid. The reactants then are heated to a temperature of about 200° F. at ambient temperature for a sufficient period of time to separate about 38 percent by weight of the reactants as water in the cold finger trap. The bis-hydroxyethylaminoethane sulfonic acid which is produced in about a 100 percent yield is diluted to about a 50 percent solution by the addition of water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCCC1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>CCOCC.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: c1ccncc1
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)N1CCCCC1

Procedure:
A solution of 120 g of dry pyridine, 103.2 g of piperidine and 1.5 liters of dry ether was stirred vigorously as 215.7 g of freshly distilled 4-chlorophenyl acetyl chloride in 250 ml of ether was added dropwise. After 4 hours the mixture was diluted with one liter of water and the organic phase collected. The aqueous phase was extracted with ether and the ether phases were combined, washed successively with 0.1N hydrochloric acid twice, 5% sodium hydroxide twice, saturated sodium chloride twice, dried and concentrated in vacuo. The residual oil was taken up in dichloromethane and percolated through a bed of neutral alumina with additional solvent. The resulting oil was crystallized from carbon tetrachloride:hexane (1:9), giving 243 g of N-(4-chlorophenylacetyl)piperidine as yellow crystals, mp 85°-85.5° C. A mixture of 200 g of N-(4-chlorophenylacetyl)piperidine, 94 g of phosphorous pentasulfide and 750 ml of pyridine was heated at reflux with vigorous stirring for 18 hours, then cooled and concentrated in vacuo. The residue was taken up in 1.8 liters of water, heated at 50° C. for 30 minutes, cooled and exhaustively extracted with ether. The ether extracts were combined, washed successively with water, 5% hydrochloric acid twice and saturated sodium chloride and dried. The solution was percolated through a bed of neutral alumina followed by elution with ether. The resulting oil was crystallized twice from methylcyclohexane, giving 100 g of N-(4-chlorophenylthioacetyl)piperidine as orange crystals, mp 82.5°-83.5° C.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.C(N(CC)CC)C.CS([Cl:30])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:30][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCN2CCCC[C@@H]2CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCN2CCCC[C@@H](Cl)C2)c1
Reaction time: 18 h

Procedure:
(R)-2-Hydroxymethyl-1-(3-methoxyphenethyl)piperidine (322 mg, 1.28 mmol) was dissolved in 10 ml of dichloromethane. Triethylamine (170 mg, 1.68 mmol) and methanesulfonyl chloride (192 mg, 1.68 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 18 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(3-methoxyphenethyl)homopiperidine in the form of a light yellow oil (182 mg, 53%).
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH2:20](O)[CH:21]=[CH:22]C>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][CH:20]=[CH:21][CH3:22])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CC=CCO
Product: CC=CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (6.0 g., 23.5 mmoles) was stirred with 15 ml. of 2-buten -1-ol for 1.5 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ice-cold ether and washed twice with ice-cold portions of 10% aqueous acetic acid, water and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil was distilled to give 2-buten-1-yl 9-xanthenyl ether, b.p. ca. 110°C. at 0.01 mm.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].O1CCOCC1.O.C(N(CC)CC)C.[C:29]([O:33][C:34](N=[N+]=[N-])=[O:35])([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:33][C:34]([C:2]([NH2:1])([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N)(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (192 mg, 1 mmole) is added to 10 ml of 1:1 dioxane-water mixture with 4 mM of triethylamine and 0.17 or tertbutoxycarbonylazide. This mixture is stirred overnight at room temperature. The mixture is diluted with water and extracted with chloroform. The chloroform is dried and evaporated. The residue is taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The organic layer is dried over magnesium sulfate and evaporated to give the title compound in a yield of about 80%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]([C:21]2[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=[CH:23][CH:22]=2)[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].I[CH3:33]>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH:15]([C:21]2[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:24]=[CH:23][CH:22]=2)[CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[CH3:33])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(C#N)cc1)c1ccnn1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)C(c1ccnn1-c1ccccc1)N(C)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a suspension of NaH (16.3 mg, 4190 mol, 60% dispersion in mineral oil) in THF (300 μL) at 0° C. was added a solution of 4-cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide (example 37, 140 mg, 340 μmol) in THF (600 EL). The reaction mixture was warmed to room temperature, and after 20 min iodomethane (45 μL, 714 μmol) was added. The mixture was allowed to stir overnight. TLC indicated that the reaction was not complete. Additional aliquots of NaH and iodomethane were added until the reaction was driven to completion. The mixture was then quenched with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:1) provided 89 mg (57% yield) of the title compound as a glassy yellow solid. mp 37.8-54° C.; Mass Spectrum (ES): 481.1;
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CC1CCCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CC1CCCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and 2-methyl-piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 3.4-3.78 (m, 15H), 1.6-2.1 (m, 6H), 1.46 (d, J=6.3 Hz, 3H); MS (DCI) m/z 433 (M+H)+;
Reaction SMILES: [CH3:1][N:2]([C:19](=[O:22])[CH2:20]Cl)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17].[SH:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>CO>[ClH:9].[CH3:1][N:2]([C:19](=[O:22])[CH2:20][S:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: Sc1ncc[nH]1
Solvent: CO
Product: CN(C(=O)CSc1ncc[nH]1)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: Cl

Procedure:
A suspension of 10.68 grams of N-methyl 2'-orthochlorobenzoyl-2,4'-dichloroacetanilide and 2.4 grams of 2-mercaptoimidazole are treated for 8 hours under reflux with methanol. After cooling, evaporation under vacuum, and taking up by an acetone-ether mixture, there is obtained by crystallization the hydrochloride of N-methyl 2'-orthochlorobenzoyl-4'-chloro 2-[(2-imidazolyl)thioacetanilide (9.12 g).