Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7](F)=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4].[CH3:22][NH:23][CH3:24]>CN(C)C=O.O>[CH3:22][N:23]([CH3:24])[C:7]1[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1
Reactant: CNC
Reactant: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(F)cc1OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(N(C)C)cc1OCC
Temperature: 50 °C
Yield: 95.3 %

Procedure:
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (1.02 g, 3.20 mmol) was taken up in 5 mL of anhydrous dimethylformamide. Dimethylamine (8.0 mL, 15.9 mmol) was added and the reaction mixture was heated at 50° C. for 16 h. The reaction was allowed to cool to room temperature and diluted with water. The product was extracted three times with methylene chloride. The combined organics extracts were washed with brine, dried over magnesium sulfate and concentrated to give ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxy-benzoate as a tan solid (1.05 g, 95%). LC-MS: 345.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH3:32][O:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[C:6]=2[N:20]=1)[C:26]([OH:28])=[O:27]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CCCC1N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1C)CCC(=O)N2C
Yield: 68.2 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-57), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.087 g of (rac)-3-methoxy-4-[5-methyl-9-(2-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-57a) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12](O)=[O:13])[CH:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].B.O1CCCC1.O>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(CC(=O)O)CCN1C(=O)OCC
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of 10 g of 1-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine-3-acetic acid in 50 ml tetrahydrofuran is cooled to 0° and 55 ml of borane/tetrahydrofuran (1 M) is added dropwise. After stirring 2 hours at 0°, 20 ml of water is added, the mixture is extracted with ethyl acetate, washed twice with water and dried over sodium sulfate. The solution is filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:1 to 7:3) to yield cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([N:19]([CH3:21])[NH2:20])[CH:14]=[N:13]1.[CH3:22]OC(OC)N(C)C>CN(C)C=O>[CH3:21][N:19]1[C:15]2[C:14](=[N:13][N:12]([C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:6]=[CH:7][C:2]=3[F:1])[C:17](=[O:18])[CH:16]=2)[CH:22]=[N:20]1
Reactant: CN(N)c1cnn(-c2cc(C(F)(F)F)ccc2F)c(=O)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2nn(-c3cc(C(F)(F)F)ccc3F)c(=O)cc21

Procedure:
In 250 ml. of absolute dimethylformamide (dried over molecular sieves) under a nitrogen atmosphere, are dissolved 14.5 grams of 2-(2-fluoro-5-trifluoromethylphenyl)-5-(1-methylhydrazino)-3(2H)-pyridazinone. To this solution are added 11.4 grams of N,N-dimethylformamide dimethyl acetal and the solution is heated at 110°-120° C. overnight. The progress of the reaction is followed by thin layer chromatography. An additional 6.0 grams of N,N-dimethylformamide dimethyl acetal is added with continued heating to complete the reaction (about 20 hours). The reaction mixture is then evaporated to dryness in vacuo and then column chromatographed on silica gel, eluting with a mixture of benzene-chloroform (50/50), to obtain the title product. (m.p. 190°-195° C.).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](Cl)=O>O1CCCC1>[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30]1[O:4][CH2:3][CH:2]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NC(CO)COc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1C1=NC(COc2ccc(Oc3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a mixture of 1.14 g (4.40 mmol.) of 2-amino-3-(4-phenoxyphenoxy)propanol, 0.58 g (5.72 mmol.) of triethylamine and 20 ml of anhydrous tetrahydrofuran, there was added dropwise a solution of 0.78 g (4.40 mmol.) of 2,6-difluorobenzoylchloride in 10 ml of anhydrous tetrahydrofuran with stirring at a temperature of from 5° C. to 10° C. for 5 minutes. After addition, the reaction mixture was stirred at room temperature for 2 hours. The above mixture was filtrated with a filter glass to remove the resultant precipitate and the filtrate was concentrated under reduced pressure. To the residue, there was added 20 ml of toluene and 10 ml of thionyl chloride and the reaction mixture was refluxed by heating with stirring for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 20 ml of methanol and further added dropwise 1 ml of a 5N aqueous solution of sodium hydroxide with stirring at a temperature of 60° C. for 5 minutes. Then the reaction mixture was stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 100 ml of ethyl acetate. The mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 1.28 g of 2-(2,6-difluorophenyl)-4-[(4-phenoxyphenoxy)methyl]-2-oxazoline as a colorless oily substance (nD19.1 1.5814).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]([CH2:19][CH2:20][CH3:21])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[CH:27](OC(=O)C)=[O:28]>ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:10]=2)[C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: CCCc1c(C(=O)C(C)C)c2ccc(NC=O)cc2n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (147 mg) in dichloromethane (2 ml) was added acetic formic anhydride (0.5 ml) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then diluted with dichloromethane. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:2) to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzyl)-6-formamido-3-isobutyryl-2-propylindole (85 mg) as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C1(C)C=CC=CC=1.Cl[C:17]1[O:18][C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1.C(N(CC)CC)C>>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17]1[O:18][C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]([C:22]([F:24])([F:23])[F:25])[N:21]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
By the procedure of Example 15, 4.19 g (0.03 mol) of glycine ethyl ester hydrochloride was added to a mixture of 100 ml toluene containing 4.87 g (0.02 mol) of ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 6.07 g (0.06 mol) of triethylamine. The reaction mixture was stirred at ambient temperature for 48 hours. The product was separated and then recrystallized from methylcyclohexane to yield 3.55 g of a yellow powder product (m.p.=62°-63° C.) identified in Table I.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[N:15]([CH3:19])[C:16](=[O:18])[CH3:17].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:19][N:15]([C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:21][CH:20]=1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)N(C)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N(C)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 24.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.96 g) and 3′-amino-N-methylacetanilide (2.03 g) in toluene (20 ml) was refluxed for 7 hours. The mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(N-methylacetamido)phenylamino]-3-nitropyridine (872 mg).
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClCCN1CCOCC1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCN2CCOCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 190° C. and MS: m/e=483.6 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and N-(2-chloroethyl)-morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].ClCCl.C(Cl)(=O)C(Cl)=O.C[N:24](C)C=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:24])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid (15.0 g, 74.0 mmol) and 200 mL of dichloromethane was reacted with oxalyl chloride (16.2 mL, 186.0 mmol) and a catalytic amount of dimethylformamide. The mixture was stirred at 25° C. for 3 hours. The solvent was removed in vacuo, and the residue was redissolved in 200 mL of dichloromethane. The solution was cooled to 0° C., and ammonia was bubbled through the cold solution for 5 minutes, whereupon the product precipitated to form solution. The product was collected by filtration to yield 6.8 g, mp 174°-175° C.
Reaction SMILES: N(=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])O.S(=O)(=O)(O)[OH:14]>C=O>[O:14]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(=NO)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: C=O
Product: O=C(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 Grams of α-oximinophenylacetic acid is dissolved in 9 ml of 37% formaldehyde containing a few drops of sulfuric acid. This is stirred overnight at RT, extracted with 3:1 ether:hexane, washed with brine, dried over sodium sulfate, stripped and distilled to yield the final product α-oxophenylacetic acid, b.p.=138°-141°/3.3 mm.
Reaction SMILES: [S:1]1[CH2:6][S:5][CH2:4][S:3][CH2:2]1.[Li].[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([OH:14])[CH:2]2[S:3][CH2:4][S:5][CH2:6][S:1]2)=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1SCSCS1
Agent: [Li]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1SCSCS1
Temperature: -60 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 2.6 g of 1,3,5-trithiane, and 12 ml of 1.6M n-bytyl lithium was added dropwise under an argon atmosphere at a temperature of about -20° C. After completion of the dropwise addition, the resulting mixture was stirred for 2 hours. Next, the reaction mixture was cooled to about -60° C., and then a solution of 4.4 g of 4,4'-difluorobenzophenone dissolved in 100 ml of tetrahydrofuran was dropped thereinto. After completion of the dropping, the reaction temperature was slowly raised to 0° C. After stirring at 0° C. for another 1 hour, the reaction mixture thus obtained was poured into ice water and the resulting mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product thus obtained was recrystallized from ether-hexane to give 5.58 g of the desired compound.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[N:44][CH:45]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:42]4[CH:43]=[N:44][CH:45]=[C:40]([O:39][CH3:38])[CH:41]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: COc1cncc(B(O)O)c1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: COc1cncc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)c1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (5-methoxypyridin-3-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=528, obsd.=528).
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:18][S:19][C:15]=2[CH:14]=1)C1C=CC=CC=1.O>C(Cl)Cl>[CH:20]1([C:17]2[C:16]3[CH:26]=[CH:27][C:13]([OH:12])=[CH:14][C:15]=3[S:19][N:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(COc2ccc3c(C4CCCCC4)nsc3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2c(C3CCCCC3)nsc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
A solution of boron tribromide 1M in CH2Cl2 (11.9 ml, 11.9 mmoles) was slowly added to a solution of 6-benzyloxy-3-cyclohexyl-1,2-benzisothiazole (3.5 g, 10 mmoles) in CH2Cl2 (50 ml) at 0° C. The mixture was stirred at room temperature for 15 min and poured into water. The precipitate was filtered, dried and crystallised from EtOH to give pure 3-cyclohexyl-1,2-benzisothiazol-6-ol (940 mg, 40.3%). mp 190° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:24](=[O:26])[CH3:25])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 0 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of (±)-cis-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50.0 mmol, 11.6 g) in anhydrous DCM (500 mL) at room temperature was added triethylamine (100 mmol, 14.0 mL). The reaction mixture was cooled to 0° C. using an ice bath. To this was added acetic anhydride (50.0 mmol, 4.72 mL) dropwise over 10 minutes. After completion of addition, the reaction was stirred for 12 hours while slowly coming to room temperature. All volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with saturated NaHCO3 (2×50 mL), water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 110 g SiO2 cartridge using ethyl acetate/hexanes gradient to provide (±)-cis-4-acetoxymethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (12.3 g).
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.[C:24]1([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.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>[C:36]1([CH:32]2[CH2:33][CH2:34][CH2:35][CH:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:31]2[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc(C2CCCC(c3ccccc3)N2)cc1
Reactant: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=CCN1C(c2ccccc2)CCCC1c1ccccc1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-acetoxy-4-dibenzylamino-2-butene (3.0 g, 9.8 mmol) and 2,6-diphenylpiperidine (2.3 g, 9.8 mmol) in THF (25 ml) is treated with tetrakis(triphenylphosphine)palladium (0) (0.5 g, 0.45 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo. The residue is redissolved in THF (100 ml) and treated with 20% aqueous sodium hydroxide (25 ml). The mixture is stirred for one hour, concentrated, and extracted with diethyl ether. The ether extracts are dried and concentrated to give an orange oil which is purified by chromatography (silica gel; 5% ethyl acetate in hexanes) to give the title compound in a yield of 2.8 g (59%) as a clear oil. MS m/z 486 (M+)
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].CCN(CC)CC>C1COCC1>[Cl:25][CH2:26][C:27]([NH:24][C:8]1[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1NC(=O)CCl

Procedure:
The title compound was prepared by acylation of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with chloroacetyl chloride, NEt3 in THF at room temperature. A tan solid was isolated, mp. 79–82° C. Anal. For C22H30CIN3O2 calc. C, 65.41; H, 7.49; N, 10.40; found: C, 65.56; H, 7.62; N, 10.98.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>O>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=4[Cl:1])=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccc(Cl)c1Cl
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1M NaHCO3 and water then dried over Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C1CNCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCCNCC1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
The 1-(4-trifluoromethylphenylsulphonyl)homopiperazine was prepared as follows. 4-Trifluoromethylphenylsulphonylchloride (1.5 g) in 20 ml dichloromethane was added dropwise to 5 g homopiperazine and 1.8 ml triethylamine in 55 ml dichloromethane and left stirring overnight. Washed with water and brine, dried (MgSO4), and evaporated to give 1-(4-trifluoromethylphenylsulphonyl)homopiperazine (1.80 g) as a colourless solid; NMR (CDCl3) 1.75 (1H,br), 1.78-1.9 (2H,m), 2.9-3.0 (4H,m), 3.3-3.44 (4H,m), 7.78 (2H,d),
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>ClCCl>[ClH:23].[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1ccccc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (16.3 g, 53 mmol) in dichloromethane (100 mL), add a solution of 4 M HCl in 1,4-dioxane (40 mL, 159 mmol) and stir the reaction mixture at room temperature overnight. Add Et2O to the resultant white suspension and evaporate solvents under reduced pressure to give 12.6 g of (2-fluoro-phenyl)-piperazin-1-yl-methanone hydrochloride. ES+ (m/z) 209[M+H]).