Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=Nc1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(Nc1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 79.9 %

Procedure:
According to the general procedure, a solution of N-(1-phenylethylidene)aniline (50 mg, 0.26 mmol) and rac-32 (7.8 mg, 0.0050 mmol, 1.9 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 72 h. Filtration of the reaction mixture and evaporation of the solvent gave 42 as a clear oil (41 mg, 81%). 1H NMR28 (300 MHz, CDCl3): δ 7.50-7.35 (m, 4H), 7.30-7.25 (m, 1H), 7.15 (t, 2H, J=7.5 Hz), 6.70 (t, 1H, J=7.5 Hz), 6.59 (d, 2H, J=7.5 Hz), 4.56 (quin, 1H, J=6.6 Hz), 4.08 (bs, 1H), 1.56 (d, 3H, J=6.6 Hz); 13C NMR (75.5 MHz, CDCl3): δ 147.4, 145.4, 129.3, 128.8, 127.0, 126.0, 117.4, 113.4, 53.6, 25.2.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].ClC1C=CC=CC=1Cl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:17]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 81.4 %

Procedure:
4.5 g (27 mmol) of diphenylamine, 11.0 g (51 mmol) of p-iodotoluene, 5.5 g (40 mmol) of anhydrous potassium carbonate, and 1.1 g of copper chips were added to 30 mL of o-dichlorobenzene. The mixture was subjected to heating and refluxing for 7 hours under stirring conditions. Upon completion of the reaction, the reaction solution was filtered, the filtrate was washed with a 3-5% aqueous solution of sodium thiosulfate, and then with saturated brine. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed. The reaction mixture obtained was recrystallized with ethanol, and 4-methyltriphenylamine was obtained in an amount of 5.7 g (yield 81.4 %).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](I)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(CC)CC)C.[CH3:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>[Cu](I)I.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:41]#[C:40][C:39]([CH3:43])([CH3:42])[CH3:38])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a 25 mL RBF under nitrogen, 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (1 eq.), copper iodide (0.025 eq.) and tris(dibenzylideneacetone) dipalladium (0) (0.01 eq.) are taken. DMF, triethylamine (2.5 eq.) and 3,3-dimethyl-but-1-yne (2 eq.) are added and the reaction mixture is stirred at 40° C. for 2 h under a N2 atmosphere. The reaction mixture is filtered on celite and washed with ethyl acetate. The solution is diluted with water and extracted 2 times with ethyl acetate. The organic phases are combined and washed 3 times with water. The organic layer is separated, dried (Na2SO4), evaporated to about 2 mL and then 8 mL of heptane is added. It is evaporated to 2-4 mL and cooled in an ice bath. The formed white solid is filtered, washed with heptane and dried in oven to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:4][Cl:5])=[CH2:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:3][C:2]([CH2:4][Cl:5])=[CH2:1]
Reactant: c1ccncc1
Agent: C=C(C)CCl
Product: c1cc[nH+]cc1
Yield: 87 %

Procedure:
This compound was prepared in a yield of 87% from pyridine and β-methallyl chloride in a manner similar to that described in Example 1.
Reaction SMILES: CNCC(OC)OC.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][B-:16]([F:19])([F:18])[F:17].N#[O+]>C1COCC1>[F:15][B-:16]([F:19])([F:18])[F:17].[NH+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccncc1
Agent: CNCC(OC)OC
Agent: F[B-](F)(F)F
Agent: N#[O+]
Solvent: C1CCOC1
Product: c1cc[nH+]cc1
Reaction time: 0.33 h

Procedure:
A solution of 1-(methylamino)-2,2-dimethoxyethane (132.6 g; 1.11 mol) and pyridine (94.5 ml; 1.17 mol) in THF (1.3 ) was brought to 0°-5° C. with an ice-bath and nitrosonium tetrafluoroborate (139.5 g; 1.19 mol) was added in portions over 35 minutes. Fuming was observed and the temperature of the reaction mixture was kept below 20° C. throughout the addition. After stirring an additional 20 minutes, the white solid which had formed (pyridinium tetrafluoroborate) was filtered and CH2Cl2 and H2O were added. The organic phase was washed a second time with H2O, dried (anhyd. Na2CO3) and concentrated in vacuo at 40° C. to yield an amber oil. This oil was distilled at vacuum pump pressure (2-4 mm Hg) to yield Compound (XXVII-A), N-Methyl-N-(2,2-dimethoxyethyl)nitrosoamine (73.0 g; 44%) as a yellow liquid: bp 75°-85° C. Both TLC and NMR indicated a mixture of Z and E isomers.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[CH3:8][O:9]C(=O)OC.[O-]CC.[Na+]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][O:7][C:8]1=[O:9]
Reactant: COC(=O)OC
Reactant: OCCNCCO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCCN1CCO

Procedure:
To a stirred solution of equimolar amount of 2-(2-hydroxy-ethylamino)-ethanol and dimethylcarbonate in ethanol (10 mL/g) was added 0.1 eqv. of sodium ethoxide. The mixture thus obtained was refluxed for 3 h and cooled. The mixture was concentrated, then dissolved in dichloromethane. It was then passed through a short pad of silica gel, washed with ethylacetate successively and concentrated to obtain 3-(2-hydroxy-ethyl)-oxazolidin-2-one as colorless oil. The product was used without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCOCC1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
Ethyl cyanoacetate (22.6 g, 0.2 mol) and bis(2-chloroethyl)ether (14 g, 0.1 mol) were added to a suspension of potassium carbonate (70 g, 0.5 mol) in N,N-dimethylformamide (150 ml), and the mixture stirred at 100° C. for 72 hours. The cooled mixture was partitioned between water and diethyl ether (500 ml), the layers separated and the aqueous solution extracted with diethyl ether (3×200 ml). The combined organic solutions were washed with 2N hydrochloric acid (3×100 ml), brine (2×100 ml), dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. This crude product was purified by column chromatography on silica gel using ethyl acetate:cyclohexane (50:50) as eluant, to afford the title compound, 9.3 g.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:31])[C:19]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:18]([CH3:31])=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)c1ccc2ccccc2c1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
A suspension consisting of 45.1 g (0.288 mol) of benzamidine hydrochloride, 119.4 g (0.864 mol) of potassium carbonate, and 240 mL of tetrahydrofuran was heated under reflux for one hour, and the foregoing toluene solution of 2-bromo-2′-propionaphthone was added dropwise over 40 minutes. After completion of addition, heating under reflux was continued for 2 hours. Next, the reaction mixture was concentrated in vacuo, the resulting concentrate was diluted with 200 mL of toluene, and the solution was poured into 600 mL of water. The mixture was stirred to precipitate a solid. This solid was collected by filtration, successively washed with toluene and water, and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from acetonitrile to obtain 55.0 g (yield: 67.2%) of a white powder.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:21])=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(SCCN2CCOCC2)ccnc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(SCCN2CCOCC2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine (6.2 g) was dissolved in chloroform and thereto was dropwise added thionyl chloride (2 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice-water and made alkaline with potassium carbonate, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 6.0 g of 2-chloromethyl-3-methyl-4-(2-morpholinoethylthio)pyridine as an oily substance. The substance was added to ethanol (60 ml) containing a solution of 5-methoxycarbonyl-2-mercaptobenzimidazole (5.1 g) and sodium hydroxide (1.6 g) in water (10 ml) and the mixture was refluxed under heating for 3.5 hours. After the completion of the reaction, the ethanol was distilled away and the residue was dissolved in water. The aqueous layer was washed with chloroform and dilute hydrochloric acid was dropwise added until crystals precipitated in the aqueous layer. The resultant crystals were collected by filtration to give 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole-5-carboxylic acid 7/2 hydrate, melting point 120°-124° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)C=O)C>[Cl:8][C:7]1[C:2]([N:13]2[CH:14]=[CH:15][C:11]([C:10]([F:17])([F:16])[F:9])=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 117.5 °C
Yield: 75.1 %

Procedure:
To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-trifluoromethyl pyrazole (83 g, 0.61 mol) in dry N,N-diethylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours. The reaction was cooled to 100° C. and filtered through Celite® diatomaceous filter aid to remove solids. N,N-Dimethylformamide and excess dichloropyridine were removed by distillation at atomospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141° C., 7 mm) afforded the title compound as a clear yellow oil (113.4 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([C:15]([F:18])=[CH:16][CH:17]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[F:18][C:15]1[CH:16]=[CH:17][C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:11][C:12]=1[CH:13]=[O:14]
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1cc(Br)ccc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc(-c2ccsc2)ccc1F
Temperature: 80 °C

Procedure:
1.89 g of 3-thiopheneboronic acid (0.015 mol) are added to a solution of 3-bromo-6-fluorobenzaldehyde (2 g, 0.016 mol) in 35 ml of 1,2-dimethoxyethane, followed by addition of aqueous 2N sodium carbonate solution (3.13 g, 0.030 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.34 g, 2.96 10−4 mol). The reaction mixture is heated at 80° C. for 20 hours and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated from the black oil obtained by bulb-to-bulb distillation at 150° C. under reduced pressure (4 10−2 mmbar). 1.36 g of a pale yellow oil which solidifies are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].[O:13]1[CH2:30][CH:14]1[CH2:15][O:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>ClC1C=CC=CC=1>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[CH:20]1[C:21]2[NH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[C:17]([O:16][CH2:15][CH:14]([OH:13])[CH2:30][NH:8][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[CH:18][CH:19]=1
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Agent: O=C(O)C(=O)O
Solvent: Clc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 125 °C

Procedure:
146.4 g (0.875 moles, 2.1 mol equivalents) of 2-(2-methoxy phenoxy)ethylamine is dissolved in 500 ml of monochlorobenzene and the temperature is raised 125° C. under stirring. 100 g (0.42 moles) of 4-(2,3-epoxy propoxy)carbazole is slowly added in lots over 1 hr at reflux temperature. Reflux is then carried on for two hrs. Distilled of the monochlorobenzene under vacuum followed by cooling of the reaction mass to 50-60° C. 1000 ml isopropyl acetate is charged followed by the addition of 1000 ml DM water. pH of reaction mass is adjusted to 2.0-2.5 with 10% oxalic acid solution at 45° C.-50° C. Stirred for one hr at 45° C.-50° C., the reaction mass is cooled to room temperature and maintained for two hrs. The material is filtered washed with isopropyl acetate and water mixture and then dried at 50° C.-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:8][C:7]=2[CH:29]=1.C([S-])C.[Na+].O>CN(C)C=O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][C:7]=3[S:8][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-methoxyphenyl)methanone (410 mg, 1.02 mmol) was dissolved in anhydrous dimethylformamide (15 ml), and sodium ethanethiolate (170 mg, 2.04 mmol) was added to the resulting solution followed by stirring for 1.5 hours at a temperature of 90° C. to 100° C. under argon atmosphere. The reaction mixture was cooled to room temperature and, after addition of water, was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give (4-hydroxyphenyl)[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]methanone (323 mg, Yield 81.6%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O.[NH2:15][NH2:16].ClCCl>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCCC2)c(Cl)nn1
Reactant: NN
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCCC2)c(Cl)nn1
Yield: 27.3 %

Procedure:
A solution of 3,6-dichloro-4-(pyrrolidin-1-yl)pyridazine (53 g, 0.24 mol) and hydrazine monohydrate (105 ml, 2.2 mol) in 1,4-dioxane (820 ml) was heated at reflux overnight. The solution was allowed to cool, and dichloromethane was added, precipitating a solid. This was filtered off, affording the title compound as a pale yellow solid (14 g, 27%). The filtrate was concentrated in vacuo, and the residue purified by flash chromatography on silica gel, eluting with 2-5% methanol in dichloromethane containing 0.1% concentrated aqueous ammonia, yielding a further 5 g (4%) of the title compound. 1H NMR (250 MHz, CDCl3) δ1.98 (4H, m), 3.26 (2H, br s), 3.57 (4H, m), 6.11 (1H, s), 6.41 (1H, br s). MS (ES+) m/e 214 [MH]+, 216 [MH]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Reactant: O=Cc1cccc(B(O)O)c1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1

Procedure:
Prepared by a method analogous to that described in example 1 from (R)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and 3-formylphenyl boronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions. The aqueous layer was extracted by chloroform and evaporated to gave the title compound; MS (ES+) 341 (MH+)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:14])[CH3:13].[C:23](Cl)(=[O:25])[CH3:24]>O>[C:12]([C:16]1[CH:21]=[C:20]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Aluminium chloride (44.4 g, 333 mmol) was cooled to −45° C., followed by addition of toluene (1.25 L). 2-tert-butylphenol (50.0 g, 333 mmol) was added further and stirred for 2 hours. Further, acetyl chloride (26.1 g, 333 mmol) was added dropwise and stirred for 2.5 hours. The resultant reaction solution was added to ice-cooled water (250 mL) dropwise and stirred at room temperature. Crystals were collected by filtration and dried under reduced pressure (50° C.) to give 48.7 g of the captioned compound as white crystals (yield: 76.1%; HPLC purity: 99.8%).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][CH2:15][CH2:16][CH2:17]Br.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:14][CH2:15][CH2:16][CH2:17][N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(c2ccccc2)CCN(CCCCl)CC1
Reaction time: 1 h

Procedure:
16.0 Grams of 4-hydroxy-4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous solution and the organic layer was extracted with chloroform, then the chloroform layer was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was purified by a silica-gel column chromatography (to obtain only the main product at the upper-most portion in the column). 14.3 Grams of 1-chloro-3-(4-hydroxy-4-phenyl-1-piperidyl)propane was obtained as in the form of colorless oily substance. Then this oily substance was distilled under a reduced pressure to obtain a fraction of distillate. The fraction of distillate was made as in the form of hydrochloride and recrystallized from ethanol to obtain 1-chloro-3-(4-hydroxy-4-phenyl-1-piperidyl)propane monohydrochloride having the melting point of 192°-195° C. as in the form of colorless needle-like crystals.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:17])=O.Cl.S(=O)=O>>[C:1]([Cl:17])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCC(=O)O
Agent: Cl
Agent: O=S=O
Product: CCCCCCCCCCCC(=O)Cl
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a stirred mass of lauric acid (200 g, 0.999 gmol) and sodium N-lauroyl, N-methyl taurate (0.6 g, 0.0017 gmol) at 25° C. under nitrogen blanket, thionyl chloride (123 g, 1.03 gmol) was added slowly at 25° C. and atmospheric pressure over a period of 2 hours maintaining temperature below 25° C. The hydrochloric acid and sulfur dioxide generated during the process was continuously scrubbed in a gas scrubber containing caustic lye. The reaction mixture was stirred for additional 4 hours at the reaction temperature. The progress of reaction in the last phase was monitored by measuring alkanoyl chloride formation. Nitrogen gas was purged through the reaction mass for 3 hours to remove the residual traces of sulfur dioxide, hydrogen chloride gas and unreacted thionyl chloride. At the end of this procedure lauroyl chloride (212 g, 97%) was obtained as practically colorless product. The detailed analysis is given in the Table 13.