Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21][N:49]1[CH2:50][CH2:51][CH:46]([C:44]([C:36]2[NH:35][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])[CH2:47][CH2:48]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Agent: I
Product: COc1ccc(OC(F)(F)F)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-trifluoromethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18]CC=C)=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[CH:28]=CC=C[C:24]=1Cl>>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[C:17]([CH2:28][CH:23]=[CH2:24])[C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCOc1ccc2c(CCc3ccccc3)csc2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c(CCc3ccccc3)csc12
Temperature: 50 °C

Procedure:
The product from Step F (4.373 grams), dissolved in 1,2-dichlorobenzene (45 mL) was refluxed under nitrogen for 8.5 hours. The solution was cooled to approx. 50° C. High vacuum was applied and the solvent removed until the residue solidified. The solid was dissolved in CH2Cl2 (100 mL), recovered, re-evaporated and chromatographed over silica gel (CH2Cl2). Evaporation of the appropriate fractions gave the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[N:25]=[C:24]([Cl:26])[NH:23][C:22]2=[CH:27][CH:28]=[CH:29][C:21]=12>CN(C)C=O>[ClH:26].[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:24]1[NH:23][C:22]2=[CH:27][CH:28]=[CH:29][C:21]2=[C:20]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]2[CH3:9])[N:25]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)[nH]c2cccc1-2
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCN1c1nc(N(C)c2ccccc2)[nH]c2cccc1-2
Product: Cl
Yield: 29.1 %

Procedure:
After N-methylaniline(0.20 ml, 1.90 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chlorocyclopenta[d]pyrimidine (0.51 g, 1.70 mmol) and dimethylformamide(5 ml), 0.20 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:47][NH2:48]>ClCCl.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:48][OH:47])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A solution (3R)-6-cyclohexyl-3-(3-{[[3-(dimethylamino)propyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 84) (566 mg, 0.88 mmol) and N-methylmorpholine (390 μl, 3.52 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (340 μl, 2.64 mmol) and stirred under an argon atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (540 μl, 4.40 mmol) was added and the mixture was stirred for 4.5 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (2.5 ml) and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (20 ml), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of 97:3:0.3 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound (150 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([N:17](CC)C(C)C)(C)C.N#CBr>ClCCl.O>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl piperazine-1-carboxylate (1.517 g, 8.14 mmol) in dichloromethane (10 mL) were added N,N-diisopropylethylamine (1.54 mL, 9.00 mmol) and cyanogen bromide (911 mg, 8.60 mmol) and the reaction was stirred for 45 min at 0° C. The reaction mixture was warmed to room temperature, poured in water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was washed twice with heptane and dried in vacuo, yielding 1.24 g (5.87 mmol, 72%) of a white solid that was used directly in the next step.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([NH:16][CH2:17][C:18](=O)[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)(=[O:15])[CH3:14]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)CNC(C)=O
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only by melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C.O>CCOCC.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCCc2ccc(Cl)cc2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccc(OCCc2ccc(Cl)cc2)nc1
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenethoxy)-5-nitropyridine (1 g), ammonium chloride (1.9 g), ethanol (40 ml) and water (20 ml) is heated to 70° and then iron powder (1 g), under nitrogen, is added in small portions over about 15 minutes. Heating is continued about 2 hours after the addition of iron is complete. The reaction is cooled and stripped. The residue is taken up in ether, washed with water, dried and solvent evaporated to give 5-amino-2-(4-chlorophenethoxy)pyridine.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H][H].I[CH3:17]>CS(C)=O.O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:17]
Reactant: NCCCNc1ccccn1
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCCN)c1ccccn1
Temperature: 85 °C
Yield: 39 %

Procedure:
To a suspension of sodium hydride (0.82 g) in DMSO (20 ml) was added 2-(3-aminopropylamino)pyridine (4.7 g). The mixture was stirred and slowly heated under nitrogen to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and iodomethane (4.41 g) in DMSO (5 ml) added keeping the temperature below 35° C. After stirring for a further 30 minutes water (200 ml) was added and the resulting mixture extracted with chloroform. The extract was washed with water followed by 2N hydrochloric acid. The pH of the acid washings was raised to 14 (NaOH) and extracted again with chloroform. This final extract was dried (K2CO3) and stripped to an oil 3.84 g. Chromatography (silica gel, 10% ammoniacal methanol/dichloromethane) afforded 2-[N-(3-aminopropyl)-N-methylamino]pyridine 2.0 g (39%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[CH:31][C:23]=2[CH3:22])[NH:27][C:26]1=[O:32]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: Cc1cccc2c1CC(=O)N2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 73.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (50 mg, 73.3%) as a yellow solid.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.Cl.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[N:31]=1>CCOC(C)=O>[CH3:29][C:30]1[N:31]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([C:9]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=4)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(N2CCC(CCC3CCNCC3)CC2)n1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCC3CCN(c4cccc(C)n4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added to an acetonitrile (10 ml) solution of 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (520 mg) and TEA (0.50 ml), followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 (v/v)) to obtain methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (424 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:25][CH3:26].C=O.[C:29]([BH3-])#N.[Na+].[BrH:33]>CC(O)C.CO>[BrH:33].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:29])[CH:9]2[C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC(C)(C)C1)NCC2
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC(C)(C)C1)N(C)CC2
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-hydroxy-6-methoxy-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline (3.7 g), methanol (50 ml) and 37-40% aqueous formaldehyde solution was cooled to 5° C. Sodium cyanoborohydride (1.4 g) was added and the mixture stirred for 1.5 hours. The solvents were removed by evaporation and the residue partitioned between water and dichloromethane. The organic layer was washed with aqueous ammonia solution and then brine, dried and the solvent removed by evaporation to give a gum which was dissolved in propan-2-ol. Addition of 48% aqueous hydrobromic acid gave 7-hydroxy-6-methoxy-2-methyl-1-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 202°-204° C. (dec).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[P:17](Cl)([Cl:20])([Cl:19])=[O:18]>CCOCC>[P:17]([Cl:20])([Cl:19])(=[O:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(OP(=O)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Dry triethylamine (4.2 ml, 30 mmol) and p-methoxyphenol (3.72 g, 30 mmol) in 100 ml dry ether were added dropwise to a stirred solution of dry ether (50 ml) containing phosphorus oxychloride (2.80 ml, 30 mmol), at −78° C. under nitrogen. Following the addition, the reaction mixture was slowly allowed to warm at room temperature and stirred for one hour. The solvent was removed under reduced pressure to give the crude product (6.6 g, 92%) as an oil, which was used in the following step without any further purification.
Reaction SMILES: [F:1][C:2]([F:10])([CH:7]([F:9])[F:8])[CH2:3][N:4]=[C:5]=S.C1(=O)[N:15]([CH2:16][CH2:17][CH2:18][S:19][C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=2)C(=O)C2=CC=CC=C12.C(#[N:35])C>CN(C)C=O.N>[F:1][C:2]([F:10])([CH:7]([F:9])[F:8])[CH2:3][N:4]=[C:5]([NH2:35])[NH:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([S:19][CH2:18][CH2:17][CH2:16][NH2:15])[N:25]=1
Reactant: Nc1ccnc(SCCCN2C(=O)c3ccccc3C2=O)n1
Reactant: FC(F)C(F)(F)CN=C=S
Reactant: CC#N
Agent: N
Solvent: CN(C)C=O
Product: NCCCSc1nccc(NC(N)=NCC(F)(F)C(F)F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,2,3,3-Tetrafluoropropylisothiocyanate (0.9 g.) and 2-(3-phthalimidopropylthio)-4-aminopyrimidine (0.9 g.) were dissolved in acetonitrile (30 ml.) and heated under reflux for 64 hours. The resulting suspension was cooled, filtered and the collected solid washed with acetonitrile (10 ml.) to give a white solid (0.9 g.). This was dissolved in a mixture of dimethylformamide (10 ml.) and saturated ethanolic ammonia solution (5 ml.) and treated with yellow mercuric oxide (0.8 g.). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the black residue was triturated with ethyl acetate and filtered. The solvent was evaporated and the residual gum was dissolved in ethanol (15 ml.) and added to a solution of hydrazine (5 ml.) in ethanol (10 ml.). The mixture was stirred at room temperature for 2 hours then the solvent was evaporated. The residue was triturated with 1 N hydrochloric acid, filtered and the filtrate was basified with 10 N sodium hydroxide solution. The product was extracted with ethyl acetate, dried (magnesium sulphate) and the solvent was evaporated to give 4-[2-(2,2,3,3-tetrafluoropropyl)guanidino]-2-[3-aminopropylthio]pyrimidine (0.5 g.) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(Cl)cc(Cl)c4)c3)cnc2c1F
Yield: 2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3,5-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′,5′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (3 mg, 2%): m/z (ES+) 434 [MH+].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:13]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14]1>C(O)C>[CH2:1]([N:8]([CH2:14][C:15]1([OH:13])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)[CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: C=C(C)CNCc1ccccc1
Solvent: CCO
Product: C=C(C)CN(Cc1ccccc1)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of N-benzyl-2-methyl-prop-2-en-1-amine (0.57 g, 3.52 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.75 g, 3.52 mmol) in ethanol (4 mL) was heated at 80° C. in a sealed vial for 16 hours. The reaction mixture was cooled and concentrated in vacuo to give tert-butyl 4-[[benzyl(2-methylallyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.32 g, 100%) as a colorless oil. ESI-MS m/z calc. 374.5. Found 375.7 (M+1)+; Retention time: 1.24 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:26][CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:9]2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCN(C(=O)Cc2ccc(OCc3ccccc3)cc2)c2ccc(F)cc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A solution of N-(4-fluorophenyl)-N-{2-(3-methoxyphenyl)ethyl}-2-{4-(phenylmethoxy)phenyl}acetamide (6.0 g, 12.8 mmol) in phosphorous oxychloride (130 mL) under nitrogen was heated to 80° C. After 20 hours, the reaction was cooled to RT and very slowly poured over ice with vigorous stirring. Ethyl acetate (500 mL) was then added and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.61 g, 80% yield): ES−MS (m/z) 452 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:18])(=O)=O>C(OCC)C>[Cl:18][CH:3]([C:2](=[O:1])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)C1CCOCC1
Yield: 85.2 %

Procedure:
Using ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.0 g, 5.0 mmol), sulfuryl chloride (810 mg, 6.0 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20-B(i), the title compound (1.0 g, 85%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=CO[CH2:25][NH:26][C:27](=[O:30])[O:28][CH3:29].C(O)(=O)C>ClC(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:21][C:25]3=[N:26][C:27](=[O:30])[O:28][CH3:29])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)NCOC=N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, 5 parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.75 parts of methyl {1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}carbamate; mp. 169.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][NH2:33])[C:6]=2[CH:34]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][NH:33][C:42](=[O:44])[CH3:43])[C:6]=2[CH:34]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN)c3cc(Cl)ccc32)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.14 g) in dichloromethane (5 ml) are added with stirring triethylamine (0.08 ml) and acetyl chloride (0.03 ml) under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and thereto is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylaminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (85 mg) as colorless amorphous.