Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][O:29][CH2:30][CH2:31]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH3:4].[N:25]1([CH2:24][C:18]2([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:4]4[CH2:5][CH2:6][CH2:7][O:1][CH2:2][CH2:3]4)=[CH:13][CH:14]=3)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NCC1(c2ccc(OCCCN3CCCOCC3)cc2)CCOCC1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N
Product: c1cc(C2(CN3CCOCC3)CCOCC2)ccc1OCCCN1CCCOCC1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
C-{4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-methylamine (150 mg, 0.43 mmol) and 1-Bromo-2-(2-bromo-ethoxy)-ethane (110 mg, 0.47 mmol) were dissolved in acetonitrile (10 ml) and K2CO3 (130 mg, 0.95 mmol) was added. The solution was heated at 60° C. for 18 hours before filtering the solution to remove to the solid K2CO3. The filtrate was concentrated in vacuo before purifying using column chromatography, eluting with a gradient of DCM:MeOH:NH3 (from 99:1:0.1 to 90:10:1) to afford the title compound as a colourless oil (75 mg, 42%). 1H NMR (400 MHz, CD3OD) δ 1.80-2.00 (m, 6H), 2.11-2.20 (m, 6H), 2.41 (s, 2H), 2.69-2.79 (m, 6H), 3.48 (m, 6H), 3.72-3.80 (m, 6H), 4.02 (t, 2H), 6.87 (d, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 419.2896 [MH]+.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][Si@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[C:36]([F:47])[CH:35]=2)[CH2:30][CH2:29]1>[Cu]I.C1COCC1>[CH2:10]([Si@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][C@H:28]2[CH2:29][CH2:30][C@H:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)=[C:36]([F:47])[CH:35]=3)[CH2:32][CH2:33]2)[CH2:5][CH2:6]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Fc1ccc(-c2ccc(C3CCC(Br)CC3)cc2F)cc1
Reactant: CCCCC[Si@H]1CC[C@H](CCBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)c(F)c3)CC2)CC1

Procedure:
27.7 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 35.1 g (0.1 mol) of 4-(4-bromocyclohexyl)-2,4'-difluorobiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,4'-difluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 13.1 g (yield 29.2%) of the trans isomer.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([O:24][CH3:25])[C:8]=1[NH2:9].O>N1C=CC=CC=1>[Br:6][C:7]1[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:16])[F:17])[CH:11]=[C:10]([O:24][CH3:25])[C:8]=1[NH:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(Br)c1N
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(Br)c1NS(C)(=O)=O
Reaction time: 8 h

Procedure:
Add 2.5 g (22 mmole) of methanesulfonyl chloride dropwise to 5.5 g (15 mmole) of 2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)-6-methoxyaniline in 30 ml of pyridine below 10° C. Allow to stand overnight. Pour into H2O and decant. Dissolve the oil in Et2O, wash with 1N HCl and extract with 1N NaOH. Acidify the NaOH with HCl and extract with Et2O. Dry and concentrate. Chromatograph the oil on silica gel, eluting with CHCl3. Recrystallize from CH2Cl2 to obtain 2'-bromo-4'-(hexafluoro-2-hydroxy-2-propyl)-6'-methoxymethanesulfonanilide; m.p. 38°-41° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([CH3:28])[C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1coc2ccc(N)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2occ(C)c2c1
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (128 mg, 0.571 mmol) in dichloromethane (3 mL) was added pyridine (110 μL, 1.36 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-3-methyl-benzofuran (80 mg, 0.54 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a yellow solid (159 mg, 87%), single spot at Rf 0.65 (2:1 hexane:ethyl acetate). mp 119.5-120.1° C., HPLC purity 99% (tR 2.22 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.82 (1H, d, J=7.9 Hz), 7.54 (1H, d, J=7.9 Hz), 7.38 (1H s), 7.28-7.22 (2H, m), 7.15 (1H, t, J=8.0 Hz), 6.83 (1H, dd, J=8.7, 2.2 Hz), 6.56 (1H, s, N—H, 2.72 (3H, s), 2.15 (3H, s). LCMS: 334.07 (M−). FAB-MS (MH+, C16H14ClNO3S): calcd 335.0383, found 335.0383.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[N:13][C:12]([O:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl.O>[ClH:26].[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=[C:12]([O:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[N:13]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(c(NCc4ccc(Cl)cc4Cl)n2)CCN(Cc2ccccc2)C3)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc3c(c(NCc4ccc(Cl)cc4Cl)n2)CCNC3)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 53 %

Procedure:
7-Benzyl-4-(2,4-dichlorobenzylamino)-2-(4-toluenesulfonyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (18.7 g, 31.9 mmol) prepared according to Process Step 2 was dissolved in 1,2-dichloroethane (110 mL), and the solution was mixed with 1-chloroethyl chloroformate (14.1 mL), followed by stirring at room temperature for 40 minutes. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was diluted with water, was stirred and was extracted with ethyl acetate. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) and thereby yielded a 4-(2,4-dichlorobenzylamino)-7-(1-chloroethoxycarbonyl)-2-(4-toluenesulfonyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine fraction. After distilling off the solvent, the residue was dissolved in methanol (150 mL), followed by stirring at room temperature for two hours. After concentrating the reaction mixture, the residue was mixed with diethyl ether for crystallization. The precipitated crystals were collected by filtration, were dried and thereby yielded 4-(2,4-dichlorobenzylamino)-2-(4-toluenesulfonyloxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (7.86 g, in a yield of 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16].[H][H]>C(O)C.[Pd]>[CH2:14]([NH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)[CH:15]([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CC(C)C=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 16.1 mmol) was added to a solution of isobutyraldehyde (1.61 mL, 17.7 mmol) and 10% Pd/C (360 mg) in ethanol (60 mL) and the reaction mixture left under about 415 kPa (about 60 psi) of hydrogen gas for 18 hours. The reaction mixture was filtered through Arbocel®, washing through thoroughly with ethyl acetate. The filtrate was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with ethyl acetate:pentane 1:1 to yield the title product, 2.8 g, (73%).
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])[CH3:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[CH:7]/[C:6]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)c1ccccn1
Reaction time: 15 h

Procedure:
A solution of NaOH (12.8 mmol, 1.28 equiv.) in water (4.55 g) and ethanol (2.32 g) are introduced into a round bottom flask with a magnetic stirrer. Into the alkaline solution is placed 2-acetyl pyridine 1a (10 mmol, 1 equiv.) and the flask is rapidly surrounded by ice and the stirrer is started. The temperature reaches 10° C.-15° C. and benzaldehyde 1b (10 mmol, 1 equiv.) is added at once. The ice bath is removed and the reaction is stirred for 15 hours. The reaction is filtered. The filtrate is concentrated under reduced pressure and the product is purified by flash column chromatography on SiO2 (33% ethyl acetate/hexanes) to give the 3-phenyl-1-pyridin-2-yl-propenone 1c as a pale yellow solid. See Kohler, E. P. & H. M. Chadwell, H. M., Org. Synth., Coll. Vol. 1, 2nd ed., p. 78.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23]>CO.O.C(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=[C:3]12
Reactant: CC1=NCCn2c1ccc2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC1NCCn2c(-c3ccccc3)ccc21
Yield: 37 %

Procedure:
3,4-Dihydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine (1.1 g) was dissolved in a mixture of 50 ml of methanol and 5 ml of water under argon. The solution was treated portionwise with 0.9 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.1 g of yellow oil, was dissolved in a 10-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The separated colourless crystals were recrystallized from a 30-fold amount of methanol. There was obtained 0.5 g (37%) of 1,2,3,4-tetrahydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 153°-154° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.C([C:25]1[S:26][C@@H:27]2[CH:43]([NH:44][C:45](=[O:53])[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:42](=[O:54])[N:28]2[CH:29]([C:39](O)=[O:40])[C:30]=1[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH2:55]>ClCCl>[C:47]1([CH2:46][C:45]([NH:44][CH:43]2[C:42](=[O:54])[N:28]3[C:29]([C:39]([O:10][CH:8]([C:4]4[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:40])=[C:30]([CH:31]=[CH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:25][S:26](=[O:55])[C@H:27]23)=[O:53])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(C=Cc3ccccn3)=C(C(c3ccccc3)c3ccccc3)S[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS(=O)[C@H]12
Reaction time: 0.17 h

Procedure:
A solution of m-chloroperbenzoic acid (9.73 g) in dichloromethane (60 ml) was added dropwise to a solution of benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-2-cephem-4-carboxylic acid (trans isomer) (27.6 g) in dichloromethane (280 ml) at -25° to -30° C. and the solution was stirred for 10 minutes at the same temperature. The reaction mixture was poured into water (100 ml). The separated organic layer was washed with 2% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate-1-oxide (trans isomer) (24.5 g)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]NC(=O)CCC(N)=O>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[Br:14]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (2.50 g, 13.7 mmol) in dichloromethane (65.4 mL) and N,N-dimethylformamide (3.3 mL) was added N-bromosuccinamide (2.69 g, 15.1 mmol). The mixture was stirred at ambient temperature. After 15 min, the mixture was quenched with saturated sodium sulfite. Hydrochloric acid (1.0 M) was added and the mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated (3.65 g). LC-MS [M]=261.0.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=[N:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[O:1]1[CH2:5][CH2:4][CH:3]([NH:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NN=C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
t-butyl 2-[dihydrofuran-3(2H)-ylidene]hydrazinecarboxylate (17.26 g) was suspended in water (130 mL). Acetic acid (57.2 mL) was added to the suspension at room temperature. The mixture was stirred at room temperature for one hour. Sodium cyanoborohydride (5.36 g) was added to the solution in small portions. The mixed solution was stirred at room temperature for two hours. The reaction mixture was cooled to 0° C. The reaction mixture was neutralized by adding a 5 N aqueous sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/ethyl acetate). The title compound (15.3 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2.[Br:17]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)Cl>[Br:17][CH2:14][CH:13]1[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:16])[CH:5]=[CH:4]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Yield: 103.6 %

Procedure:
A suspension of 5-hydroxy-8-methyl-6-(2-propenyl) carbostyril (64.57 g) in chloroform (2000 ml) was combined with N-bromosuccinimide (56.47 g) and refluxed with heat for 3 hours while stirring. The reaction mixture became yellow uniform solution. The reaction solution was washed with water, dried and condensed. n-Hexane was added to the concentrate, and crystallized. 91.40 g of the title compound was obtained as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:18]#[N:19].[Na+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A mixture of 2-bromomethyl-4-bromophenyl benzyl ether (0.28 moles) and NaCN (16 g) in DMF (200 ml) was stirred at ambient temperature for 16 hours, then heated at 100° C. for 5 hours. A further 2 g of NaCN was added and the reaction heated for 5 hours at 100° C. The mixture was diluted with water (200 ml) and stirred (1 hour). The resulting solid was filtered off and recrystallised from methanol to give 4-bromo-2-cyanomethylphenyl benzyl ether (48 g) mpt. 75°-76° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4([C:26](O)=O)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[F:29].[NH:30]1[CH2:35][CH2:34]C[CH2:32][CH:31]1[CH2:36][CH2:37][NH2:38].CN([C:42]([O:46]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4([CH:26]5[CH2:34][CH2:35][NH:30][CH:31]([CH2:36][CH2:37][NH:38][CH:42]=[O:46])[CH2:32]5)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[F:29]
Reactant: NCCC1CCCCN1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2ccc(Br)c(F)c2)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2ccc(Br)c(F)c2)nc2cc(OC3(C4CCNC(CCNC=O)C4)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[4-bromo-3-fluorophenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-bromo-3-fluorophenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)carboxamide. MS: MH+=567.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([C:18]2[C:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:7]4[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]=4[CH:10]=3)=[O:16])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
The product from step (c) (8.1 g) was dissolved in THF (100 mL) and methanol (100 mL). Under stirring conditions was added LiOH (2 g) in water (100 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated in vacuo, acidified by adding 1N HCl solution. The product was extracted with ether (2×300 mL), and combined organic layers were washed with brine (2×50 mL) and then dried over MgSO4. The organic layer was then concentrated in vacuo to give the crude product which was purified by recrystallization from ether/hexane to give 7.1 g of the title compound.
Reaction SMILES: N[C:2]1[N:10]=[C:9](C)C=C(C)C=1C(N)=O.[K].[K].Br[NH:16][C:17](=O)[CH2:18][CH2:19][C:20](O)=O.Br[N:25]1[C:29](=[O:30])CC[C:26]1=O.[OH-].[K+]>O.CO>[CH3:9][N:10]1[C:26]2=[N:25][C:29](=[O:30])[NH:16][C:17]2=[CH:18][C:19]([CH3:20])=[CH:2]1
Reactant: O=C(O)CCC(=O)NBr
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(C(N)=O)c(N)n1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2[nH]c(=O)nc-2n(C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
In a 250-mL three-necked flask containing methanol (42 mL) fitted with an overhead stirrer is added 2-amino-4,6-dimethylnicotinamide (8a) (3.0 g, 0.018 mol) as a solid at 23° C. under a nitrogen atmosphere. The resulting mixture is stirred at room temperature under a nitrogen atmosphere for five minutes to dissolve 8a a completely. The solution is cooled to -20° C. before the addition of 9a. To the clear, colorless solution of 8a at -20° C. is added the solution of 9 [prepared from 0.018 mol of N-bromosuccinimide and 0.045 mol of potassium hydroxide in water (18 mL)]via a double-tipped needle under a nitrogen atmosphere. The solution of 9a must be maintained at -5° C. during the addition in order to prevent decomposition to 13 and rearrangement to 15. The resulting mixture is aged at -20° C. for 5 hours. The product 10a precipitates out of the reaction mixture during the age. The reaction mixture is filtered and the filter cake is washed with water (10 mL) and vacuum dried to afford 2.39 g of 10a as a white solid in 81% yield. The purity is 99 W % by HPLC as compared to a recrystallized sample of 10a and the A % purity is 99%. The amount of product in the mother liquors is 321 mg(11%) by assay. The mother liquor also contains 274 mg of 8a (9%) by assay. ##STR41##
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(CN)o1
Reactant: Nc1ccncc1
Reactant: Clc1ccc2c(I)cccc2n1
Product: Cc1ccc(CNc2ccc3c(Nc4ccncc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 4-aminopyridine.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CCO>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=1)[CH2:20][CH3:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A solution the compound of Example 1 Step 4 (200 mg, 0.55 mmol) in EtOH (25 mL) was treated with N-BOC-1,3-diaminopropane (240 mg, 1.38 mmol) and stirred at reflux for 6 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on SiO2 (50% EtOAc/Hexane) to afford the desired product as a yellow oil (165 mg, 66%); 1H NMR (DMSO-d6) δ 7.35 (m, 5H), 5.47 (m, 2H), 4.67 (s, 1H), 2.84 (m, 2H), 2.54 (m, 2H), 2.50 (s, 3H), 1.83 (m, 2H), 1.60 (m, 2H), 1.37 (s, 9H), 0.71 (m, 3H); (LC/MS (ESI): 456 (M+H)+.