Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]1(C)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1(C2CCCCC=2)CCCC1.[OH2:29]>>[CH2:1]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]1=[O:29])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: Cc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Reactant: O
Agent: C1=C(N2CCCC2)CCCC1
Product: O=C(CC1CCCCC1=O)c1ccccc1

Procedure:
A solution of 60.9 g (0.31 mole) of phenacyl bromide in 150 ml. of toluene was added dropwise with stirring to a refluxing solution of 46.6 g. of 1-pyrrolidino-1-cyclohexene in 150 ml. of toluene. The mixture was heated under reflux for 2 hours, diluted with 150 ml. of water, refluxed for 3 hours and cooled. The layers were separated, and the aqueous phase was extracted with ether. The organic solution was dried and concentrated to an oil. Distillation gave 42.1 g. (64%) of orange liquid, b.p. 135°-141° (0.05 mm.), which solidified. Recrystallization from ether-petroleum ether gave tan crystals, m.p. 44°-45°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[I:9]I.C([O-])(O)=O.[Na+]>CC(O)=O.O>[I:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=1
Reactant: CNc1ccccn1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(I)cn1
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a solution of 2-methylaminopyridine (Aldrich; 1.00 g, 9.25 mmol) in 10 mL of 1:1 HOAc and water was added 2.35 g (9.25 mmol) of I2. The resulting brown solution was heated to 80° C. for 3 h. After cooling to room temperature, the mixture was neutralized with saturated NaHCO3 and extracted with Et2O. The extract was washed with water and brine, dried with MgSO4, filtered, and concentrated to provide 540 mg of (5-iodo-pyridin-2-yl)-methyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate, hydrochloride (71 g), and potassium hydroxide (38 g) in ethanol (450 ml) was refluxed for 6 hours. After cooling inorganic salts were filtered off and ethanol evaporated in vacuo. To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml). The organic phase was separated and worked-up as above. Yield of crude title product: 45 g (semicrystalline).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:8]1[C:9](Cl)=[N:10][C:11]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH3:7].B(O)(O)[C:29]1[CH:30]=[CH:31][C:32](C)=[CH:33][CH:34]=1.[CH:38](N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:29]1([C:9]2[C:8]([CH:4]([CH2:5][CH2:6][CH3:7])[C:3]([O:2][CH3:1])=[O:27])=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:38])=[CH:16][CH:15]=3)[N:12]=[C:11]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:10]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 17.8 %

Procedure:
methyl-2-(4-chloro-6-phenyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.031 g; 0.228 mmol), p-tolylboronic acid (0.031 g; 0.228 mmol), tetrakis(triphenylphosphine) palladium(0) (0.013 g; 0.011 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (0.75 mL) and water (0.25 mL). N,N-Diisopropylethylamine (0.060 mL; 0.344 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 30 min. The reaction mixture was partitioned between a solution of hydrochloric acid 1N and ethyl acetate. The phases were separated and the organic phase was washed with a 1N sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (0-10%) in heptane to give 0.018 g (45%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:7]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>CC(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: Brc1cncc(OCC2CO2)c1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: OC(COc1cncc(Br)c1)Cn1cnc2ccccc21
Yield: 49.8 %

Procedure:
A solution of Example 436A (500 mg, 2.17 mmol) and 1H-Benzoimidazole (28 mg, 2.39 mmol) in 2-propanol (10 mL) was refluxed under N2 for 2 hrs. The reaction mixture was cooled, diluted with ethyl acetate(50 mL) and washed with brine (2×25 mL). The residue was concentrated and purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to 5% methanol/ethyl acetate to provide the desire product (1.08 mmol, 50%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([F:10])[C:3]=1[Cl:11].[NH3:12]>C(#N)C>[NH2:12][C:6]1[C:7]([F:8])=[C:2]([Br:1])[C:3]([Cl:11])=[C:4]([F:10])[N:5]=1
Reactant: N
Reactant: Fc1nc(F)c(Cl)c(Br)c1F
Solvent: CC#N
Product: Nc1nc(F)c(Cl)c(Br)c1F
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 20 ml of acetonitrile were added 4.9 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 4 ml of 25% aqueous solution of ammonia, and the mixture was stirred at 55° C. for 2 hours. The solvent and the like were distilled off under reduced pressure. 50 ml of chloroform was added to the residue, and the solution was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dispersed in the mixed solution of diisopropylether and n-hexane and collected by filtration to obtain 3.8 g of the title compound as pale yellow needle crystals. 5
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(#N)C.CN(C=O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 6-chloro-2-methoxy-3-nitropyridine (283 mg, 1.5 mmol) in acetonitrile/DMF (2:1, 3 mL) was added morpholine (0.13 mL, 1.5 mmol) and triethylamine (0.21 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% cyclohexane in EtOAc to give the title compound (280 mg, 78%). 1H NMR (500 MHz, CDCl3): δ 8.28 (d, J=9.0 Hz, 1H), 6.16 (d, J=9.0 Hz, 1H), 4.04 (s, 3H), 3.82 (t, J=4.5 Hz, 4H), 3.71 (t, J=4.5 Hz, 4H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:14]=[CH:15][C:16]([C:18](O)=[O:19])=[CH:17][C:12]=2[C:11]2[C:10](=[O:21])[NH:9][CH:8]=[CH:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH:1]([C:4]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:24])=[O:19])=[CH:17][C:12]=2[C:11]2[C:10](=[O:21])[NH:9][CH:8]=[CH:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1nc2cc[nH]c(=O)c2c2cc(C(=O)O)ccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc[nH]c(=O)c2c2cc(C(N)=O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carboxylic acid (78 mg, 0.28 mmol) in DMF (1.0 mL) was added 1,1′-carbonylbis(1H-imidazole) (CDI, 68 mg, 0.42 mmol). The reaction mixture was stirred for 1 hour at room temperature. Ammonium hydroxide (0.19 mL, 1.3 mmol) was added, and the resulting mixture was stirred for 15 minutes. The reaction mixture was diluted with DMF and purified directly by preparative reverse phase HPLC, eluting with an acetonitrile/water (with 0.05% TFA modifier) gradient to afford 6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carboxamide. 1H NMR (500 MHz, DMSO-D6) δ 11.86 (s, 1H), 10.46 (s, 1H), 8.50 (d, 1H), 8.20 (s, 1H), 8.09 (d, 1H), 7.61 (s, 1H), 7.56 (t, 1H), 6.78 (d, 1H), 4.12 (septet, 1H), 1.37 (d, 6H). LRMS (ESI) calc'd for (C16H15N3O2) [M+H]+, 282.1; found 282.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CC#N>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:17])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 6-nitroindole (4.9 g 30 mmol) in DMF (24 mL) and CH3CN (240 mL) was added dropwise a solution of ClSO2NCO (5.0 mL) in CH3CN (39 mL) at 0° C. After addition, the reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was then poured into ice-water and basified with sat. NaHCO3 solution to pH 7-8. The mixture was extracted with ethyl acetate. The organics were washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:8]=3[O:7][C:6]=2[CH:15]=1.[Cu][C:17]#[N:18].[CH3:19][N:20](C=O)C>>[C:19]([C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:17]#[N:18])=[CH:13][C:8]=3[O:7][C:6]=2[CH:15]=1)#[N:20]
Reactant: N#C[Cu]
Reactant: Brc1ccc2c(c1)oc1cc(Br)ccc12
Reactant: CN(C)C=O
Product: N#Cc1ccc2c(c1)oc1cc(C#N)ccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.43 %

Procedure:
A suspension of 3,7-dibromo-dibenzofuran (18, 10.27 g, 31.51 mmol) and copper(I) cyanide (8.23 g, 94.5 mmol) in DMF (80 mL) was refluxed under N2 for 6 h. The reaction mixture was poured into ice-water (300 mL). The precipitated solid was collected and stirred for 5 h in a solution of ethylenediamine (50 mL) in water (300 mL). The solid was filtered off, washed with water, then stirred in 10% sodium cyanide solution (100 mL) for 4 h. The solid was further purified by suspension in hot ethanol (100 mL) to give a pale yellow powder (6.69 g, 97.43%): mp 322-325° C. (dec.); HPLC method 3 tR=16.56 min (96.6 area %); 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=8.3 Hz, 2 H), 8.48 (s, 2 H), 7.95 (dd, J1=8.3 Hz, J2=1.0 Hz, 2 H); EI-MS m/z 218 (M+). Anal. (C14H6N2.0.23H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:26]([O:27][CH2:28][CH3:29])=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([OH:23])[CH:16]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:30][CH2:31][CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH2:31][CH3:32])=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:15]3[CH:16]=[C:17]([O:23][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:24])[CH2:9][CH2:8]2)=[CH:25][C:26]=1[O:27][CH2:28][CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 72a), N-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 258) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 541.2 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:14]1[CH:28]=[CH:27][C:17]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1.[C:29]([OH:32])(=O)[CH3:30]>N1C=CC=CC=1>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10]([C:11](=[O:12])[N:2]([NH:1][C:29](=[O:32])[CH3:30])[CH:3]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:27][CH:28]=3)[N:4]2[NH:2][C:11](=[O:12])[CH3:10])=[CH:9][CH:8]=1
Reactant: CC(=O)O
Reactant: CCOP(=O)(Cc1ccc(-c2nc3cc(Cl)ccc3c(=O)n2N)cc1)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C2N(NC(C)=O)C(=O)c3ccc(Cl)cc3N2NC(C)=O)cc1)OCC
Temperature: 25 °C
Yield: 123.7 %

Procedure:
The compound obtained in Example 57 (3.0 g) and anhydrous acetic acid (2.2 g) were suspended in 20 ml of pyridine and refluxed at room temperature for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=50:1) and recrystallized from dichloromethane-n-hexane to provide 2.3 g of the desired compound as colorless crystals. Table 3 shows the chemical structure and property (melting point) of the compound obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H][H].[C:23]([OH:33])(=[O:32])[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>[Pt].CO>[C:23]([OH:33])(=[O:32])[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:11])[NH:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NCc1ccccc1
Agent: [Pt]
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: CO
Product: COc1ccc(CC(C)NCc2ccccc2)cc1
Temperature: 45 °C

Procedure:
To 800 mL of methanol were added 328 g of 4-methoxyphenylacetone (2 mol) and 214 g of N-benzylamine (2 mol). The imine formation was exothermic and the solution warmed to 45° C. After reaction was complete, the solution was hydrogenated at 50 psi for 6-8 hours in the presence of 3.3 g of 5% platinum on carbon catalyst. When the hydrogen uptake had stopped, the reaction was filtered through diatomaceous earth, and the filter cake was washed with 200 mL of methanol. The combined filtrates were placed in a 6-liter flask and diluted with 4.2 liters of methanol. (S)-L-Mandelic acid (304 g, 2 mol) was added and the mixture heated with stirring to reflux to obtain a clear solution. The solution was cooled to room temperature, stirred at room temperature for two hours and the mandelic acid salt filtered off. The recrystallization was repeated three times to obtain 60-70 g of the mandelic acid salt of the benzyl amine having an isomeric purity greater than 99.8% and a melting point of 164° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[C:12]([F:19])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:1])=[N:15][OH:16])=[C:12]([F:19])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Br)cc1F
Yield: 324.4 %

Procedure:
N-Chlorosuccinimide (0.075 g) was added to a solution of 4-bromo-2-fluorobenzaldehyde oxime (Intermediate 50) (0.44 g) in DMF (1 ml) then heated for several minutes at 55°. The mixture was allowed to cool to <50° then more N-chlorosuccinimide (0.22 g) was added. After a few minutes the mixture was allowed to cool to room temp. then partitioned between water and ether. The layers were separated, the aqueous layer was re-extracted with ether (×2) and the combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under vacuum to give a white solid (0.46 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[C:11]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH2:23][CH2:22]2)(B2OC(C)(C)C(C)(C)O2)[CH:10]=[C:9]([F:35])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH2:23][CH2:22]2)=[CH:10][C:9]([F:35])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:59][O:60][CH2:61]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1C=CC(F)=CC1(B1OC(C)(C)C(C)(C)O1)N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 56.1 %

Procedure:
Following Example 148h, 400 mg of (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b and 336 mg of 5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridine-2(1H)-one 210c were reacted to give 211a as a yellow solid (319 mg, 56%). LCMS: (M+H)+ 713
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][CH:15]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Br)nc1
Product: CSc1ccc(-c2ccc(Br)cn2)cc1

Procedure:
Prepared according to the procedure Coupling-2 using [4-(methylthio)phenyl]boronic acid and 2,5-dibromo pyridine afforded the title compound in a mixture of isomer containing 2-bromo-5-[4-(methylthio)phenyl]pyridine.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Cl:7][CH2:8][C:9]([OH:11])=O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:7][CH2:8][C:9]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:9](=[O:11])[CH2:8][Cl:7])=[O:11]
Reactant: OCCCCO
Reactant: O=C(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCl)OCCCCOC(=O)CCl
Temperature: 25 °C

Procedure:
In a 2 liter, 4 neck round bottom flask equipped with a mechanical stirrer, a solution of 75 grams of 1,4-butanediol, 240 grams of chloroacetic acid and 3 grams of para-toluenesulphonic acid 750 ml toluene was refluxed for 6 hours using a Dean-Stark apparatus. The solution was then cooled to room temperature. The toluene layer was washed with water (2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml), dried over sodium sulfate, and distilled to get crude 21, which was purified by recrystallization in chloroform:hexane (1:7) to get 92 grams of pure 21 as a white fluffy powder. m.p: 74-76.5° C., 1H NMR (CDCl3) δ 1.78 (t, 2H, CH2), 4.05 (s, 2H, CH2), 4.25 (t, 2H, CH2)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([NH:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])=[O:17])[CH2:14][CH2:15]2)[N:5]=1
Reactant: Nc1ccncc1
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1nc(Nc2ccncc2)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (75 mg, 0.18 mmol, 1.0 equiv) and diisopropylethylamine (DIEA, 154 □l, 0.875 mmol, 5.00 equiv) in acetonitrile (3 ml) at room temperature, 4-aminopyridine (43.0 mg, 0.349 mmol, 2.00 equiv) was added. The reaction mixture was heated to 65° C. and stirring was continued overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved up in 1.5 ml DMSO and purified via reverse-phase HPLC purification to afford the title compound. MS (ES+): m/e 487.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[NH:4][CH2:3]1.[OH-].[Na+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH3:1][CH:2]1[N:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([Cl:7])=[CH:9][CH:10]=2)=[O:13])[CH2:3]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC1CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CN1C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of propyleneimine (12.3 mL) in tetrahydrofuran (160 mL) was added to an 1N aqueous sodium hydroxide solution. To the mixture was added dropwise 4-chlorobenzoyl chloride (25 g) at 0° C. After addition, the mixture was stirred for additional 30 min. The reaction mixture was extracted with ethyl acetate. The extract was dried, concentrated under reduced pressure to afford the title compound (24.9 g, yield 89%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:22]([I:23])=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1>C(O)(=O)C.CO>[CH:24]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:21]=[C:22]([I:23])[C:12]([O:11][C:8]4[N:7]=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCC1
Reactant: CNC(=O)c1ccc(Oc2cc3c(cc2I)CCNCC3)nc1
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1ccc(Oc2cc3c(cc2I)CCN(C2CCC2)CC3)nc1
Reaction time: 0.5 h

Procedure:
N-Methyl-6-(8-iodo-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D43) (423 mg, 1.0 mmol) was dissolved in 2.5% acetic acid in methanol (5 ml) and treated dropwise with cyclobutanone (0.11 ml, 1.5 mmol). The mixture was stirred for 30 minutes and then (polystyrylmethyl)trimethylammonium cyanoborohydride (2.0 mmol/g, 1 g, 2 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:2.25:97.5) to afford the title compound (E225). MS (ES+) m/e 478 [M+H]+.