Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:36][CH3:37])=[CH:4][C:5]([C:10]2[CH:11]=[N:12][C:13]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].[N:38]([O-])=O.[Na+]>O.O1CCOCC1>[C:8]([C:7]1[C:2]2[N:1]=[N:38][N:36]([CH3:37])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[C:13]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:25][CH2:24]3)=[N:12][CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2cnc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnc2c(C#N)nc(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a suspension of tert-butyl 4-(2-(5-amino-6-cyano-4-(methylamino)-5′-(trifluoromethyl)-2,3′-bipyridin-6′-yloxy)ethyl)piperidine-1-carboxylate (5.20 g) in water (40 ml) and 1,4-dioxane (40 ml) was added 2N hydrichloric acid (6.89 ml) at 0° C. To above suspension was then added dropwise sodium nitrite (0.92 g) in water (10 ml). The mixture was then stirred at 0° C. for 10 min and at 20° C. for 16 h. The solid product was collected by filtration and washed with water, dried in vacuum oven to give 4.61 g tert-butyl 4-(2-(5-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(trifluoro-methyl)pyridin-2-yloxy)ethyl)piperidine-1-carboxylate (94%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](C)[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:18][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(C)c(I)c1
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2C3=C(COCC3=O)NC3=C2C(=O)OC3)cc1I
Temperature: -10 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
The product from Example 5A (0.60 g, 1.4 mmol) in chloroform (10 mL) under a nitrogen atmosphere was treated with pyridine (0.13 mL, 1.6 mmol) and pyridinium tribromide (0.48 g, 1.5 mmol) at −10° C. After stirring at −10° C. for 2 hours, the mixture was allowed to warm to ambient temperature and then was treated with 1M HCl and extracted with chloroform. The chloroform layer was dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 1 hour and cooled to ambient temperature. Purification of the residue by chromatography on silica gel eluting with 10% methanol in dichloromethane provided the title compound (0.28 g).
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN(C=O)C>[CH2:1]([C:4]1[C:10]([O:11][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3]
Reactant: CCCc1c(O)cccc1O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(O)cccc1OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-propyl resorcinol (178.27 g; 1.171 mol) in dry DMF (1200 mL) was added cesium carbonate (104.95 g; 322.12 mmol). The mixture was stirred at room temperature and treated dropwise with a solution of 2-bromoacetophenone (58.29 G; 292.84 mmol) in dry DMF (500 mL) over 2 hours. The was stirred at ambient temperature for 64 hours. The reaction mixture was partitioned between isopropyl acetate and water. The aqueous was adjusted to pH 13 by addition of aq. 5N sodium hydroxide. The organic was dried over magnesium sulfate, filtered and evaporated to a residue. The residue was dissolved in methylene chloride (110 mL) and hexane (350 mL) and heated to reflux. The solution was cooled to -10° C. Stirring was continued for 1 hour. The title compound was recovered by filtration.
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:19]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)c1cccc(N2CCOCC2)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 5.4 %

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), methyl-3-bromo-benzoate (107 mg, 0.5 mmol), and morpholine (52 μL, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by preparatory TLC (EtOAc/hexanes as the eluent) to yield 6 mg of the desired product (which was used for calibration with the internal standard). The GC yield was calculated to be 18%.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Agent: Cl
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 73 %

Procedure:
In analogy to the procedure described in example 58F, (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) and 3-chlorophenyl isocyanate (without addition of 0.1 eq. of 3-chlorophenyl isocyanate) gave 0.081 g (73%) of the title compound as white foam. MS: 449.3 (MH+, 1Cl).
Reaction SMILES: Cl.[CH2:2]=[C:3]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.O.[SH:13][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:22]1[C:14]([S:13][CH2:2][CH:3]2[C:8](=[O:9])[CH:7]3[CH2:10][CH2:11][N:4]2[CH2:5][CH2:6]3)=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[N:20][CH:21]=1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: C=C1C(=O)C2CCN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: O=C1C2CCN(CC2)C1CSc1ncnc2[nH]cnc12
Temperature: 85 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone hydrochloride (0.5 g, 3.6 mmol) in water (6 ml) triethylamine (1.5 ml), tetra-n-butyl ammonium bromide (120 mg) and 6-mercapto-purine monohydrate (0.62 g) were added and the reaction mixture was allowed to stir at 85° C. for 14 h. The completion of reaction was monitored by tlc. The reaction mixture was quenched with ice-cold water (10 ml), extracted with dichloromethane (2×25 ml), the organic layers were washed with water, brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified (140 mg, 14%) by flash column chromatography on neutral silica gel using 9:1 chloroform:methanol as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:11]2[N:12]([CH:26]=[N:27][CH:28]=2)[C:13]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]3)[CH:17]=[CH:16][C:14]=2[N:15]=1.CC(OC(=O)N)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:11]2[N:12]([CH:26]=[N:27][CH:28]=2)[C:13]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)[CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2ccc(N3CC[C@H](O)C3)nc2n2cncc12
Agent: CC(C)(C)OC(N)=O
Product: Cc1cccc(Cl)c1Nc1nc2ccc(N3CC[C@@H](O)C3)nc2n2cncc12

Procedure:
(S)-1-[6-[(2-Chloro-6-methylphenyl)amino]imidazo[1,5-a]pyrido[3,2-e]pyrazin-2-yl]-3-pyrrolidinol]carbamic acid 1,1-dimethylethyl ester;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[CH:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][CH:8]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Oc1ccc(-c2ccsc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3ccsc3)cc2)cc1
Temperature: 98 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a 25 mL pressure resistant vial which contained a solution of the product from step 1 (44 mg, 0.25 mmol) and the product from step 2 (130 mg, 0.33 mmol) in anhydrous dioxane (4 mL) were added cesium carbonate (300 mg, 1.5 mmol) and N,N-dimethylglycine.HCl (25 mg, 0.66 mmol) at rt. The reaction mixture was flushed with argon and copper (I) iodide (14 mg, 0.06 mmol) was added. The vial was sealed and the reaction mixture was stirred at 98° C. for 72 h. After cooling to rt, the mixture was poured onto 50 mL ice-water solution and this solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (80 mg, 70%); LCMS; 100%, APCI+ Calcd: 451.6, found m/z: 451.6 (M); 1H NMR (400 MHz, CDCl3); δ 1.48 (s, 9H), 1.81-2.09 (m, 4H), 3.27-3.48 (m, 2H), 3.70-3.97 (m, 1H), 4.02-4.21 (m, 2H), 6.88-7.05. (m, 6H), 7.32-7.38 (m, 3H), 7.52 (d, J=8.8 Hz, 2H):
Reaction SMILES: [H][H].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1O.C(O)(=O)C>O>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH:13]=[CH:12]1
Reactant: [H][H]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Temperature: 60 °C

Procedure:
Refer to Chart E, wherein E is --CH=CH--, R2 is methyl, R4 is hydrogen, V is --(CH2)5 --, and W is 1-pentyl. A mixture of PGE1, 15-methyl ether, (0.4 g.), glacial acetic acid (9 ml.), and water (1 ml.) is heated under nitrogen at 60° C. for 18 hrs. The mixture is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography, eluting with 25-100% ethyl acetate-Skellysolve B. The fractions shown by TLC to contain the desired product free of starting material and impurities are combined and concentrated to give the Formula-X PGA1 -type title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CN(C=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[OH:30].C(N(CC)CC)C>O>[OH:30][C:21]1[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:20]=1[NH:19][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][N:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1]
Reactant: O=C(Cl)c1ccncc1C(F)(F)F
Reactant: Nc1cc(C(F)(F)F)ccc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.72 g of 3-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to give 3-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 3-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.66 g of 2-amino-4-trifluoromethylphenol, 0.76 g of triethylamine, 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour and stirred while heating at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.62 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)isonicotinamide.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[O:26]=[C:27]1[N:32]([CH2:33][CH:34]=O)[C:31]2[N:36]=[C:37]([N:40]3[CH:44]=[N:43][CH:42]=[N:41]3)[CH:38]=[CH:39][C:30]=2[N:29]=[CH:28]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][N:32]4[C:27](=[O:26])[CH:28]=[N:29][C:30]5[CH:39]=[CH:38][C:37]([N:40]6[CH:44]=[N:43][CH:42]=[N:41]6)=[N:36][C:31]4=5)[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cnc2ccc(-n3cncn3)nc21
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(-n4cncn4)nc32)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 43.2 %

Procedure:
To a solution of 48 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 2 mL of methanol, 50 mg of (3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, 2.5 mL of dichloromethane and 20 μL of acetic acid were added, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, 9.0 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour 30 minutes. Thereto were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=50:1 to obtain 35 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:12]Br>C(Cl)Cl>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[N:3][CH:4]=1
Reactant: BrBr
Reactant: Oc1nccc2ccccc12
Solvent: ClCCl
Product: Oc1ncc(Br)c2ccccc12
Reaction time: 4 h
Yield: 63.4 %

Procedure:
To a suspension of 5.0 g (34.5 mmol) of 1-hydroxyisoquinoline in 100 ml of methylene chloride was added 6.0 g (37.7 mmol) of bromine in 20 ml of methylene chloride. The mixture was stirred for four hours, the solid was filtered and washed with methylene chloride. This solid was recrystallized from ethanol to give 4.9 g (63%) of the desired product; mp 245°-250° (dec).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22]Cl>>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][N:8]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])[S:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:11]
Reactant: COCCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2cccs2)c1C
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1cccs1
Yield: 34 %

Procedure:
N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32B using N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide and methoxyethoxymethyl chloride resulting in 34% yield. HPLC analysis of the crude oil obtained after workup showed that the oil was approximately 96% pure and so was used in the next step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>Br>[CH3:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][NH:4]1
Reactant: CC(NCCO)c1ccccc1
Agent: Br
Product: CC1NCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.23 %

Procedure:
100 g(605.32 mmole) of N-(2-hydroxyethyl)-α-methylbenzylamine produced in Example 5(1) above was suspended in 515 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 465 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550 ml of acetone, and 500 ml of ethyl acetate and 670 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 400 ml of ethyl acetate and then dried to obtain 97 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 450 ml of acetone, diluted with 680 ml of ether and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected, and washed with 450 ml of ethyl acetate to obtain 32.5 g of the second crop of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:17][CH:16]=1)#[N:13]
Reactant: COC(C(=O)O)c1ccccn1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccn1

Procedure:
(RS)-Methoxy-pyridin-2-yl-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-pyridin-2-yl-acetamide. Brown oil. MS 282.2 ([M+H]+)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([C:41]([O:43][CH3:44])=[O:42])=[N:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31]CC2C=CC(OC)=CC=2)[CH:25]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([C:41]([O:43][CH3:44])=[O:42])=[N:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([OH:31])[CH:25]=1
Reactant: CCOc1ccc(Cl)c(-c2ccc(C(=O)OC)nc2-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Cl)c(-c2ccc(C(=O)OC)nc2-c2ccc(Cl)c(O)c2)c1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
Add 1 mL (13 mmol) of trifluoroacetic acid to a solution of 700 mg (1.3 mmol) of methyl 5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylate in 10 mL of DCM stirred at 0° C. Stir the reaction mixture for 2 h at 20° C. then concentrate under reduced pressure. Take up the residue in 50 mL of DCM and wash with 50 mL of a saturated aqueous solution of NaHCO3. Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 524 mg of methyl 5-(2-chloro-5-ethoxyphenyl)-6-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C2(O)CCN(C)CC2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[ClH:38].C([O:42][CH2:43][CH3:44])(=O)C>CO>[ClH:38].[ClH:38].[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]2[CH2:44][CH:43]([OH:42])[CH2:8][CH2:9][N:10]2[CH3:15])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(O)(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: CN1CCC(O)CC1C(CN1CCN(CCCCc2cccc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
33 mg of 4-{1-(4-Fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]ethyl}-1-methylpiperidin-4-ol was dissolved in 4 ml of methanol, and 1 ml of 4M hydrogen chloride/ethyl acetate solution was added. The solution was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to give 35 mg of 4-{(1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]ethyl}-1-methylpiperidin-4-ol trihydrochloride.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH2:12]Br.[CH2:15]([NH2:24])[C:16]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH3:21][O:20][C:19]1[CH:22]=[CH:23][C:16]([CH2:15][N:24]2[CH2:12][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([C:10]#[N:11])[CH:6]=3)[C:3]2=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(C#N)cc1CBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(C#N)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography (11.69 g, 56.0%) as a solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[CH:16][N:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cn2ccnc2c(Nc2ccc(N3CCNCC3)cn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 106a (260 mg, 0.5 mmol) in CH2Cl2 (3 mL) was added TFA (0.5 ml) and the reaction mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated to give 106b as a pale yellow liquid without purification for next step (210 mg, 97%). MS: [M+H]+ 374.