Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]2)=[C:5]2[NH:16][CH:17]=[CH:18][C:4]=12.C([Mg]Br)C.N1C=CC=CC=1.Cl[C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[OH:15][CH2:14][C:11]1[N:12]=[CH:13][N:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:18]([C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][NH:16][C:5]=23)[N:10]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cnc(CO)n2)c2[nH]ccc12
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(CO)n3)ncc(OC)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of (1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)methanol (70 mg, 0.285 mmol) in THF (5 mL) was added ethylmagnesium bromide (1.284 mL, 1.284 mmol) at −40° C. After stirring at −5° C. for 1H, pyridine (0.012 mL, 0.143 mmol) was added quickly. The mixture was cooled to −40° C. and ethyl 2-chloro-2-oxoacetate (0.130 mL, 1.142 mmol) was added. After stirring at −40° C. for 30 min, the reaction mixture was quenched by adding i-PrOH and water. The mixture was extracted with EtOAc (2×40 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under vacuum to give crude product ethyl 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (70 mg, 0.203 mmol, 71.0% yield). LCMS: m/z 346.1 (M+H)+, 1.42 min (method 8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)O)=[C:4]([CH3:17])[CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].ClC1C=C(Cl)C=CC=1C([C:34]1[C:42]2[C:37](=[C:38]([CH2:44][S:45][CH3:46])[CH:39]=[C:40](F)[CH:41]=2)[NH:36][CH:35]=1)CCO.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:34]2[C:42]3[C:37](=[C:38]([CH2:44][S:45][CH3:46])[CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: Cc1cc(F)ccc1C(O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
509 mg (2.17 mmol) of the compound from Example 82A and 437 mg (1.97 mmol) of indium(III) chloride were added to 350 mg (1.97 mmol) of the compound from Example 8 in 15 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 174 mg (22% of theory) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>CN(C)C=O.O>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[N+:21]([O-:23])=[O:22])=[CH:28][CH:27]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCc2ccc(OC)cc2)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 79 %

Procedure:
DIEA (389.0 g, 3.02 mol) was added to a solution of methyl 4-fluoro-3-nitrobenzoate (200.0 g, 1.00 mol) in N,N-dimethylformamide (2 L) at room temperature. Then (4-methoxyphenyl)methanamine (275 g, 2.00 mol) was added dropwise. After 2 h, the reaction was diluted with water (5 L), the solids were collected by filtration to afford methyl 4-(4-methoxybenzylamino)-3-nitrobenzoate as a yellow solid (250 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[OH:10].F[C:12]1[C:17](F)=[CH:16]C(B2OC(=O)CN(C)CC(=O)O2)=[C:14](O[C@H](CC=C)C)[CH:13]=1>>[Br:1][C:2]1[C:3]([O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16])=[CH:4][C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: Oc1cc(F)cc(F)c1Br
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1Br
Yield: 80 %

Procedure:
Prepared from 2-bromo-3,5-difluorophenol in 80% yield following the procedure for (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 6.59-6.43 (m, 2H), 5.94-5.80 (m, 1H), 5.22-5.09 (m, 2H), 4.47-4.36 (m, 1H), 2.59-2.37 (m, 2H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16].CCOCC.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])[OH:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Oc1ccc(C2CO2)c(C(F)(F)F)c1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccc(C(O)CNCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g; 79.2 mmol) was dissolved in benzylamine (26 mL). The resulting mixture was stirrred at 80° C. for 4 h. After cooling to RT, Et2O was added and the mixture cooled to 0° C. The formed precipitate was collected by filtration, washed with Et2O, and dried under vacuum, at 40° C., to afford methanesulfonic acid 4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester as a white solid (26.87 g) which was used as such.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O.Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=[C:29]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:28]=1>C(#N)C>[C:41]1([NH:40][C:29]2[N:30]=[C:31]([NH:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:32]=[C:27]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[N:28]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Clc1nc(Nc2ccccc2)nc(Nc2ccccc2)n1
Reactant: NCc1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CNc2nc(Nc3ccccc3)nc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A 7.5 mg (60 μmol) portion of p-fluorobenzylamine and 52 μl of diisopropylethylamine were added to a mixed solution of 400 μl of acetonitrile and 120 μl of N-methylpyrrolidone containing 8.9 mg (30 μmol) of 6-chloro-N,N′-diphenyl-1,3,5-triazine-2,4-diamine and stirred at 80° C. for 3 hours. The reaction solution was filtered and then injected into a fractional LC-MS apparatus to collect a fraction containing the desired molecular weight. By evaporating the solvent, 6.1 mg (yield 45%) of N,N′-diphenyl-N″-(4-fluorobenzyl)-1,3,5-triazine-2,4,6-triamine was obtained. A retention time of 2.77 minutes and a purity of 93% were determined by an analytical LC-MS.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]([CH3:10])=O>[OH-].[OH-].[Pd+2]>[CH:8]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:10])[CH3:7]
Reactant: CC(C)=O
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)NC1CCCC1

Procedure:
Pearlman's catalyst (20% w/w palladium hydroxide-on-carbon) (1.5 g) was added to a solution of cyclopentylamine (15 ml, 0.21 mol) in acetone (200 ml). The reaction mixture was stirred under an atmosphere of hydrogen gas at 414 kPa (60 psi). After stirring for 16 hours the reaction mixture was filtered through Arbocel (trade mark) and the solvent removed under reduced pressure to give the title compound (15 ml) as a thin oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([NH:31][CH2:30][CH2:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([C:19]([F:33])([F:18])[F:32])[CH:21]=3)[NH:25][CH:24]=2)=[O:12])[CH:6]=1
Reactant: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(C(F)(F)F)cc12)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.08 g, 0.334 mmol), 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine (0.080 g; 0.334 mmol), HATU (0.127 g; 0.334 mmol) and N,N diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.013 g (9%) of 5-(2,5-difluorobenzyl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.O.N.Cl.C([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([NH2:37])=[O:30])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(=O)O)co3)c1)C2=O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(N)=O)co3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
(S)-2-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylic acid (300 mg, 0.685 mmol) obtained in Step 1 of Example 124 was dissolved in DMF (7 mL), and the mixture was stirred at room temperature for 2 hours after adding 28% ammonia water (0.0830 mL, 1.37 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (263 mg, 1.37 mmol), and 1-hydroxybenzotriazole.monohydrate (210 mg, 1.37 mmol). Thereafter, ethyl acetate was added to the mixture, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxamide (261 mg, 87%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19]C)=[CH:12][C:11]=1[CH3:21])=[O:9].Cl.O>C(Cl)Cl>[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][C:11]=1[CH3:21])=[O:9]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c([N+](=O)[O-])cc1C(=O)c1c(Cl)cccc1Cl
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Aluminumchloride (1.5 g; 11 mmol) is added to a solution of 2,6-dichloro-5'-nitro-4'-methoxy-2'-methyl-benzophenone (1.8 g; 5.3 mmol) in methylenechloride (6 ml). The mixture is stirred for 30 minutes at 20° C. and for 1 hour at 45° C., 5 ml conc. hydrochloric acid/ice are added. After shaking with 20 ml of methylenechloride the organic layer is treated with 2N hydrochloric acid and with water. After drying the solvent is evaporated, the residue purified by chromatography (flash column filled with 30 g of silicagel, elution with toluene). The residue from the main fraction is treated with diisopropylether to give yellow crystals; (1.2 g; 73% y); mp. 170° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][CH3:16])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([O:19]CC)=O)=[N:3]1.C[N:23](C)C=O.O.[NH4+]>CO>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][CH3:16])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([NH2:23])=[O:19])=[N:3]1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(SC)nc1-2
Reactant: CN(C)C=O
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CSc1ncc2c(n1)-c1c(c(C(N)=O)nn1C)CC2
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
13.00 g (0.043 mol) of ethyl 1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were suspended in a mixture of 200 mL of methanol, 200 mL of dimethylformamide and 200 mL of ammonium hydrate 30%. The mixture was stirred at 65° C. in a closed bottle for about 8 hours. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was purified by chromatography on a silica gel column eluted by a mixture cyclohexane/ethyl acetate, giving 6.16 g (52% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH3:25])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 60 °C
Yield: 100.1 %

Procedure:
To a solution of the 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.28 mmol), prepared as described in Example 1, in DMF (3 mL) at RT was added K2CO3 (116 mg, 0.84 mmol), followed by iodomethane (79 mg, 0.56 mmol). The reaction was heated at 60° C. for overnight. The reaction was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (20 mL×3). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound, 7,8-bis(4-chlorophenyl)-2-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (104 mg, 100%) as a yellow oil. HPLC retention time: 3.67 min; MS [M+H]+: found 371.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:4][CH2:3]1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>>[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:4][CH2:3]1
Reactant: OC1COC(c2cccc(Cl)c2)OC1
Reactant: Cc1ccccc1CCl
Product: Cc1ccccc1COC1COC(c2cccc(Cl)c2)OC1
Yield: 39.2 %

Procedure:
Using the procedure of Example 9, 5-hydroxy-2-(3-chlorophenyl)-1,3-dioxane (21.5 g, 0.1 mole) was reacted with 2-methylbenzyl chloride (14.0 g, 0.1 mole) to give a heavy oil, which on distillation under 1 × 10-4 mm pressure gave 12.5 g of product which distilled at a pot temperature of 160°-170° C. Analysis by nmr indicated this product to contain 18% cis-5-(2-methylbenzyloxy)-2-(3-chlorophenyl)-1,3-dioxane.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[CH3:17][C:18]1([CH2:22]O)[CH2:21][O:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][C:18]3([CH3:22])[CH2:21][O:20][CH2:19]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(CO)COC1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A vial was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.00 mmol), (3-methyloxetan-3-yl)methanol (122 mg, 1.20 mmol), triphenylphosphine (353 mg, 1.50 mmol) and tetrahydrofuran (2 mL). The mixture was stirred at 30° C. for 15 min under nitrogen atmosphere. To the mixture was added Diisopropyl azodicarboxylate (300 mg, 1.50 mmol). The mixture was purged with nitrogen and heated to 50° C. for 17 hrs. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (sodium sulfate) and concentrated to give crude product (900 mg) as yellow gum, which was purified through flash column chromatography to give the title compound (263 mg, 87%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10]N=C2CCCCC2=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].OS(O)(=O)=O.[C:24]([O-:27])([O-])=O.[Na+].[Na+]>CC#N>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[C:2]1[CH2:7][CH2:6][CH2:5][C:24](=[O:27])[C:3]=1[NH:10]2
Reactant: O=C1CCCCC1=NNc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1cc(Cl)c(Cl)c(Cl)c21
Temperature: 80 °C
Yield: 16 %

Procedure:
2-(2-(3,4,5-Trichlorophenyl)hydrazono)cyclohexanone (1 g, 3.2 mmol) was dissolved in MeCN (10 mL) and aqueous H2SO4 (0.5 mL, 1.8M solution) was added. The reaction mixture was heated to 80° C. for 6 h, basified with saturated Na2CO3 and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography [EtOAc-hexane (1:9) as eluant] to give the title compound (0.15 g, 16%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 12.3 (bs, 1H), 7.58 (s, 1H), 3.24 (t, J=12.0 Hz, 2H), 2.59 (t, J=13.0 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:27])[N:29]([CH3:28])[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNCc1cccnc1
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(CC(=O)N(C)Cc3cccnc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with methyl-pyridin-3-ylmethyl-amine to give {6,7-dimethoxy-4-[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H32N4O5+H 481.6; found 481.0.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[Cl:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>CCCCCC.C1COCC1.C(OCC)C>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([B:29]([OH:34])[OH:30])=[CH:19][C:14]=1[N:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(Cl)c(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon and at −78° C., 20.2 ml (50.42 mmol) of a 2.5 M solution of n-butyllithium in hexane were slowly added dropwise to a solution of 15 g (38.79 mmol) of N,N-dibenzyl-5-bromo-2-chloroaniline in 350 ml of THF/diethyl ether (1:1). The reaction solution was stirred at −78° C. for 60 min, and 14.3 ml (62.1 mmol) of triisopropyl borate were then added slowly. The reaction solution was subsequently stirred at −78° C. for another 15 min, then slowly warmed to room temperature, and stirring at this temperature was continued overnight. 150 ml of ice-water were then metered in. The organic phase was separated off, and the aqueous phase was then extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 9 g (66% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([OH:31])=O)[C:22]3=[O:32])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([NH:41][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:31])[C:22]3=[O:32])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)NCc4ccccc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
The mixtures of (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid (50.0 mg, 0.1 mmol), benzyl amine (0.2 mL), HATU (50 mg), and diisopropylethyl amine (0.3 mL) in DMF (5 mL) was stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with NaHCO3 (sat.) and water, dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS: 564 (M++1). 1H NMR (CD3OD) δ 7.82 (d, 1H), 7.45 (s, 1H), 7.25 (m, 4H), 7.20 (m, 2H), 6.30 (s, 1H), 4.65 (d, 1H), 4.40 (s, 2H), 4.15 (m, 2H), 3.75 (m, 1H), 3.65 (m, 4H), 3.30 (m, 1H), 3.10 (m, 4H), 1.96 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)=[CH:10][CH:9]=1)[NH2:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:5][C@H:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:28][CH:29]=2)=[CH:12][CH:13]=1)[CH2:3][OH:2]
Reactant: COC(=O)[C@@H](N)COc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@@H](CO)COc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
O-[4-[3-[4-[2-(1-Pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]phenyl]-L-serine methyl ester in THF (4 mL) was treated with lithium aluminum hydride (22 mg) at ambient temperature under argon for 5 h. The reaction was quenched with water (0.5 mL) and sodium hydroxide solution (1.0 M, 1 mL) and stirred for 10 more min. before it was concentrated under reduced pressure. The residue was extracted with dichloromethane (20 mL×3) from brine (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) followed by NH4OH:MeOH:EtOAc (5:10:85) afforded the product (27 mg).