Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1.CN(C)C=O.O1CCOCC1>C(OCC)(=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 200 °C

Procedure:
A suspension of 2,6-dichloro-4-iodopyridine (6 g, 21.9 mmol) and trans 4-aminocyclohexanol (5.05 g, 43.8 mmol) in 15 mL of a 1:4 mixture of N,N-dimethylformamide/1,4-dioxane was heated in a Biotage Initiator microwave at 200° C. for 55 min. Ethyl acetate (150 mL) was added and the mixture washed with water (100 mL) and brine (50 mL). The organics were concentrated and the residue purified by flash chromatography on silica gel eluting with 60% ethyl acetate in hexanes to provide the title compound. Yield: 3.8 g (49%). MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C[C:14]([CH3:17])([O-:16])[CH3:15].[K+].[Cl:19][C:20]1[C:21]([C:29]([NH2:31])=[O:30])=[N:22][C:23]([CH2:27][CH3:28])=[C:24](Cl)[N:25]=1>CN(C)C=O>[CH:14]([O:16][CH:2]([CH3:5])[CH3:3])([CH3:17])[CH3:15].[C:29]([C:21]1[N:22]=[C:23]([CH2:27][CH3:28])[C:24]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[N:25][C:20]=1[Cl:19])(=[O:30])[NH2:31]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: CCc1nc(C(N)=O)c(Cl)nc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (420 mg) and N,N-dimethylformamide (12.5 mL) was added potassium tert-butoxide (260 mg) under ice-cooling, followed by stirring for 1 hour, and then 3,5-dichloro-6-ethylpyrazine-2-carboxamide (500 mg) was added thereto, followed by stirring for 1 hour. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate), and then washed with a mixed solvent of hexane:diisopropyl ether to obtain tert-butyl 3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]azetidine-1-carboxylate (318 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[S:22]1[C:26](B(O)O)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:22]1[C:26]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cc4ccccc4s3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), benzo[b]thien-2-ylboronic acid (103 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(benzo[b]thiophen-2-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.2 (d, 1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.2-7.3 (m, 3H), 7.1 (d, 1H), 7.04 (d, 1H), 4.4 (m, 2H), 3.6 (m, 2H), 3.2 (m, 2H), 3.1 (s, 3H), 2.9 (m, 2H), 2.7 (m, 2H), 2.41 (s, 3H), 2.3 m, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([F:10])[CH:9]=1.Cl[CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([F:10])[CH:9]=1)[O:11][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCCl
Reactant: Oc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.77 g (69.18 mmol) of sodium hydride (60% in mineral oil) were dissolved in 80 ml of DMF. At 0° C., 7.50 g (57.65 mmol) of 3,5-difluorophenol in 15 ml of DMF were added dropwise and, after the gas evolution subsided, the mixture was stirred at RT for 30 min. The solution was cooled to 0° C., 5.45 g (57.65 mmol) of 3-chloro-1-propanol in 15 ml of DMF were added, and the mixture was then stirred at 60° C. for 2 h and at 75° C. for 16 h. The precipitated salts were filtered off, and DMF was removed in a rotary evaporator. The residue was taken up in water and extracted twice with diethyl ether. The combined organic phases were washed successively with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to result in 8.15 g (75% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][CH:35]=1)[CH2:18][CH2:19][NH:20][C:21]1[C:22](=[O:32])[N:23]([CH2:28][C:29](O)=[O:30])[C:24]([CH3:27])=[CH:25][N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH2:46][NH2:47])[CH:44]=2)[NH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:27][C:24]1[N:23]([CH2:28][C:29]([NH:47][CH2:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[C:37]3[CH3:36])=[O:30])[C:22](=[O:32])[C:21]([NH:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH:35]=[CH:34][CH:33]=2)[O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:26][CH:25]=1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Reactant: Cc1cnc(NCCc2cccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(OC[C@H]5CCCN5C(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 102.8 %

Procedure:
A mixture of 2-[3-[(3-{[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]methoxy}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 136) (65 mg, 0.13 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (25 mg, 0.16 mmol), HOBT (20 mg, 0.15 mmol), WSCDl.HCl (31 mg, 0.16 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) in N,N-dimethylformamide (2.5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with water, brine, then dried over MgSO4 and evaporated under reduced pressure to give the title compound, (84 mg, 100%).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClCCl.C(N(C(C)C)CC)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[CH3:30][S:31]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 97.4 %

Procedure:
Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1-hexadecanol 3 (3.78 kg), anhydrous dichloromethane (40 L) and diisopropylethylamine (2.21 kg). The reaction mixture was cooled to −5 to 5° C. and methanesulfonyl chloride (1.87 kg) was added at a controlled rate over 2 hours to ensure that the reaction temperature was kept below 5° C. After the addition was complete, the mixture was warmed to 20 to 30° C. and stirred for one to two hours. The reaction was monitored by GC-MS and was deemed complete when the conversion rate was ≧95%. The reaction was maintained at 20 to 30° C. while being diluted with water (15 L). The organic layer was separated, washed with water (0.50 kg), and concentrated to dryness to yield 4 as a light yellow solid (4.87 kg, 96%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+].CO.Cl>CO.O>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
14.9 g (38.5 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester was dissolved/suspended in 300 mL of a 1:1 methanol-water mixture. 1.11 g (46.2 mmol) of lithium hydroxide was added and the mixture was heated up to 65° C. and stirred overnight. The mixture was cooled down to r.t., 300 mL of methanol and 4 mL of concentrated aqueous HCl were added and the solids were filtered off. The solids were then dissolved/suspended in 300 mL ethanol, brought to reflux, cooled down to rt, filtered, washed with 50 mL diethyl ether and dried to yield 9.5 g of the product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C(Cl)=O)=C1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]4[C:30]5[C:35]([CH:36]=[CH:37][C:22]3=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:17][CH:16]=2)=[O:13])=[CH:3]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: Cn1cc(C(=O)Cl)c2ccccc21
Product: Cn1cc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c2ccccc21
Yield: 14.7 %

Procedure:
1-Methyl-1H-indole-3-carboxylic acid (55 mg, 0.314 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, and 1-methyl-1H-indole-3-carboxylic acid chloride mentioned above, the title compound (11 mg, yield 15%) was obtained in the same manner as that of Example 1.
Reaction SMILES: FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[NH2:16][CH2:17][C:18]1[C:19]([Cl:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22].[C:29](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30]>C1COCC1>[Cl:28][C:19]1[C:18]([CH2:17][NH:16][C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:26][CH:25]=[C:24]([F:27])[C:20]=1[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(F)c(C(=O)O)c1Cl
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)O)c1Cl

Procedure:
BSTFA (0.18 mL; 1.15 mmol) was added to a mixture of 3-aminomethyl-2-chlor-6-fluorobenzoic acid (270 mg; 1.12 mmol, HCl-salt) in 8 mL THF, it was stirred at reflux for 20 min, and then cooled in an ice bath. TEA (0.783 mL; 5.62 mmol) and Piv-Cl (142 μL; 1.16 mmol) in 2 mL THF were added and it was stirred overnight. The solvent was removed i.vac. and the residue was diluted with water and 10 mL HOAc, extracted (3×) with DCM, dried over Na2SO4 and concentrated i vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[C:37]1([CH2:43]O)([CH2:41][OH:42])[CH2:40][CH2:39][CH2:38]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:38]1[C:37]2([CH2:41][O:42][C:24]3([CH2:23][CH2:22][CH:21]([N:11]4[C:10](=[O:28])[C:9]([CH2:8][C:7]5[CH:6]=[CH:5][C:4]([C:29]6[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:3][C:2]=5[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]5[N:18]=[CH:19][N:20]=[C:12]45)[CH2:26][CH2:25]3)[O:27][CH2:43]2)[CH2:40][CH2:39]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OCC1(CO)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)CO3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.5 g), cyclobutane-1,1-diyldimethanol (1 g), p-toluenesulfonic acid monohydrate (0.014 g) and toluene (60 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.6 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].[NH:39]([C:43]1[S:44][CH:45]=[C:46]([CH2:48][S:49][CH2:50][CH2:51][NH2:52])[N:47]=1)[C:40]([NH2:42])=[NH:41]>>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:27]([NH:52][CH2:51][CH2:50][S:49][CH2:48][C:46]2[N:47]=[C:43]([NH:39][C:40]([NH2:42])=[NH:41])[S:44][CH:45]=2)=[O:28])[CH3:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CN(CCCCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.50 g (1.4 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=616 ([M+H]+, 12), 229 (100); IR (KBr): 1640 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 95° C. (ethanol/ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCC1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:4]=1/[CH:5]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1c(C)cc(C)cc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNC1
Product: COc1c(C)cc(C)cc1/C=C/C(=O)O
Yield: 81.4 %

Procedure:
A solution of 2-methoxy-3,5-dimethylbenzaldehyde (9.40 g, 57.2 mmol), malonic acid (8.90 g, 85.8 mmol), and pyrrolidine (730 mg, 8.58 mmol) in pyridine (80 mL) was refluxed for 14 hours. This reaction mixture was poured in iced water and extracted with ethyl acetate. The extract was washed with 2N-hydrochloric acid, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 9.60 g of the title compound. Yield 81%.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][NH2:27])=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][N:27]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(CCNCC(O)COc2ccc(NN)nn2)cc1OC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc(CCNCC(O)COc2ccc(NN=Cc3ccccc3)nn2)cc1OC
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of (RS)-3-[3-[[2-(3,4-Dimethoxyphenyl)ethyl)amino]-2-hydroxypropoxy]-6-hydrazinopyridazine dihydrochloride (2 g) in 40 ml of 90% aqueous methanol, (1 ml) of benzaldehyde was added. Stirring was continued at room temperature for two hours, then the solvent was evaporated under vacuum and the residue was triturated with isopropanol to afford the title compound in 8% yield. m.p. 207°-210° C. (with decomp).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:25]([O:29][C:30](=[O:36])[NH:31][CH2:32][CH2:33][CH2:34]Br)([CH3:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:36])[CH:9]=2
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: COC(C)=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCNC(=O)OC(C)(C)C)cc21

Procedure:
The title compound is prepared using the procedure of Example 75 and (1-ethyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (3-bromo-propyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>C(O)(C)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][N:35]([CH2:20][CH:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5]1)[CH2:34][CH2:33]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)CN1CCC(c3noc4cc(F)ccc34)CC1)CC2
Reaction time: 8 h
Yield: 11 %

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g, 11.6 mmol), K2CO3 (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153°-154° C.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]([CH:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH:54]2[CH2:67][CH2:68][N:69]([C:70](=[O:79])[CH:71]([NH2:78])[CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH:53]12)=[O:51]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:48][O:49][C:50]([CH:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[O:58])[CH:54]2[CH2:67][CH2:68][N:69]([C:70](=[O:79])[CH:71]([NH:78][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH:53]12)=[O:51]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(N)C3CCCCC3)C12
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: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 115.7 %

Procedure:
A solution of Boc-N(Me)Ala-OH (113 mg, 0.56 mmol) in NMP (4 mL) was cooled to 0° C. and treated with HATU (207 mg, 0.54 mmol) followed by DIPEA (0.15 mL, 0.87 mmol). After 10 min, 17 (245 mg, 0.55 mmol) in NMP (5 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to afford 18 as an orange-colored oil (400 mg) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][C:18](=[O:20])[NH:17][C:16](=[O:21])[CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:40])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:15][C:16](=[O:21])[NH:17][C:18](=[O:20])[CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 63.7 %

Procedure:
A solution of 190 mg (0.338 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with MeOH (200 μL) and TFA (3 mL) at RT for 1.5 h. MeOH (30 mL) was added, the mixture was concentrated to half volume, MeOH (15 mL) was added, and the solvents were removed completely in vacuo at <35° C. Silica gel chromatography of the residue with 25-75% EtOAc-hexane afforded 92.9 mg (64%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.22 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.26 (dd, 1H, J=8.4, 2.4 Hz), 7.18 (d, 1H, J=2.4 Hz), 5.79-5.75 (m, 1H), 3.52-3.42 (m, 1H), 2.93-2.76 (m, 4H), 2.37-2.30 (m, 2H), 2.12-2.07 (m, 2H), 1.62 (t, 2H, J=5.6 Hz), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C24H25N5O3, 432.2 (M+H), found 432.1.