Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:44]1[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45]1>C(Cl)Cl>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:49][C:46]5[CH:47]=[CH:48][O:44][CH:45]=5)[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2Cc1ccoc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
To a sample of compound 10a (0.65 g, 1.7 mmol) dissolved in 20 mL CH2Cl2 was added sodium triacetoxyborohydride (0.53 g, 2.5 mmol) and 3-furaldehyde (0.17 mL, 2.0 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with 10 mL CH2Cl2 and washed with 1 N NaOH. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography, eluting with 5% 0.5 M NH3 in methanol/CH2Cl2 to give Compound 12a (0.25 g, 0.53 mmol). MS m/z=469.0 (M+1); 1H NMR 300 MHz (DMSO-d6) δ 1.1 (br s, 6H), 1.35 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 3.0 (m, 2H), 3.2 (m, 2H), 3.5 (m, 2H), 3.85 (br s, 2H), 4.05 (d, 2H), 6.8 (s, 1H), 7.1-7.5 (m, 7H), 7.8 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4c(C)cccc4C)CC3)c(OC)nc2c1
Yield: 91 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 6H), 3.17-3.21 (m, 4H), 3.68-3.71 (m, 4H), 3.91 (s, 3H), 4.14 (s, 3H), 6.95-7.03 (m, 3H), 7.14-7.21 (m, 3H), 7.77-7.80 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:3]1.[CH3:26][N:27]=[C:28]=[O:29]>N1C=CC=CC=1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N:19]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:28](=[O:29])[NH:27][CH3:26])[CH2:3]1
Reactant: CN=C=O
Reactant: COC(=O)CCNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Solvent: c1ccncc1
Product: CNC(=O)N(CCC(=O)OC)C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 60 °C

Procedure:
A mixture of 8.5 g of 6-methyl-8β-[N-(2-methoxycarbonylethyl)-aminomethyl]-ergoline (prepared as described in Example 1) and 2.95 ml of methyl isocyanate in 100 ml of pyridine was heated at 60° C. for one hour. After evaporating off the solvent, the residue was crystallized from methanol to give 8.5 of the title compound, m.p. 140°-142° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].N1C=CC=C[CH:14]=1>>[CH3:14][C:5]1[O:4][C:2](=[O:3])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: c1ccncc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Cc1nc2ccccc2c(=O)o1
Temperature: 45 °C
Yield: 86 %

Procedure:
The isatoic anhydride and pyridine were combined in a round bottomed, 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, dropping funnel and drying tube. The isatoic anhydride suspension was heated to 45° C and the acetic anhydride was added over a period of 30 minutes. Carbon dioxide evolution occurred during the addition of the acetic anhydride. The reaction mixture was heated to 90° C for 1.5 hours. The evolution of carbon dioxide stopped. The reaction mixture was concentrated under reduced pressure (15 mm. of Hg). The residue was crystallized from 100 ml of cyclohexane to give 42 parts by weight (86% yield) of 2-methyl-4H-3,1-benzoxazine-4-one with m.p. 79°-81° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#N>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH2:17][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: N#Cc1ccncc1
Agent: [Li]CCCC
Product: c1ccc2cc(Cc3ccncc3)ccc2c1

Procedure:
4-((2-Naphthyl)methyl)pyridine was prepared from 2-bromonaphthalene, n-BuLi and 4-cyanopyridine in two steps as a yellow solid: mp 66-67° C., 1H NMR (CDCl3) 4.13 (s, 2H), 7.14 (d, J=6.0 Hz, 2H), 7.27 (dd, J=5.7 and 1.8 Hz, 1H), 7.42-7.52 (m, 2H), 7.64 (s, 1H), 7.74-7.86 (m, 3H), 8.51 (dd, 4.8 and 1.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Li+].CCC[CH2-].[Cl-].[CH:17]([SiH:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18].O>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(C)[SiH](C(C)C)C(C)C
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
To a solution of 400 mg (2.96 mmol) of 6-fluoroindole dissolved in 6 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 1.18 ml of a N-butyllithium solution (2.5M in hexane, 2.96 mmol). The reaction mixture is stirred for 5 min at −78° C., then 634 μL (2.96 mmol) of triisopropylsilane chloride are added dropwise at −78° C. to the reaction mixture. This mixture is stirred for 20 min at room temperature then water is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 99:1) to yield 760 mg (89%) of 6-fluoro-1-triisopropylsilylindole as a colourless oil.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.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>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:35]3[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ncccc1B(O)O
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)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: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 90 °C
Yield: 98.8 %

Procedure:
A reaction mixture of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (1.04 g, 3.00 mmol), potassium carbonate (1.00 g, 7.20 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.92 g, 6.00 mmol) in dioxane (30 mL) was degassed three times with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15 mmol) was added and the reaction mixture was degassed three further times with nitrogen. The resulting mixture was heated at 90° C. for 19 h, and then the reaction was cooled to ambient temperature, (2-methoxypyridin-3-yr)boronic acid (0.46 g, 3.00 mmol) and tetrakis(triphenylphosphfne)-pailadium(0) (0.09 g, 0.08 mmol) were added and the reaction was degassed three times with nitrogen and heated at 90° C. for further 7 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (15% ethyl acetate in hexanes) afforded the title compound as a colorless solid (1.11 g, 98%): 1H NMR (300 MHz, CDCl3) δ 8.20-8.16 (m, 1H), 7.62-7.48 (m, 3H), 6.96-6.91 (m, 2H), 3.87 (s, 3H), 3.48 (s, 2H), 1.89 (br s, 3H), 1.68-1.35 (m, 12H); MS (ES+) m/z: 375.2, (M+1).
Reaction SMILES: C(O)(=O)C.C(N(CC1C=CC=CC=1)CCN)C1C=CC=CC=1.[N+:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CCCCCCCCCC)([O-:25])=[O:24].C=O>C(O)C.C(OCC)(=O)C>[N+:23]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([O-:25])=[O:24]
Reactant: CCCCCCCCCCCCCCCCCC[N+](=O)[O-]
Agent: C=O
Agent: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])CCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (1.5 mL) was added to a solution of N,N-dibenzylethylene diamine (3.0 g, 12.5 mmol) in ethanol (25 mL) and the solution was stirred at 60° C. for 10 min A white solid formed which dissolved on heating to 80° C. Compound 3 (1.73 g, 6.25 mmol) was added and the stirring was continued at 80° C. for an additional 10 min. Paraformaldehyde (2.5. g, 88 mmol) was added to this solution in small portions over a period of 30 min and the suspension was stirred for 5 h at 80° C. Solvents were removed and the residue was treated with water. The pasty solid obtained was dissolved in ethyl acetate, washed with water and dried (Na2SO4). The oil obtained was purified by silica gel chromatography. (hexane/ethyl acetate, 9/1, 7/3). UV visible fractions were collected and evaporated to give 4 as an oil. Yield: 3.2 g (64%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)Nc2ccccc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-phenylacetamide according to the method of Example 1; m.p. 125-127°.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)NCCCn1ccnc1
Temperature: 90 °C

Procedure:
A mixture of 2.39 of isatoic anhydride, 2.50 g of 1H-imidazol-1-propanamine and 30 ml of toluene was heated at 90° C. for 45 minutes and cooled. The toluene layer was decanted and the residue was dissolved in methylene chloride, washed with dilute sodium hydroxide solution, water and dried over magnesium sulfate. The organic layer was concentrated to obtain the desired product, mp 107°-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:9]2[C:5]([C:6]3[CH2:20][CH2:19][O:18][C:17]([CH2:26][CH3:27])([CH2:21][C:22]([O:24]C)=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])=[C:9]2[C:5]([C:6]3[CH2:20][CH2:19][O:18][C:17]([CH2:26][CH3:27])([CH2:21][C:22]([OH:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(OCC(F)(F)F)c(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1c(OCC(F)(F)F)c(Cl)ccc21
Yield: 89.3 %

Procedure:
A mixture of methyl 7-chloro-1-ethyl-1,3,4,9-tetrahydro-8-(2,2,2-trifluoroethoxy)-pyrano[3,4-b]indole-1-acetate (3.2 g, 8 mmol) EtOH (25 mL) and 1N NaOH (10 mL) was refluxed for 2 hours. At the end of this time the EtOH was removed in vacuo and the rsidue diluted with H2O (25 mL). This aqueous mixture was acidified with 1N HCl, then extracted with ether (150 mL). The ether layer was washed with saturated brine (2×100 mL), dried (MgSO4), and concentrated to yield a light yellow oil. This oil was dissolved in toluene and petroleum ether added (~10 volumes). After cooling, the crystals were removed by filtration to yield 2.8 g (90%) of 7-chloro-1-ethyl-1,3,4,9-tetrahydro-8-(2,2,2-trifluoroethoxy)-pyrano[3,4-b]indole-1-acetic acid, m.p. 157° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[N+:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][CH2:2][C:1]2=[O:10])([O-:13])=[O:12]
Reactant: O=C1CCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2c1cccc2[N+](=O)[O-]
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a 0° C. solution of indanone (1.1 mL, 9.16 mmol, 1.0 equiv) in concentrated H2SO4 (9 mL) was added KNO3 (926 mg, 9.16 mmol, 1.0 equiv) as a solid in several portions over 5 min. After stirring for 1 h, the reaction mixture was poured onto ice. The aqueous suspension was extracted with EtOAC (3×30 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (20%-50% EtOAc/Hexanes) provided the desired compound as a yellow solid (288 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:14][C:15](=[O:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](Br)[CH:7]=1.[P:19]([O-:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].CN1CCOCC1>C1(C)C=CC=CC=1.CC#N.[NH4+].[Cl-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:14][C:15](=[O:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: COC(=O)C(Cc1ccc(O)c(Br)c1)NC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOP(=O)(OCC)c1cc(CC(NC(C)=O)C(=O)OC)ccc1O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To 2-Acetylamino-3-(3-bromo-4-hydroxy-phenyl)-propionic acid methyl ester (3 g, 9 mmol), diethyl phosphite (1.6 ml, 11 mmol) and 4-methylmorpholine (1.5 mL, 13.5 mmol) in toluene (10 mL) and MeCN (10 mL) was added Pd(Ph3)4 (0.5 g, 0.45 mmol). The mixture was allowed to stir for two days at 100° C. It was then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over magnesium sulfate, concentrated , and chromatographed over silica gel (5% MeOH/CHCl3) to an oil. MS [M+H]+ 374 and [M−H]− 372.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>>[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH:22][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared by the general method of Example 1 using 24.9 g (0.1 mole) of t-butoxycarbonyl-D-methionine (BOC-D-Met) and 13.8 g (0.11 mole) of glycine methyl ester hydrochloride. The crude product was recrystallized from ethyl acetate/Skellysolve B to give the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:19]([O:26][CH3:27])(=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][CH:10]([CH:20]([C:19]([O:26][CH3:27])=[O:25])[C:21]([O:23][CH3:24])=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: COC(=O)CC(=O)OC
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc(Br)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-bromophenyl)-3-(4-chlorophenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(3-(4-bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl)malonate was obtained as colourless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:12]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[C:13]3[CH2:18][CH2:17][CH2:16][N:14]3[N:15]=2)[N:6]=1)=O.[BH4-].[Li+].Cl>CO>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]([C:12]2[C:11]([C:7]3[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=3)=[N:15][N:14]3[CH2:16][CH2:17][CH2:18][C:13]=23)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: OCc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of 6-(3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)pyridine-2-carboxylic acid methyl ester (0.550 g, 1.48 mmol) in methanol (20 mL) is added lithium borohydride (35.5 mg, 1.63 mmol). The mixture is stirred 1 h, additional lithium borohydride (35.5 mg, 1.63 mmol) added, and the resulting mixture stirred at room temperature for 16 h. 4 N Hydrochloric acid (3 mL) is added slowly and the resulting mixture concentrated in vacuo. The residue is taken up in methanol (10 mL) and partitioned between ethyl acetate (150 mL) and saturated potassium carbonate (150 mL). The organic portion is washed with brine (150 mL), dried (magnesium sulfate), and a concentrated in vacuo. The residue is precipitated from ethyl acetate with hexanes to yield 296 mg (58%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[CH:18]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[CH2:19]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([CH:18]=[CH2:19])=[CH:21][CH:22]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: C=Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 88.4 %

Procedure:
Following General Procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.200 g, 0.75 mmol) was reacted with 4-vinylaniline (0.099 g, 0.83 mmol) to afford the title compound (0.230 g, 100%) as a tan solid. MW=346.85. 1H NMR (CDCl3, 500 MHz) δ 7.88-7.85 (m, 1H), 7.73-7.68 (m, 1H), 7.47-7.42 (m, 2H), 7.35-7.29 (m, 2H), 7.21 (s, 1H), 7.20-7.16 (m, 2H), 6.72 (q, J=10.5 Hz, 1H), 5.78 (s, 1H), 5.74-5.70 (m, 1H), 5.24-5.22 (m, 1H), 3.09 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.22 (quin, J=7.6 Hz, 2H); APCI MS m/z 347 [M+H]+.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)=[O:6]>C(O)C.O>[C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc2cccc(C(C)C)cc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc2ccc(C(=O)O)c-2c1
Temperature: 25 °C

Procedure:
Potassium hydroxide (10.5 g) was dissolved in a mixture of ethanol (80 ml) and water (15 ml). The compound (17) (12.43 g) was added thereto and the mixture was heated under reflux for 50 minutes in an oil bath. The reaction solution was cooled to room temperature, and then poured into water (400 ml). The solution was made acidic (pH 3) with conc. HC1. The precipitate was filtered, washed with water and dried to obtain 1-carboxy-7-isopropylazulene (18), at a yield of 2.1 g (92.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[CH:7]=[O:8].[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=1[CH:7]=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1[nH]ncc1Br
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(Br)c1C=O
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a stirred suspension of 4-bromo-1H-pyrazole-5-carbaldehyde (1.93 g, 11 mmol) in THF (50 mL) was added sodium hydride (0.484 g, 12.1 mmol) at 0° C. After 10 min, [2-(chloromethoxy)ethyl](trimethyl)silane (2.34 mL, 13.2 mmol) was added. After 2 h, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 80:20 hexane/EtOAc) to afford the title compound (2.30 g, 69%) as a colorless oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18](=[O:25])[N:19]([CH2:21][C:22](O)=[O:23])[CH:20]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18](=[O:25])[N:19]([CH2:21][C:22]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[O:23])[CH:20]=1
Reactant: O=C(O)Cn1cc(Br)ccc1=O
Reactant: COc1ccc2c(N)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(NC(=O)Cn3cc(Br)ccc3=O)ccnc2c1
Temperature: 40 °C
Yield: 12.9 %

Procedure:
To a solution of 7-methoxyquinolin-4-amine (0.275 g, 2 mmol) and 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetic acid (0.273 g, 1 mmol) in 5 mL of DMF at rt was added triethylamine (0.2 ml, 2 mmol) followed by HATU (0.7 g, 2 mmol) solid. The reaction was then heated up to 40° C. for 8 hours and was cooled to rt and diluted with 60 mL of EtOAc and 30 mL of satd. NaHCO3 solution. The organic phase was separated, washed with 30 mL of brine and dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give a white solid (0.05 g, 11% yield). MS (ESI pos. ion) m/z (MH+): 388.0. Calc'd Exact Mass for C17H14BrN3O3: 387.02.
Reaction SMILES: [ClH:1].C([O:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:11]1=[O:22])C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[ClH:1].[OH:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:11]1=[O:22]
Reactant: [H][H]
Reactant: CN1CCC2(CC1)CC(=O)N(OCc1ccccc1)C2=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCC2(CC1)CC(=O)N(O)C2=O
Yield: 93 %

Procedure:
The compound No. 1 (2-benzyloxy-8-methyl-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (6.4 g), listed in Table 1 in Example 4) was dissolved in 50 ml of methanol-water (1 to 1, v/v), and this was followed by catalytic hydrogen reduction for about 1 hour in the presence of palladium catalyst. The resulting solid was recrystallized from ethanol to obtain 4.3 g of a colorless crystal having a melting point of from 284° to 286° C.