Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][C:16](=[O:23])[C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C>[CH3:13][O:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:14][CH2:15][C@H:16]([OH:23])[C:17]#[C:18][Si:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)[C@H](CCC(=O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Solvent: CC(C)O
Product: COC(=O)[C@H](CC[C@H](O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A 50-L flask was charged with the product from Example 1 (2.4.3 kg, 7.11 mol) and isopropanol (29 L). The solution was sparged with dry argon gas for about 50 minutes and the reaction was run under an argon atmosphere. [(1S,2S)—N-(p-toluenesulfonyl)-1,2-diphenylethanediamine](p-cymene) ruthenium (I) (Kanto Chemical Co. Inc. Catalog #41067-95, CAS#188444-42-0, 21.31 g, 0.036 mol) was added under positive argon. The reaction was followed by HPLC and additional charges of catalyst were made (21.31 g, 0.036 mol at 6 hours and 8.27 g, 0.014 mol at 8 hours) and the mixture was stirred at room temperature overnight. After a total of 22 hours, the reaction was complete. The reaction was concentrated and isopropyl acetate was added and the concentration was continued to completely replace the alcohol solvent. The final solution was distilled to about 9 L. Heptane (20 L) was added and the mixture was stirred at room temperature for 30 minutes and at 0° C. for 1 hour. The solid was collected by filtration and the solid was washed with cold heptane (2×4 L) and dried in a vacuum oven at 35-40° C. The procedure gave 2.27 kg (91.5% yield) of white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.16 (s, 9H) 1.44 (s, 9H) 1.66-1.86 (m, 3H) 1.93-2.06 (m, 1H) 2.18 (d, J=4.67 Hz, 1H) 3.73 (s, 3H) 4.29-4.43 (m, 2H) 5.11 (d, J=7.41 Hz, 1H) 13C NMR (101 MHz, CDCl3) δ ppm 0.24, 28.56, 28.62, 33.42, 52.46, 53.14, 62.14, 79.97, 89.84, 105.77, 116.39, 154.97, 172.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1.[N:24]1([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([NH2:40])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:40][C:33]3[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:31][CH:32]=3)=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(N=C=S)N=C(c2cccnc2)c2cc(Cl)ccc21
Reactant: Nc1ccc(N2CCOCC2)c2ccccc12
Product: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2cccnc2)c2cc(Cl)ccc21
Yield: 56 %

Procedure:
A solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3-pyridinyl)-2H-1,4-benzodiazepin-2-one (0.0282 g, 0.0823 mmol) and 4-(4-morpholinyl)-1-naphthalenamine (0.0188 g, 0.0823 mmol) in (CH2Cl)2 (2.5 mL) was heated at 70° C. for 24 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (1:2 CH2Cl2:EtOAc) to provide the title compound (0.0263 g, 56%). 1H-NMR (CDCl3): δ 8.72-8.68 (m, 2H), 8.29-8.25 (m, 1H), 8.11-8.07 (m, 1H), 8.05-8.00 (m, 2H), 7.64-7.55 (m, 5H), 7.38-7.33 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 4.03-3.96 (br m, 4H), 3.39 (s, 3H), 3.15 (br s, 4H). HRMS calculated for (C30H27ClN6O2S+H) (M+H)+: 571.1683. Found (ESI): 571.1699. Anal. Calcd for C30H27ClN6O2S+0.7 H2O: C, 61.73; H, 4.90; N, 14.40. Found: C, 61.93;H, 4.79; N, 13.87.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]2[CH:17]=[C:16]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:19]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(Cc4ccccc4)CC3)n2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCNCC3)n2)cc1
Yield: 66.7 %

Procedure:
A solution of 2-(4-benzyl-1-piperazinyl)-N-(4-methylphenyl)-6-(1-piperidinyl)-4-pyrimidinamine (0.40 g, 0.90 mmol) and ammonium formate (0.28 g, 4.5 mmol) in methanol over 10% palladium/charcoal was stirred at 70° C. for 3 hours. The solution was cooled and passed through celite. The solvent was removed, giving the desired product as a solid (0.21 g, 0.60 mmol, 66%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[CH:6]=[CH:5][S:4][C:3]=4[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: OC(CCCc1ccccc1)c1sccc1Br
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4ccsc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(3-bromo-thiophen-2-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([NH:20][C:21]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Solvent: CCOCC
Product: Cc1ccc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)c1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a stirred mixture of 4.5 g of 2-amino-5-methylbenzamide and 200 ml of ether was added dropwise, a solution of 4.9 g of benzoyl isothiocyanate in 100 ml of ether over 20 minutes. After stirring overnight, the solid was collected, giving 8.7 g of 2-[[(benzoylamino)thioxomethyl]amino]-5-methylbenzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15]C)=O)=[CH:7]2.[NH3:17].CO>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([NH2:17])=[O:15])=[CH:7]2
Reactant: N
Reactant: COC(=O)c1cc2cccc(F)c2c(=O)[nH]1
Solvent: CO
Product: NC(=O)c1cc2cccc(F)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vessel containing NH3/MeOH (140 mL) was added methyl 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (5 g, 15 mmol). The vessel was sealed and the solution was stirred at RT for 30 minutes and then heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound, which was used without further purification (5 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.82-7.81 (m, 1H), 7.61-7.59 (d, J=8.0 Hz, 1H), 7.41-7.35 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate (0.95 g, 3 mmol) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C., lithium hydroxide monohydrate (250 mg, 6 mmol) was added. The mixture was stirred at that temperature for 2 h. The resulting mixture was neutralized to pH=5 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4) and concentrated to obtain a white solid of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (0.76 g, yield 83%). LC-MS (ESI) m/z: 303 (M+1)+. 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (610 mg, 2 mmol) was added to thionyl chloride (10 mL), and the mixture was added at room temperature for 48 h. Then the solvent was removed under reduced pressure, dried in vacuum to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[NH:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[CH:17]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(CNC(=O)OC(C)(C)C)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-(tert-butoxycarbonylamino-methyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=506.44.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].O.Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1>C1(C)C=CC=CC=1.CS(C)=O.C(O)(=O)C>[Cl:21][C:20]1[C:15]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[O:9][CH3:10])[NH2:1])=[N:16][CH:17]=[C:18]([Cl:22])[CH:19]=1
Reactant: COc1ccc(N)cc1O
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(N)cc1Oc1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A mixture of 14.0 g (0.1 mol) of 5-amino-2-methoxyphenol and 6.7 g (0.1 mol) of potassium hydroxide (85%) in 100 ml of toluene and 100 ml of dimethyl sulfoxide is dewatered at 150° C. in a sulfonating flask equipped with a water separator. After 3 hours the toluene is distilled off, the mixture is cooled to 80° C. and 18.2 g (0.1 mol) of 2,3,5-trichloropyridine in 25 ml of dimethyl sulfoxide are added. The mixture is stirred for 3 hours at 120° C. and then cooled and 5 ml of acetic acid are added. After distillation under a high vacuum, the residue is extracted with 200 ml of water and 300 ml of methylene chloride. The organic phase affords 28 g of 3-(3,5-dichloropyrid-2-yloxy)-4-methoxyaniline as congealing oil. Melting point 95°-105° C.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5](=[O:7])[NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][SiH:16]([CH3:18])Cl>O1CCCC1>[CH3:15][SiH:16]([CH3:18])[N:4]1[CH2:3][CH:2]([CH3:1])[O:6][C:5]1=[O:7]
Reactant: C[SiH](C)Cl
Reactant: CC1CNC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CN([SiH](C)C)C(=O)O1

Procedure:
A 3-dimethylsilyl-5-methyl-2-oxazolidinone was prepared in accordance with the following procedure. A stirred mixture of 60.6 grams of 5-methyl-2-oxazolidinone and 62.4 grams of triethylamine was prepared in a tetrahydrofuran solvent. To this mixture, 67.5 ml of dimethylchlorosilane was added dropwise over a period of 90 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCCC1=O.C[O-].[Na+].[CH3:22][C:23]1([CH3:35])[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH:24]1[CH2:30][CH2:31][CH:32](Cl)[CH3:33]>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:33][CH2:32][CH2:31][CH2:30][CH:24]2[CH:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:23]2([CH3:22])[CH3:35])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(Cl)CCC1C(C)CCCC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[O-]
Agent: [I-]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(OCCCCC2C(C)CCCC2(C)C)cc1
Temperature: 25 °C

Procedure:
Methanol was removed by distillation from a mixture of 11.7 g (77 mmol) 4-hydroxybenzoic acid methyl ester, 200 ml N-methylpyrrolidone, and I3.8 g (77 mmol) 30% sodium methylate solution in methanol, then 0.6 g tetrabutylammonium iodide and 20.0 g (92 mmol) 4-(1,1,3-trimethyl-2-cyclohexyl)-2-butyl chloride were added. This was followed by heating with stirring for 8 hours to 160° C. After cooling to room temperature, the reacted solution was filtered off from the sodium chloride formed, concentrated to dryness under reduced pressure, the evaporation residue was taken up in methylene chloride, washed with water, dried with sodium sulfate and, after concentration by evaporation, chromatographed on silica gel (Merck) (eluent: methylene chloride/toluene 7:3). 13.9 g (54% of the theoretical) of 4-(4-(1,1,3-trimethyl-2-cyclohexyl)-butoxy)-benzoic acid methyl ester were obtained in the form of a colorless oil having a refractive index at 20° C. of 1.5197.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[I-].[Li+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH:16]1[CH2:20][C:19](=[O:21])[CH:18]=[CH:17]1.[OH-].[Na+]>COC(C)(C)C.C1(C)C=CC=CC=1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]1[CH2:20][C@H:19]([OH:21])[CH:18]=[CH:17]1
Reactant: O=C1C=CC(OC2CCCCO2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A slurry of lithium aluminum hydride (222 mg, 5.8 mmol), lithium iodide (3.2 g, 24 mmol), tert-butyl methyl ether (6 mL) and toluene (16 mL) is cooled to -15° C. A solution of 4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enone (2.179 g, 11.97 mmol, prepared in example 5) in tert-butyl methyl ether (2 mL) and toluene (2 mL) is added dropwise over 40 minutes. The reaction mixture is allowed to stir for 30 minutes. Then sodium hydroxide (1N, 5 mL) is added slowly to the reaction mixture. The slurry is filtered and the resulting phases separated. The aqueous phase is extracted with ethyl acetate (2×10 mL). The organic extracts are combined with the organic phase, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude oil is then purified by chromatography (silica gel, 30 g, 50% ethyl acetate/hexane, 400 mL) to provide the title compound (1.62 g, 73%), cis/trans/1-2+1-4 addition, 88/8/4; 1H NMR (CDCl3) δ6.1 (m, 1H), 4.7 (m, 1H), 4.6 (m, 2H), 3.9 (m, 1H), 3.5 (m, 1H), 2.7 (m, 1H), 1.4-2.0 (m, 8H); 13C NMR (CDCl3) δ 137.2,137.1, 134.8, 133.6, 98.3, 97.8, 79.7, 79.5, 74.7, 74.5, 62.6, 62.5, 42.0, 41.1, 31.1, 30.9, 25.4, 19.6, 19.5; IR (neat) νmax 2944, 2870, 2855, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm-1 ; MS (CI) m/e (% relative intensity) 183 (M+H+, 7), 167 (M+H+ -H2O, 40), 85(100).
Reaction SMILES: C(Cl)CCl.C1C=[CH:7][C:8]2N(O)N=N[C:9]=2[CH:10]=1.C1(C(O)=O)CC1.[NH:21]([C:23]1[N:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[C:26]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:27]([C:33]1[CH:38]=[CH:37][C:36]([C:39]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=1)=[N:28]2)[NH2:22].C(O)(=O)C>C(OCC)(=O)C.CN1C(=O)CCC1.C(Cl)Cl>[CH:9]1([C:10]2[N:32]3[C:23]([C:24]4[CH:25]=[C:26]([C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=5)[C:27]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41][CH2:40]6)=[CH:35][CH:34]=5)=[N:28][C:29]=4[CH:30]=[CH:31]3)=[N:21][N:22]=2)[CH2:7][CH2:8]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Agent: O=C(O)C1CC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(C6CC6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added EDC (535 mg, 2.79 mmol), HOBt (377 mg, 2.79 mmol), anhydrous DCM (17.5 mL), anhydrous NMP (.2.5 mL), and cyclopropanecarboxylic acid (248 mg, 5.40 mmol). The reaction mixture was then stirred at room temperature under an atmosphere of nitrogen for 30 minutes. Then added tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (1.221 g, 2.54 mmol). The reaction mixture was then permitted to stir overnight (18 hours) at room temperature under an atmosphere of nitrogen. Acetic acid (2.178 mL, 38.0 mmol) was added and the reaction mixture was heated in a hot oil bath at 80° C. for 2 hours. The reaction mixture was permitted to cool to room temperature and ethyl acetate was added and the mixture was washed with a saturated solution of sodium bicarbonate, water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 90% EtOAc/DCM (isocratic). The appropriate fractions were combined and the solvent was removed in vacuo to give tert-butyl {1-[4-(3-cyclopropyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6 g) as a pink solid. HRMS (M+H)+: observed=532.2729, calculated=532.2707.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.Cl[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C>ClCCl>[CH2:32]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1)[C:31]1[CH:34]=[CH:35][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1NCCc2ccc(NCc3ccccc3)cc21
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Sodium triacetoxyborohydride (1.29 g, 6.16 mmol) was added to a stirred solution of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 3.08 mmol), 4-chlorobenzaldehyde (431 mg, 3.08 mmol) and acetic acid (183 μl, 3.08 mmol) in anhydrous dichloromethane (25 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (50% ethyl acetate in dichloromethane) to yield the title compound as a pale yellow solid (287 mg, 16%). HPLC retention time 4.09 min. Mass spectrum (ES+) m/z 287 (M+H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:13])/[CH:10]=[CH:11]/[CH3:12]>[Cl-].[Zn+2].[Cl-]>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:9](=[O:13])[CH2:10][CH:11]([CH3:12])[O:5][C:4]=2[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: C/C=C/C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1CC(=O)c2ccc(O)cc2O1
Yield: 41 %

Procedure:
Resorcinol (11 g) and 17.2 g of crotonic acid were heated at 180° C. for 30 minutes together with 15 g of zinc chloride with stirring. The reaction mixture was extracted with ethyl acetate, and purified by column chromatography to give 7.3 g of 2,3-dihydro-7-hydroxy-2-methyl-4-oxobenzopyran. The OH group of the compound was benzylated in a customary manner, and then the product was reacted with CH3MgBr in tetrahydrofuran. The product was then hydrogenated in ethanol at room temperature for 13 hours in the presence of 5% palladium-carbon. The hydrogenated product was purified by column chromatography to give 4.2 g (yield 24%) of the desired product as a brown liquid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([C@H:15]([OH:19])[CH:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C@@H:9]([C@H:15]([OH:19])[CH:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@H]([C@H](O)C(C)C)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)[C@H](O)C(C)C
Yield: 92.9 %

Procedure:
In a pear flask, at rt, ethyl (2S*,3R*)-2-(dibenzylamino)-3-hydroxy-4-methyl-pentanoate (1.24 g, 3.5 mmol) was dissolved in EtOH (75 mL) and passed through the H-Cube® hydrogenator flow reactor, using 10% Pd/C as catalyst [flow:1.0 mL/min; P=1.0 bar, T=70° C.]. After evaporation of the solvent, the title compound (0.57 g, quant.) was obtained as yellowish oil and used without further purification in the following step. MS (ESI) m/z: 176 [M−H]+. 1H NMR (DMSO-d6) δ 0.83 (d, J=6.72 Hz, 3H), 0.90 (d, J=6.69 Hz, 3H), 1.19 (t, J=7.10 Hz, 3H), 1.64-1.80 (m, 1H), 3.29 (dd, J=3.36, 8.06 Hz, 1H), 3.35 (d, J=3.37 Hz, 1H), 4.08 (qd, J=0.99, 7.13 Hz, 2H).
Reaction SMILES: O1[CH:11]2[C:2]1(C)[CH2:3][C:4]1[C:5](C)(C)[CH:6](C)[CH2:7][C:8](C)(C)[C:9]=1[CH2:10]2.O1C2C1CC1C(C)(C)C(C)C(C)(C)C=1C2>>[CH2:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CC1CC(C)(C)C2=C(CC3(C)OC3C2)C1(C)C
Agent: CC1C(C)(C)C2=C(CC3OC3C2)C1(C)C
Product: c1ccc2c(c1)CCCC2

Procedure:
In Examples 13A-13J hereinafter the numerals given after the notation "epoxide" denotes the number of the respective Examples hereinbefore. The preferred compounds are "epoxide 1", "epoxide 2" and "epoxide 8", i.e. the novel epoxides 6,7-epoxy-1,1,4,4,6-pentamethyl-1,2,3,4,5,6,7,8-octahydronaphthalene, 6,7-epoxy-1,1,3,4,4,6-hexamethyl-1,2,3,4,5,6,7,8-octahydronaphthalene and 5,6-epoxy-1,1,2,3,3-pentamethyl-4,5,6,7-tetrahydroindane referred to in Examples 1, 2 and 8, respectively.
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][N:18]([C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCNCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane dihydrobromide (1.3.13.30), sodium hydride and trityl chloride.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.Br[CH2:18][C:19]#[CH:20].C([Li])CCC>O1CCCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:20][C:19]#[CH:18])[C:6]=12
Reactant: C#CCBr
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCN1c2ccccc2NC(=O)c2csc(C)c21
Yield: 50 %

Procedure:
Prepared analogously to Example la) from 4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-bromo-prop-1-yne in the presence of butyllithium and tetrahydrofuran in a yield of 50% of theory. The crude crystalline product was used for subsequent reactions without being further purified by chromatography.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][N:19]=3)=[N:13][CH:14]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:20][C:17]1[S:16][C:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:19][CH:18]=1
Reactant: COc1ccc(COc2ccc(-c3ncc(C)s3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(-c2ccc(O)cn2)s1

Procedure:
A solution of 2-(5-(4-methoxybenzyloxy)pyridin-2-yl)-5-methylthiazole (2.0 g) in TFA (10 mL) was stirred at 80° C. for 2 hours. After the reaction was complete, the mixture was evaporated. The residue was purified by chromatography (silica gel, EA/PE 1:2 to EA) to provide the title compound. MS ESI+: m/z=193 [M+H]+.