Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]=CC2C=CC(OC)=CC=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl>C(O)C>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)[CH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH3:36])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)CCCCN(CCOC(C)=O)Cc1ccc(CN=Cc2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CCCN(CCC)CCCCN(CCOC(C)=O)Cc1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 97.4 %

Procedure:
In a 50 ml recovery flask, 430 mg (0.867 mmol, 1.0 equivalent) of {(4-dipropylaminobutyl)-[4-(4-methoxybenzylidene)aminomethylbenzyl]}amino}ethyl acetate (30) was dissolved in 4.3 ml of ethanol. The solution was cooled to 0° C. After the dropwise addition of 4.3 ml of 2N hydrochloric acid over about five minutes, the mixture was stirred at 5° C. or less for 22 hours. The mixture was added with 4.3 ml of 2N hydrochloric acid at 0° C., stirred for three hours, and extracted five times with 25 ml of chloroform. The aqueous layer was slowly added with 50 ml of chloroform and 40 ml of a 3N sodium hydroxide aqueous solution to make the mixture basic, and the mixture was subjected to phase separation. The mixture was then extracted three times with 25 ml of chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated, thereby obtaining 319 mg of [(4-aminomethylbenzyl)-(4-dipropylaminobutyl)amino]ethyl acetate (14) as a slightly yellow oily substance (yield: 98%). [HPLC: 95.9% (HPLC measurement conditions A)]
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: COc1ccc(OC(=O)C2CCCc3ccc([N+](=O)[O-])cc32)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(OC(=O)C2CCCc3ccc(N)cc32)cc1

Procedure:
A 0.8-g portion of the p-methoxyphenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate obtained above was catalytically reduced with 5% palladium-carbon in acetic acid. After removal of the catalyst by filtration, the acetic acid was removed by distillation under reduced pressure to obtain p-methoxyphenyl 7-amino-1,2,3,4-tetrahydro-1-naphthoate, which was then dissolved in diethyl ether, and dry gaseous hydrogen chloride was introduced into the resulting solution to obtain 520 mg of p-methoxyphenyl 7-amino-1,2,3,4-tetrahydro-1-naphthoate hydrochloride, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:27][CH:28]=[CH:29][N:30]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Fc1ccccc1-c1ncco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A solution of N-benzylpiperazine (3.56 g, 20.2 mmol) in 25 mL of THF was cooled to 0° C. and then n-butyllithium was added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for an additional hour. The mixture was cooled to 0° C. and then 2-fluoro-1-oxazol-2-ylbenzene (1.1 g, 6.75 mmol) was slowly added. The mixture was allowed to warm to room temperature and stirred at room temperature for 90 minutes. The mixture was quenched with water and the aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (10:1) to give 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.805 g, 2.52 mmol).
Reaction SMILES: ClC1N=[C:4]([NH:18][C:19]2[C:24]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]([Cl:31])=[CH:21][N:20]=2)[C:5](=[O:17])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:31][C:22]1[CH:21]=[N:20][C:19]2[NH:18][C:4]3[C:5](=[O:17])[N:6]([CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[CH:7]=[C:26]([Si:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=3[C:24]=2[CH:23]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(Cl)cc3C#C[Si](C)(C)C)c2=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(Cl)cc43)c2=O)cc1
Yield: 86.8 %

Procedure:
Compound 66 (5.8 g, 12.3 mmol) and DIEA (3.2 mL, 18.4 mmol) were dissolved in toluene (600 mL), and the solution was heated at reflux under N2 for four days. The solution was concentrated and purified by flash chromatography (30% EtOAc/CH2Cl2) to give 4.4 g (87%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 8.54 (d, 1H, J=2.4 Hz), 8.20 (d, 1H, J=2.4 Hz), 7.37 (s, 1H), 7.32 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.8 Hz), 5.25 (s, 2H), 3.71 (s, 3H), 0.39 (s, 9H). MS (ES) [m+H] calc'd for C21H22ClN3O2Si, 412, 414; found 412, 414.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])[C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[FH:28]>>[C:19]([NH:18][C@@H:16]([C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[F:28])[CH3:17])(=[O:21])[CH3:20]
Reactant: F
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (640 mg) was added to a solution of methyl (R)-3-amino-4-(1-acetamidoethyl)benzoate (2 g) in hydrogen fluoride-pyridine (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to give 690 mg of methyl (R)-4-(1-acetamidoethyl)-3-fluorobenzoate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O.[C:18](OC(C)=C)(=[O:20])[CH3:19]>>[C:18]([O:1][C:2]1[CH:3]2[CH:5]([CH2:6][CH:7]=1)[C@@H:4]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:20])[CH3:19]
Reactant: C=C(C)OC(C)=O
Reactant: CCOC(=O)[C@H]1C2CCC(=O)C21
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H]1C2CC=C(OC(C)=O)C21

Procedure:
A mixture of ethyl (6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate (380.1 g, 2.26 mol) and sulfuric acid (18 M, 6.3 mL, 0.11 mol) in isopropenyl acetate (2.26 L) is heated at reflux using a Dean-Stark apparatus for 2.5 hours, at which time GC analysis revealed a 9:1 mixture of the title compound versus ethyl (6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate. After the removal of 950 mL of solvent by distillation over 1 hour, GC shows that the product/starting material ratio is 17:1. Additional isopropenyl acetate (900 mL) and conc. H2SO4 (3.15 mL) are added, and the mixture is stirred at reflux for another 15 hours, at which time GC shows 27:1 product/starting material. After another 1.35 L of solvent is distilled off, the mixture is cooled to room temperature before it is diluted with MTBE (2 L), H2O (250 mL), and aqueous saturated NaHCO3 (600 mL). The layers are separated and the organic layer is washed with brine (400 mL). The combined aqueous layers are extracted with MTBE (400 mL), and the combined organic layers are dried (Na2SO4), filtered, and concentrated to a dark red/brown oil (540 g). The crude oil is split into two equal portions and filtered through a pad of flash SiO2 (713 g for each batch), eluting with 10:1/heptane:ethyl acetate. The product-containing fractions from both plugs are combined and concentrated to afford the title compound as a yellow oil (460 g, 97%; 90% corrected for solvent by NMR). Column chromatography on silica gel eluting with ethyl acetate/hexanes (1:5) provides an analytically pure sample of the title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]([CH2:45][C:46]#[C:47][CH3:48])[C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:32]=[C:33]5[C:38](=[C:39]([CH3:41])[CH:40]=4)[N:37]=[C:36]([CH3:42])[C:35]([CH3:43])=[N:34]5)[N:26]=[CH:25][C:24]=3[N:44]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([C:21]2[N:22]([CH2:45][C:46]#[C:47][CH3:48])[C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:32]=[C:33]5[C:38](=[C:39]([CH3:41])[CH:40]=4)[N:37]=[C:36]([CH3:42])[C:35]([CH3:43])=[N:34]5)[N:26]=[CH:25][C:24]=3[N:44]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(Cc3cc(C)c4nc(C)c(C)nc4c3)c(=O)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2cnn(Cc3cc(C)c4nc(C)c(C)nc4c3)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of trifluoroacetic acid are added to 220 mg of 2-(4-tert.-butyloxycarbonyl-piperazin-1-yl)-3-(2-butyn-1-yl)-5-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 4 ml methylene chloride. The reaction mixture is stirred for one hour at ambient temperature. Then it is diluted with methylene chloride and washed with saturated sodium hydrogen carbonate solution. The organic phase is dried and evaporated down. The glassy residue is dissolved in dioxane, frozen with liquid nitrogen and dried at 6×10−3 mbar. A white solid remains.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:33]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)=[O:7].[H][H]>CO.[Pd]>[F:53][C:50]([F:51])([F:52])[C:48]1[CH:47]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:54])[F:55])[CH:49]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH2:33])[CH:27]=1)=[O:7]
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N=C(c4ccccc4)c4ccccc4)c3)C2)CCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N)c3)C2)CCO1
Yield: 35.2 %

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(diphenylmethyleneamino)-4-methylbenzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (65 mg) in methanol was subjected to hydrogenolysis (3 atm hydrogen pressure) using 10% palladium on carbon (6 mg, 50% wet) at 50° C. for 16 hours. After cooling, the mixture was filtered and the filtrate was evaporated in vacuo. Ethyl acetate and water were added to the residue and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (NH-DM1020, Fuji Silysis Chemical Ltd.) with a mixture of hexane and ethyl acetate (1:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-piperazine (18 mg). To a solution of the obtained compound in methanol was added 4N hydrogen chloride in ethyl acetate (0.05 ml) and the mixture was evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2-((2S)-2-(methoxymethyl)morpholino]ethyl]-piperazine trihydrochloride (20 mg).
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.BrC1C=CC(Br)=CC=1[N+]([O-])=O.[Br:27][C:28]1[CH:48]=[CH:47][C:31]([NH:32][C:33]2[S:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C:34]=2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:30]([N+:49]([O-])=O)[CH:29]=1.Cl.O.O.[Sn](Cl)Cl>C(O)C>[NH2:49][C:30]1[CH:29]=[C:28]([Br:27])[CH:48]=[CH:47][C:31]=1[NH:32][C:33]1[S:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[C:34]=1[C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)c1c(Nc2ccc(Br)cc2[N+](=O)[O-])sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.0 g), 2,5-dibromonitrobenzene (8.5 g) and dimethyl sufoxide (70 ml), crude crystals (7.3 g) of ethyl 2-(4-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (70 ml), 18% hydrochloric acid (70 ml) and tin(II) chloride-dihydrate (15.7 g), ethyl 2-(2-amino-4-bromoanilino)benzo[b]thiophene-3-carboxylate (3.3 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11])=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CS(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[C:5]([F:11])[CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(Oc2ccccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
156 mg (1 mmol) of 2,4-difluoracetophenone were dissolved in 5 ml DMSO, taken and combined with 200 mg (1.45 mmol) of K2CO3. 128 mg (1 mmol) of 2-chlorophenol were dissolved in 5 ml DMSO and added thereto and the mixture was stirred for 2 days at ambient temperature. The reaction mixture was filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. The substance was purified by reversed-phase chromatography.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][CH2:23][CH2:24]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCC)(=O)C1C=CC=CC=1>>[NH2:18][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:21][CH2:22][CH2:23][CH3:24])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: CCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-5-nitro-3-n-propoxybenzoic acid and following the procedure described, 5-amino-4-benzoyl-3-n-propoxybenzoic acid is obtained with a melting point of 220° -222° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=O)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[S:45])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (211 mg, 0.45 mmol) in toluene (15 mL) was added lawesson's reagent (181 mg, 0.45 mmol) under nitrogen. The resulting mixture was heated under reflux for 2 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 5% MeOH in dichloromethane) to give the title compound as a yellow solid (124 mg, 57%). 1H NMR (500 MHz, CDCl3): 9.47 (1H, br s), 7.30-7.24 (7H, m), 7.18 (1H, s), 7.16-7.14 (2H, m), 5.17 (2H, s), 5.04 (1H, br s), 2.55-2.25 (4H, m), 2.10-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:52][CH2:51][C:46]2([O:50][CH2:49][CH2:48][O:47]2)[CH2:45][CH2:44]1)=O>>[O:50]1[C:46]2([CH2:45][CH2:44][N:43]([CH2:41][CH2:40][O:1][C:2]3[CH:38]=[CH:37][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=4[CH:20]4[CH2:29][CH2:28][C:27]5[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=5[CH2:21]4)=[CH:4][CH:3]=3)[CH2:52][CH2:51]2)[O:47][CH2:48][CH2:49]1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCC4(CC3)OCCO4)cc2)c1
Yield: 38.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.1 mg) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)=[N+:24]=[N-:25].CCN(C(C)C)C(C)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C.CCOC(C)=O>[N:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:32])=[CH:33][CH:34]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
TBTU (1.28 g; 3.98 mmol; 1.3 eq.) was added to a cooled (0° C.) solution of 4-azidobenzoic acid (500 mg; 3.06 mmol; 1.0 eq.) and DIEA (1.2 mL; 7.05 mmol; 2.3 eq.) in DMF (10 mL). After 15 min, morpholine (324 μl; 3.68 mmol; 1.2 eq.) was added and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was diluted with EtOAc and washed twice with an aqueous saturated solution of NaHCO3 then with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound as a beige solid (710 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 7.46 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 3.59-3.47 (m, 8H). HPLC (Condition A): Rt 2.21 min (purity 98.2%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([CH3:16])=[N:10]2)=[O:4].FC1C(C(=O)C)=C2C(=CC=1)N=C(C)C(NC1(C)CC1)=N2>>[Br:1][CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][C:18]1([CH3:21])[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)(C)C
Agent: CC(=O)c1c(F)ccc2nc(C)c(NC3(C)CC3)nc12
Product: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1(C)CC1
Yield: 56 %

Procedure:
2-Bromo-1-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (610) (846 mg, 56% yield) as a light yellow solid was prepared according to the procedure described for Intermediate 605, using 1-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (610b) (1.18 g, 4.31 mmol) as the starting material. m/z (ESI, +ve ion) 352.1/354.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[H-].[Na+].Cl[C:12]1[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH:3]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reaction time: 0.33 h

Procedure:
7-2 (2.0 g, 15.4 mmol) and 1 equivalent of sodium hydride (0.62 g, 15.4 mmol) were suspended in THF and stirred for 20 minutes before adding 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (2.23 g, 15.4 mmol) and the other equivalent sodium hydride simultaneously. The reaction was refluxed for 1.5 hours, cooled, quenched with methanol and water, evaporated to dryness and partitioned between methylene chloride, methanol and water. The aqueous layer was evaporated to dryness and purified on a silica column (DCM to 9:1:0.1 DCM:MeOH:NH4OH) to afford 35-1. 1H-NMR (CD3OD): 8.75(s, 1H); 8.10(s, 1H); 7.09(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]([CH:6](O)/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C(/C1C(=O)CC([OH:25])C=1C)=C/CCC>O>[CH:7](/[CH:6]1[C:2]([OH:13])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:25])=[CH:8]/[CH2:9][CH2:10][CH3:11]
Reactant: CCC/C=C\C(O)c1ccc(C)o1
Reactant: CCC/C=C\C1=C(C)C(O)CC1=O
Solvent: O
Product: CCC/C=C\C1C(=O)C=CC1(C)O
Temperature: 100 °C

Procedure:
In the same flask as used in Example 1, there were charged 5-methyl-α-(2-cis-pentenyl)furfuryl alcohol (I-2) (18 g) and water (720 g), and the mixture was stirred at 100° C. under a pH of 4.7-4.9. The reaction mixture was then treated in the same manner as in Example 1 to give a mixture (14.2 g) of 2-(2-cis-pentenyl)-3-hydroxy-3-methyl-4-cyclopentenone (II-2) and 2-(2-cis-pentenyl)-4-hydroxy-3-methyl-2-cyclopentenone (III-2). Yield, 79%.
Reaction SMILES: Cl.[CH3:2][C:3]([N+:13]([O-])=O)([CH3:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>CCO.O.[Zn]>[NH2:13][C:3]([CH3:12])([CH3:2])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CC(C)(C(O)c1ccccc1)[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CC(C)(N)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
37% Hydrochloric acid (1 mL) was added to a stirred solution of 2-methyl-2-nitro-1-phenylpropan-1-ol (26c, 0.12 g, 0.6 mmol in EtOH (10 mL) and water (5 mL). Zinc powder (0.241 g, 3.6 mmol) was slowly added in small portions, the mixture was stirred for 4 hours at +70° C. The mixture was filtered to remove solid zinc residues and concentrated to ⅓ volume by evaporation, diluted with water (50 mL) and washed with ether (125 mL). The acidic waterphase was made basic using KOH (aq) solution, the formed slurry was extracted with ether (3×150 mL). The organic phase was dried (MgSO4) filtered and evaporated. The crude product was further purified by HPLC. Yield 60 mg (60%).