Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])(O)=O.[Na+]>CC(N(C)C)=O.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:24][C@H:23]([CH2:27][OH:26])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:30])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([S:32][CH3:31])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:15])([CH3:16])[C:9]=2[CH:17]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)O1
Reactant: C[S-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CSc1ccc2c3c([nH]c2c1)C(C)(C)c1cc(OC[C@H](O)CO)ccc1C3=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (47.3 mg, 0.101 mmol), sodium methanethiolate (34.6 mg, 0.493 mmol), Pd2(dba)3 (13.1 mg, 0.0413 mmol), and Xantphos (17.9 mg, 0.0309 mmol) were dissolved in DMA (0.5 ml) and subjected to microwave irradiation at 200° C. for 30 min under nitrogen atmosphere. The resultant was partitioned between aqueous solution of potassium dihydrophosphoric acid and ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by thin layer chromatography (ethyl acetate/DCM). The resulting solid was dissolved in THF (0.23 ml) and MeOH (0.06 ml), and then added with 0.5 M sulfuric acid (0.12 ml). The resulting mixture was stirred at 60° C. for 2 hrs. The reaction solution was diluted with diethyl ether and neutralized with sodium hydrocarbonate (15.5 mg, 0.185 mmol). Thereafter, the solution was partitioned between brine and ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting residues were added with diethyl ether. The precipitated solid was filtered to obtain the title compound as a white solid (15.8 mg, 39%).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:15][CH:14]([NH2:16])[CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O.O>[N+:30]([C:29]1[C:24]([NH:16][CH:14]2[CH2:13][N:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=3)[CH2:15]2)=[N:25][CH:26]=[CH:27][CH:28]=1)([O-:32])=[O:31]
Reactant: NC1CN(c2ccc3ccccc3n2)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Yield: 83.3 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (0.90 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitro-pyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give 3-nitro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyridin-2-amine (1.05 g, 3.20 mmol, 85% yield) as yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[C:13]=1[Cl:14]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: OCCCCBr
Product: Clc1cccc(OCCCCBr)c1Cl

Procedure:
This example was prepared by substituting 3-bromopropanol with 4-bromobutanol and substituting 1-naphthol with 2,3-dichlorophenol in EXAMPLE 31A.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c2cccnc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(F)c(Cl)c2cccnc12
Yield: 49.3 %

Procedure:
In a similar fashion using route 6 general procedure 14, 5-chloro-6-fluoro-8-nitroquinoline (Intermediate 41) (300 mg, 1.34 mmol), Raney nickel (60 mg, 20% wt), hydrazine hydrate (270 mg, 5.40 mmol) and MeOH (5 ml) gave the title compound (130 mg, 49%) which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][NH:10][C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Br[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][N:20]2[Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[NH:3][C@H:4]2[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[N:10]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][N:20]3[Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])=[CH:16][CH:15]=2)[CH2:11]1
Reactant: CC1(C)CN[C@H]2CCCC[C@H]2N1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CC(C)(C)N[C@@H]4CCCC[C@@H]43)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.3 %

Procedure:
A toluene (8 mL) suspension of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (337 mg, 2.00 mmol), 6-bromo-1-(triisopropylsilyl)-1H-indole (846 mg, 2.40 mmol), sodium tert-butoxide (269 mg, 2.80 mmol), palladium (II) acetate (22.5 mg, 0.0902 mmol), and tri-tert -butylphosphine tetrafluoroborate (29.1 mg, 0.101 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature. Then, water (0.5 mL) and ethyl acetate (10 mL) were added thereto, and the mixture was stirred, followed by addition of magnesium sulfate. Insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane:ethyl acetate) to obtain colorless, amorphous (4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline (0.75 g, yield; 85%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>CC#N>[CH:18]1([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccc(OCC2CCCCC2)cc1

Procedure:
A mixture of 4-hydroxybenzaldehyde (1.22 g, 10.0 mmol), K2CO3 (1.45 g, 10.5 mmol), and bromomethylcyclohexane (1.54 mL, 11.0 mmol) in CH3CN (20 mL) was stirred at reflux for three days. The reaction mixture was then cooled, poured into 1 M aq NaOH and extracted with Et2O. The extract was washed with H2O and brine. The aqueous washes were reextracted once with Et2O, and the combined extracts were dried over MgSO4 and concentrated to 2.03 g (93%) of ether as a solid. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)NCC(=O)OCc1ccccc1

Procedure:
10.3 Parts N-t-butoxycarbonylglycylglycine benzyl ester is dissolved in 200 parts dioxane and treated with a 10 fold excess of 2 N hydrochloric acid in dioxane for 10 minutes. Removal of the solvent under reduced pressure affords pure glycylglycine benzyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Br[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:13]([CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])[CH:14]=2)=[CH:26][CH:27]=1
Reactant: CC(Br)C(N)=O
Reactant: COc1ccc(COc2ccc(NS(=O)(=O)c3ccc(C)cc3)nc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(=NS(=O)(=O)c3ccc(C)cc3)n(C(C)C(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
To a solution of N-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-4-methylbenzenesulfonamide (3 g, 7.80 mmol) in N,N-dimethylformamide (30 mL) were added 2-bromopropanamide (2.82 g, 18.4 mmol) and N,N-diisopropylethylamine (4.04 mL, 23.4 mmol), and the mixture was stirred at room temperature for 2 days. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) to give the title compound (2.64 g, 74%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([CH:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:41]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1cnn(C2CCOCC2)c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnn(C3CCOCC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 18 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-(tetrahydro-pyran-4-yl)-1H-pyrazole following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 3): tR=2.98 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[CH2:21]([CH2:23][NH2:24])[OH:22]>>[NH2:24][CH2:23][CH2:21][O:22][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2
Reactant: NCCO
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Product: NCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 84 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) and ethanolamine to give 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-chlorophenol in 84% yield. NMR spectrum (DMSO-d6) 3.12 (t, 2H), 4.27 (t, 2H), 6.96 (d, 1H), 7.11 (d, 1H), 7.31 (d, 1H), 7.53 (dd, 1H), 8.08 (d, 1H), 8.47 (s, 1H); Mass spectrum MH+ 331.0.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH:1](=[N:17][NH:18][C:19]([NH2:21])=[NH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC=O
Reactant: N=C(N)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCC=NNC(=N)N

Procedure:
1 mol (170.3 g) of undecanal, 1.1 mol (150 g) of aminoguanidine hydrogen carbonate and 1 g of p-toluenesulphonic acid are mixed with 500 ml of toluene and refluxed with stirring. As soon as 2 mol of water have been separated using the water separator, the mixture is allowed to cool, concentrated by rotary evaporation and the dark red oil is taken up in 250 ml of petroleum ether 40/60°. The precipitate formed is filtered and washed again with petroleum ether. For recrystallisation the precipitate is dissolved in ethyl acetate and mixed with petroleum ether at boiling temperature (boiling range 40 to 60° C.) until beginning to turn cloudy. Fine crystals are obtained, m.p. 101° C. The structure and purity of the compound were confirmed by analytical and spectroscopic data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14]C)=[O:12])=[CH:5]2.[Mg].C([O-])(O)=O.[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]2
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Product: COC(=O)C1Cc2cc(N)ccc2N1
Temperature: 23.5 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
A stirred solution of the product from Step 1 (8.81 g, 0.0431 mol), under nitrogen, is treated with magnesium turnings (3.3 g) and kept for about 10 min when the solution became cloudy and an exothermic reaction began. It is stirred for an additional 5 min (23-24° C.), cooled to 6-7° C. in a water bath and kept for 5.5 h. This mixture is kept at 8° C. for 18 h, acidified to pH 3 with ice cold 6N HCl, neutralized with saturated NaHCO3, and extracted with EtOAc. The extracts are washed with water, dried (Na2SO4) and concentrated in vacuo to give 7.39 g of the titled product: MS (ES) m/z 193 (M+H+), 215 (17+Na+); 1H NMR (300 MHz, CDCl3); δ3.28 (m, 2H), 3.52 (broad s, 3H), 374 (s, 3H), 4.33 (q, 1H), 6.46 (m, 1H), 6.56 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4][N:3]=[N:2]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC.CN(C)C=O>[CH2:25]([N:4]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:1][N:2]=[N:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccccc1-c1nnnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 2-(1H-tetrazol-5-yl)benzaldehyde (100 mg, 0.57 mmol, synthesized in Example 117 (1)) in a 3:1 solution (4 mL) of tetrahydrofuran and N,N-dimethylformamide was added potassium carbonate (0.12 g, 0.86 mmol), benzyl bromide (82 μL, 0.69 mmol) at room temperature, successively. After being stirred at room temperature overnight, the reaction mixture was diluted with a 5:2 solution (7 mL) of ethyl acetate and hexane. The solution was washed with water twice, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 80/20) to obtain the title compound (126 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][S:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH:17]1([CH2:23][NH:24][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][S:15][CH3:16])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
A mixture of (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylthio)butanoic acid (4.57 g), cyclohexanemethylamine (2.28 g), HOBt (2.72 g), and EDCI (3.87 g) in DMF (50 mL) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with aqueous ammonium chloride, aqueous sodium hydrogen carbonate, and brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was crystallized from ethyl acetate and hexane to give tert-butyl [(1R)-1-{[(cyclohexylmethyl)amino]carbonyl}-3-(methylthio)propyl]carbamate (5.65 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([CH3:36])[CH:27]=4)=[CH:20][CH:19]=3)[CH2:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][C:10]1([CH:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([CH3:36])[CH:27]=4)=[CH:22][CH:23]=3)[CH2:14]2)[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:42]
Reactant: CCOC(=O)CC1(C2CC(c3ccc(OCc4cc(C)nc5ccccc45)cc3)=NO2)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1(C2CC(c3ccc(OCc4cc(C)nc5ccccc45)cc3)=NO2)CCNC1
Reaction time: 2 h

Procedure:
The intermediate 3-ethoxycarbonylmethyl-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.35 g, 0.61 mmol) from example 41 was dissolved in methylene chloride (5 mL) and TFA (3 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 2 h and was concentrated in vacuo to give (3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-pyrrolidin-3-yl)-acetic acid ethyl ester as a crude oily residue. MS found: (M+H)+=474.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccc1I
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 88 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.9 g, 25 mmole), biphenylboronic acid (5.0 g, 25 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (60 ml). To the obtained solution, an aqueous solution of sodium carbonate (8.0 g, 75 mmole, 3 eq/40 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and white needle crystals (6.8 g, 88%) were obtained.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.C(Cl)CCl>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](=[O:5])[NH:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5.00 g Z-Pro-OH in 50 ml DMF were added 3.84 g EDC, 2.73 g HOAt, 7.3 ml DIPEA and 2.2 ml benzylamine at 0° C. After stirring for 2 h the reaction mixture was concentrated, the residue was dissolved in dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation. Yield: 7.11 g colorless amorphous solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C[O-].[Na+].Br[CH2:11][C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13]>CO>[CH2:15]([N:14]([CH2:17][CH3:18])[C:12]([CH2:11][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:13])[CH3:16]
Reactant: O=C(O)CCS
Reactant: CCN(CC)C(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(=O)CSCCC(=O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 3-mercaptopropionic acid (200 mg, 1.884 mmol) in methanol (3 mL) are added sodium methoxide (204 mg, 3.768 mmol) and 2-Bromo-N,N-diethyl-acetamide (402 mg, 2.070 mmol). After stirring at 80° C. during 4 h and evaporation of solvent, the residue is treated with ethyl acetate and water, the pH is adjusted to 10 with an aqueous NaHCO3 solution and the aqueous phase is extracted with ethyl acetate. After acidification of the aqueous phase to pH 2 with an aqueous 1N HCl solution, it is extracted with ethyl acetate, then the organic phase is dried and evaporated to give the title compound.
Reaction SMILES: [N+](C1C=CC(C([N:10]2[C:16]3OC=C[C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=O)=CC=1)([O-])=O.NN>C(O)C.[Pd]>[CH:11]1[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[CH2:14][CH:15]=[CH:16][N:10]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: C1=CN=Cc2cccn2C1

Procedure:
To a solution of i mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]-diazepine in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The room temperature reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:10]=[CH:11]/[C:12]([O:14]CC)=O)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C[O-].[Na+].CO>C(O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]2[NH:1][C:12](=[O:14])[CH:11]=[CH:10][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ncc(OC)nc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1cnc2ccc(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of 0.85 g of ethyl (2E)-3-(3-amino-5-methoxypyrazin-2-yl)acrylate in 40 mL of ethanol, 2.20 g of a 28% sodium methoxide/methanol solution was added, and the mixture was heated under reflux while stirring for 7 hours 30 minutes. The reaction mixture was cooled to room temperature, the solvent was then distilled off under reduced pressure, and to the resultant residue, water, a saturated aqueous ammonium chloride solution and chloroform were added, the organic layer was separated, and the aqueous layer was added with sodium chloride and extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off and washed with diethyl ether to obtain 0.64 g of 3-methoxypyrido(2,3-b)pyrazin-6(5H)-one as a light yellow solid.