Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][CH:2]1[N:7]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc2ccccc2n1
Temperature: 130 °C

Procedure:
A reaction mixture of 1 g (4.99 mmol) of tert.butyl 3-methyl-piperazine-1-carboxylate, 0.588 g (3.6 mmol) of 2-chloroquinoline and 0.498 g (3.6 mmol) of potassium carbonate is heated to 130° C. for three hours. Then the solvent is distilled off. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=30:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[C@@H:49]1(O)[CH2:53][CH2:52][CH2:51][C@H:50]1[OH:54].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([C@@H:49]2[CH2:53][CH2:52][CH2:51][C@H:50]2[OH:54])[CH:7]=1
Reactant: O[C@@H]1CCC[C@H]1O
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@@H]1CCC[C@H]1c1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step 2.3 g) and (trans)-cyclopentane-1,2-diol (1 g) in THF (50 ml) was added NaH (0.30 g) slowly and the reaction was then allowed to stir for 18 h at RT. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting clear oil was purified by column chromatography on silica gel EtOAc/iso-Hexane (2:8) to give the subtitle compound as a clear colourless oil. Yield 0.94 g
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N+:15]([C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)([O-:17])=[O:16].O[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCCC(C)C.CCOC(C)=O>[N+:15]([C:18]1[CH:19]=[N:20][N:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:22]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
DIAD (3.92 mL, 19.90 mmol) was added dropwise to a stirred solution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.67 g, 13.27 mmol) and triphenylphosphine (5.22 g, 19.90 mmol) in THF (30 mL) cooled to 0° C. under a nitrogen atmosphere. The resulting solution was stirred at 0° C. for 10 minutes then allowed to warm to room temperature and stirred overnight. The mixture was diluted with isohexane (80 mL) and EtOAc (20 mL) and then stirred vigorously. The mixture was filtered and the solid washed with isohexane (20 mL). The combined filtrates were evaporated and the residue was purified by chromatography on silica, eluting with a gradient of 20-50% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (3.63 g, 92% yield); 1H NMR spectrum: (300 MHz, DMSO) 1.42 (9H, s), 1.79-1.84 (2H, m), 2.01-2.05 (2H, m), 2.87-2.98 (2H, m), 4.40-4.47 (1H, m), 8.28 (1H, s), 8.95 (1H, s). b) A mixture of tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (3.63 g, 12.25 mmol) and 10% palladium on carbon (0.326 g, 0.31 mmol) in EtOH (200 mL) were stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through Celite and the filtrate loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (2.100 g, 64% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.41 (9H, s), 1.65-1.74 (2H, m), 1.89-1.92 (2H, m), 2.81-2.93 (2H, m), 3.75 (2H, s), 3.99 (2H, d), 4.09-4.16 (1H, m), 6.91 (1H, s), 7.06 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=211.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[C:8]3[C:14](=[O:21])[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[O:17][C:7]=3[C:6]=2[N:5]=[C:4]([C:22]([OH:24])=[O:23])[CH:3]=1.C(=O)(O)[O-].[Na+:29].CC(C)=O>O>[Cl:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[C:8]3[C:14](=[O:21])[CH:15]=[C:16]([C:18]([O-:20])=[O:19])[O:17][C:7]=3[C:6]=2[N:5]=[C:4]([C:22]([O-:24])=[O:23])[CH:3]=1.[Na+:29].[Na+:29]
Reactant: COc1cc2c(Cl)cc(C(=O)O)nc2c2oc(C(=O)O)cc(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc2c(Cl)cc(C(=O)[O-])nc2c2oc(C(=O)[O-])cc(=O)c12
Yield: 46.1 %

Procedure:
The product of step (f) (0.7316 g) suspended in water was treated with sodium bicarbonate (0.45 g) and stirred until complete dissolution occurred. The solution was treated with pure acetone and cooled. The precipitated product was collected by filtration and dried under reduced pressure at 80° C. for four hours, affording (0.38 g) of the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[CH3:1][O:29][C:28](=[O:30])[C@H:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.6 %

Procedure:
Potassium carbonate (2.07 g), methyl iodide (1.25 mL) were added to a solution of N-tert-butoxycarbonyl-O-benzyl-L-homoserine (3.10 g) in DMF (15 mL). After stirring at room temperature for 5 hr, the solvent was removed in vacuo. Ethyl acetate and water were added to the residue. The separated organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound (3.13 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.44 (m, 9H), 1.95-2.15 (m, 2H), 3.55 (m, 2H), 3.68 (s, 3H), 4.44 (m, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.7 Hz, 1H), 5.47 (m, 1H), and 7.27-7.37 (m, 5H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:16][CH:17]([CH2:20][CH3:21])[C:18]#[CH:19]>C(Cl)Cl>[OH:16][CH:17]([CH2:20][CH3:21])[C:18]#[C:19][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: C#CC(O)CC
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Solvent: ClCCl
Product: CCC(O)C#Cc1cnc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
546 mg of dimethyl 5-bromodicarboxylate (from Example 3) and 202 mg of 3-hydroxy-1-pentine are dissolved in methylene chloride in a flask flushed with argon, and 840 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 28 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 18 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation, 404 mg of a yellow oil which crystallizes at 0° C. remain.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:22]=[O:23])=[CH:11][CH:10]=1.[CH3:24][NH:25][CH3:26]>CO>[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([N:25]([CH3:26])[CH3:24])=[O:23])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)Nc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude intermediate from Step A in 4 mL of methanol was treated with 4 mL of 40% aqueous dimethylamine. After stirring at room temperature for 15 minutes, the reaction mixture was evaporated under vacuum and the residue dissolved in 4 mL of methanol and treated with 1 mL of 10% methanolic p-toluenesulfonic acid. After 15 minutes at room temperature, the reaction mixture was treated with saturated aqueous sodium bicarbonate. The mixture was diluted with water then extracted with methylene chloride. The organic layer was dried and evaporated under vacuum; the residue was purified by preparative thin layer chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to afford 133 mg of product.
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:45][O:46][C:47](=[O:64])[C@@H:48]([NH2:63])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][C:57]2[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:64])[C@@H:48]([NH:63][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][C:57]2[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=2)=[CH:54][CH:55]=1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccncc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccncc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Yield: 40.1 %

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (57 mg) was prepared from (S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-Amino-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride (63 mg) following general procedure A. LC-MS (m/z) 858.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.[CH:24]1([NH:29]N)[CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([N:29]2[C:16]([C:11]3[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:17][CH:18]=[N:19]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NNC1CCCC1
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: OCc1cccnc1-c1ccnn1C1CCCC1
Temperature: 80 °C

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 3.205 g, 10.0 mmol, 1 eq.) in EtOH (30 mL) was added cyclopentylhydrazine HCl salt (1.639 g, 12.0 mmol, 1.2 eq) at RT. The mixture was heated at 80° C. for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of regio-isomers, the less polar (2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (440 mg). MS (ESI) m/z 244.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([CH2:18][CH:17]=[CH2:16])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cnccc1Cl
Temperature: 60 °C
Yield: 70.9 %

Procedure:
A mixture of (4-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (6.78 g, 29.7 mmol), allyl bromide (5.1 g, 40.8 mmol) and cesium carbonate (20.1 g, 61.8 mmol) in DMF (200 mL) is heated at 60° C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to afford allyl-(4-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (5.66 g, 71%). MS: 269 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.42(d, 1H), 7.40 (d, 1H), 5.80-5.98 (m, 1H), 4.35-4.51 (m, 1H), 3.90-4.07 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.N1C=CC=CC=1.[CH2:21]1[O:31][C:24]2([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[O:23][CH2:22]1>C1COCC1.CO.C(Cl)Cl>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2([OH:30])[CH2:28][CH2:29][C:24]3([O:31][CH2:21][CH2:22][O:23]3)[CH2:25][CH2:26]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
In a dried 3-neck flask, 5-bromo-2-methoxypyridine (12.6 g, 67.2 mmol) was dissolved in dry THF (130 mL) and cooled to −78° C. under N2. 2.5M n-BuLi in hexanes (28.2 mL, 70.4 mmol) was added dropwise and the mixture stirred at −78° C. for 50 min. To pyridine mixture was slowly added a solution of 1,4-cyclohexanedione mono-ethylene ketal (10.0 g, 64.0 mmol) in dry THF (25 mL). The resulting mixture was stirred at −78° C. for 80 min. The reaction was quenched with sat'd NH4Cl and extracted with CH2Cl2 (3×). The combined extracts were dried (MgSO4), filtered, and concentrated to give a yellow oil. Flash chromatography on silica gel eluting with 10% MeOH/CH2Cl2 afforded the title compound as a yellow solid; yield 16.5 g, 62.2 mmol, 97%; 1H NMR (CDCl3) δ 8.26 (s, 1H), 7.72 (d, 1H), 6.69 (d, 1H), 3.96 (t, 4H), 3.91 (s, 3H), 2.21 (s, 1H), 2.08 (m, 4H), 1.82 (m, 2H), 1.66 (m, 2H); MS m/z/z=266.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)=[C:11]([O:26][CH3:27])[CH:10]=1)C>O>[CH3:23][C:22]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:28])=[O:5])=[CH:10][C:11]=2[O:26][CH3:27])=[N:18][C:19]([CH3:25])=[C:20]([CH3:24])[N:21]=1
Reactant: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(/C=C/C(=O)O)ccc1OCc1nc(C)c(C)nc1C
Yield: 94.6 %

Procedure:
Adding water (20 mL), NaOH (0.14 g, 3.5 mmol) into a 100 mL round-bottom flask, stirring to dissolve, then adding 95% alcohol (20 mL), (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl) methoxy)-3-methoxyphenyl)acrylic acid ethyl ester (1.0 g, 2.8 mmol), stifling under room temperature to react for 4 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.5, Rf of product=0), distilling out the alcohol under reduced pressure, adjusting pH of the reaction solution to 4-5 with 6.0M HCl while keeping the reaction solution cool to separate out solid, filtering, washing the solid with cool water for three times, processing with vacuum filtration, recrystallizing with anhydrous alcohol, drying under 70° C. for 8 hours to obtain 0.87 g white crystalloid of (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-3-methoxyphenyl)acrylic acid, wherein a yield is 94.6%, m.p. 156-158° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cn1ccc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of ethyl 2-(6-nitro-1H-indol-1-yl)acetate (20.96 mmol, 1 equiv.), iron powder (83.8 mmol, 4 equiv.), ammonium chloride (83.87 mmol, 1 equiv.) and ethanol/water (2.5:1, 56 ml) was stirred for 2 h at boiling temperature. The reaction mixture was cooled to 25° C. and filtered over celite. The filtrate was diluted with ethyl acetate and water, the phases were separated, and the organic phase was washed with sodium hydrogen carbonate solution and sat. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (15% ethyl acetate in hexane). Yield: 55%
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([NH2:21])[N:12]=[C:13](N3C=NC=N3)[C:14]=2[N:15]=1>C1COCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([NH2:21])[N:12]=[C:13]([O:1][CH2:2][CH3:3])[C:14]=2[N:15]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium ethoxide (2.2 mL; 21 wt % in ethanol) was added to a suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1 g) in THF (50 mL). After stirring at room temperature for 30 minutes, THF was removed in vacuo and the residue was diluted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine as a beige solid (0.71 g, yield: 79%) which was characterized by its mass spectrum as follows: MS (m/z) 225.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH2:10].CO.[OH-].[Na+]>O.C(O)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:9][CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Oc1cccc(NCCc2ccccn2)c1
Yield: 79.9 %

Procedure:
With stirring a mixture of 44.0 g of 3-hydroxyaniline, 60.0 g of 2-vinylpyridine, 140.0 ml of methyl alcohol and 5.0 ml of glacial acetic acid was maintained at reflux temperature for approximately twenty-four hours. The methyl alcohol was removed by distillation and a mixture of water and toluene was added to the resultant residue. Three layers resulted. Sufficient 5 percent aqueous sodium hydroxide was added to adjust the water layer to approximately pH 7. The bottom oil layer was separated, and dried under reduced pressure to obtain a gummy solid which was triturated with hexane to obtain 69.0 g of N-[2-(2-pyridyl)ethyl]-3-hydroxyaniline(Formula V: R4 =R9 =H; R10 =OH), a pale tan solid which after being exposed to air turned into a taffy-like solid. The nuclear magnetic resonance spectrum was concordant with the assigned structure. The water layer was discarded. The toluene layer was washed first with water and then with saturated sodium chloride solution and evaporated to dryness under reduced pressure. The residue was recrystallized from a mixture of ispropanol and hexane to obtain 3.9 g of N-[2-(2-pyridyl)ethyl]-3-hydroxyaniline, a white solid which melted at 118°-120° C. A significant infrared maximum appeared at 1195 cm-1 (N--C;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:31][C@@H:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:34]3([CH2:35][CH2:36]3)[CH2:33]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: Cc1c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (50 mg, 0.170 mmol), (7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (108 mg, 0.509 mmol) and dimethyl sulfoxide (4 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-amino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 10%. Also, residual ratio of the starting material was 90%.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH2:45]([O:44][CH:43]([O:47][CH2:48][CH3:49])[C@@H:42]([N:30]([CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[C:28](=[O:29])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)[CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH3:50])[CH3:46]
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 78 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.