Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>CCOCC>[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Product: CCCCC(=O)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
To a suspension of copper bromide-dimethylsulfide complex (11.0 g, 53.5 mmol) in 200 mL ether at −78° C. was added 65 mL of n-BuLi (1.6M, 104.0 mmol) dropwise. The mixture was stirred at −78° C. for 45 min, warmed to −40° C. for 10 min and then re-cooled to −78° C. A solution of 4-trifluoromethylbenzoyl chloride (10.0 g, 48.0 mmol) in 50 mL ether was added dropwise at −78° C. After addition was complete, the reaction was stirred at −78° C. for 30 min, quenched with saturated (sat.) ammonium chloride and allowed to warm to room temperature (RT). The mixture was poured into ether containing ca 10 mL methanol and was washed with a mixture of ammonium chloride/ammonium hydroxide. The combined aqueous layers were extracted with ether. The combined ether layers were dried (MgSO4), filtered and concentrated to give 11.0 g of a solid. 1H NMR (CDCl3) δ 8.05 (d,2H), 7.72 (d,2H), 2.99 (t,2H), 1.80-1.67 (m,2H), 1.50-1.35 (m,2H), 0.96 (t,3H). 19F NMR (CDCl3) δ −63.13.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[S:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:36][C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Reactant: O=Cc1ccsc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccsc3)CC2)cc1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of compound 1 (500 mg; 0.99 mmol) in methanol (10 ml) was added thiophene 3-carboxaldehyde (104 ul; 1.19 mmol) followed by acetic acid (0.1 ml; 1%) and sodium cyano borohydride (186.6 mg; 2.97 mmol). The reaction mixture was stirred overnight, then sodium hydroxide 2N was added and the mixture extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave 258 mg of desired product (TFA salt).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:7][S:8][C:9]=1S(C)(=O)=O)=[O:4].C[N:19](C=O)C.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:7][S:8][C:9]=1[NH2:19])=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(S(C)(=O)=O)nsc1S(C)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(S(C)(=O)=O)nsc1N
Yield: 75 %

Procedure:
In a 3 neck flask fitted with a condenser, compound 16 (1 g, 3.33 mmol) is dissolved in THF (20 mL) and DMF (2 mL) and warmed to 50° C. Ammonia gas is then bubbled into the reaction mixture for 16 hrs. The solvent is then removed in vacuo to provide a crude solid. Water is added to the solid and the mixture is then filtered and washed with water (2×) followed by methylene chloride (5 mL×2) to provide 17 (588 mg, 75%) as a yellow powder. 1H NMR (d6 DMSO): δ 8.11 (2H, br. s), 3.74 (3H, s), 3.30 (3H, s). LRMS (M+): 237.1, (M−): 235.0.
Reaction SMILES: [CH2:1]([C@:8]12[CH2:16][C@H:12]([C:13](=[O:15])[O:14]1)[C@@H:11]([C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]1)=[O:18])[CH2:10][CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][OH:32]>CO>[CH2:1]([C@@:8]1([OH:14])[CH2:16][C@H:12]([C:13]([NH:31][OH:32])=[O:15])[C@@H:11]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1O[C@@]2(Cc3ccccc3)CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H]1C2
Solvent: CO
Product: O=C(NO)[C@H]1C[C@](O)(Cc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To a stirred solution of (1S,2S,5S)-5-benzyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-6-oxabicyclo[3.2.1]-octan-7-one (8.0 mg, 0.020 mmol) in anhydrous methanol (1.0 mL, 0.025 mol) at rt was added 1.50 M of hydroxylamine in methanol (0.396 mL). The reaction mixture was stirred at rt for 3 h. The reaction was quenched with saturated aqueous NH4Cl (15 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O (with 0.05% TFA) to give the pure product as a colorless solid (2.3 mg, 26% in yield). MS (ESI): (M+H)+=438.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=C[C:45]([O:49]C)=CC=3)CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][C:23]([O:49][CH3:45])=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCc3cc(OC)ccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2cc(OC)ccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ) 1.28, 1.95, 2.51, 2.65, 2.80, 2.95, 3.02, 3.85, 4.14, 4.65, 5.73, 6.82, 6.87, 7.28-7.35, 7.5; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1450.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH3:30])=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:29][CH3:30])[N:19]=[CH:18][N:17]=[C:16]2[O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH3:28]
Reactant: CCOc1cc2c(Cl)ncnc2cc1OC
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc2c(Oc3cccc(N)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred suspension of cesium carbonate (3.60 g, 11.06 mmol) in THF (50 mL) was added 3-aminophenol (0.91 g, 8.38 mmol). After stirring for 30 minutes at rt, 4-chloro-6-ethoxy-7-methoxyquinazoline described in Example 11A (2.00 g, 8.38 mmol) was added and the reaction mixture was heated at 50° C. for 15 h. The reaction mixture was cooled to rt and diluted with ethyl acetate. The solution was washed with aqueous 1 M NaOH solution, then brine, and dried over MgSO4. Filtration and concentrated under reduced pressure, gave a solid that was triturated with ethyl acetate. Filtration and drying afforded 3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline (1.30 g, 50%) as a cream solid, which did not require further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.08 (dd, J=8, 8 Hz, 1H), 6.36-6.49 (m, 3H), 5.30 (brs, 2H), 4.21 (q, J=7 Hz, 2H), 3.98 (s, 3H), 1.41 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 312 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][CH2:44][CH2:45][CH3:46])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][CH2:44][CH2:45][CH3:46])(=[O:42])=[O:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCCS(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CCCCS(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-butylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H36N4O5S
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2=[N:10][C:11]3[C:16]([C:17](=[O:18])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[CH:15][CH:14]=[C:13]([C:19]([OH:21])=[O:20])[CH:12]=3.[H][H]>CO.[Pd]>[CH3:1][CH:2]1[C:9]2=[N:10][C:11]3[C:16]([C:17](=[O:18])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[CH:15][CH:14]=[C:13]([C:19]([OH:21])=[O:20])[CH:12]=3
Reactant: [H][H]
Reactant: C=C1CCCCCn2c1nc1cc(C(=O)O)ccc1c2=O
Agent: [Pd]
Solvent: CO
Product: CC1CCCCCn2c1nc1cc(C(=O)O)ccc1c2=O

Procedure:
6-methylene-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (50 mg) was dissolved in MeOH (5 mL). To the mixture was added a catalytic amount of Pd/C. The reaction mixture was vacuumed and then back filled with hydrogen gas three times. After completion, the reaction was filtered and washed with methanol. The filtrate was concentrated to give the desired product. MS (ESI): 287 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:10](/[CH:12]=[N:13]\O)[N:11]=1)=[O:5].CCN(CC)CC>C(Cl)Cl>[C:12]([C:10]1[N:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:2]=2[F:1])[S:8][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=1)#[N:13]
Reactant: O=C(Nc1nc(/C=N\O)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1

Procedure:
Into a solution of Compound 72 (90 mg, 0.21 mmol) in 10 mL of CH2Cl2 was added 2-chloro-1-methylpyridium iodide (128 mg, 0.5 mmol) and NEt3 (0.1 mL).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.O>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CCOCC1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(COC2CCOCC2)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.90 mL of 4-hydroxy-tetrahydropyran in 30 mL of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 0.84 g of sodium hydride (95%, dispersion in mineral oil) in 30 mL of dry N,N-dimethylformamide at 5° C. The resulting clear solution was allowed to come to room temperature and stirring was continued for 24 hours, followed by dropwise addition of 9.40 g of 4-bromo-benzylbromide in 50 mL of dry N,N-dimethylformamide at 5° C. and stirring at room temperature for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 5.40 g of 4-(4-bromo-benzyloxy)-tetrahydropyran as an oil. EI-MS: 270 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][N:12]=1
Reactant: NCCSCc1nccs1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1cccnc1

Procedure:
5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.74 g) was reacted with 2-(2-thiazolylmethylthio)-ethylamine (1.30 g) according to the procedure in Example 2. The reaction mixture was triturated in hot water to give 2-[2-(2-thiazolylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone and this product was treated with dilute hydrobromic acid to give the title compound, m.p. 229°-233.5° (ex. methanol-water).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[CH3:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N+:15]=1[O-]>C(Cl)Cl>[Cl:3][CH2:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CC(=O)Oc1c(C)c(C)[n+]([O-])c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
A solution of 1.38 g (9.04 mmols) of phosphorus oxychloride in 5 ml of methylene chloride and a solution of 913 mg (9.04 mmols) of triethylamine in 5 ml of methylene chloride were, respectively, dropped almost simultaneously in 15 minutes into a solution of 1.85 g (8.00 mmols) of the crude product of 2, 3-dimethyl-4-acetoxyquinoline oxide in 5 ml of methylene chloride, followed by stirring at room temperature for 10 minutes. The reaction solution was washed with a saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, followed by purification by silica gel column chromatography (Wako (solvent: n-hexane : ethyl acetate=5:1) to obtain 700 mg (yield 36%) of 2-chloromethyl-3-methyl-4-acetoxyquinoline.
Reaction SMILES: Cl[C:2]1[C:3]([F:17])=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[N:7]([CH2:11][CH3:12])[C:8](=[O:10])[CH3:9].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:11]([N:7]([C:8](=[O:10])[CH3:9])[C:6]1[CH:13]=[C:2]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:3]([F:17])=[CH:4][C:5]=1[N+:14]([O-:16])=[O:15])[CH3:12]
Reactant: CN1CCNCC1
Reactant: CCN(C(C)=O)c1cc(Cl)c(F)cc1[N+](=O)[O-]
Product: CCN(C(C)=O)c1cc(N2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 78488.3 %

Procedure:
5'-Chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide (74 g, 0.284 mmol) is treated with N-methylpiperazine (126 ml, 1.13 mol) and the solution obtained is stirred at 60° for 2 hours. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate (250 ml) and washed in succession with water (3×100 ml) and 10 percent sodium chloride solution (100 ml). The organic solution is dried over magnesium sulfate and evaporated. The residue is recrystallized from ethyl acetate/n-hexane. There are obtained 72.3 g (78.5%) of N-ethyl-4'-fluoro-5'-(4-methyl-1-piperazinyl)-2'-nitroacetanilide with a m.p. of 117°-119°.
Reaction SMILES: C(O)(=O)C.[NH2:5]/[C:6](/[C:24]1[CH:29]=[N:28][C:27]([NH2:30])=[C:26]([C:31]2[O:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:34][N:35]=2)[N:25]=1)=[N:7]\[NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O>O1CCOCC1>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:6]2[NH:7][N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:5]=2)=[N:25][C:26]=1[C:31]1[O:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2cnc(N)c(-c3nnc(C(C)(C)C)o3)n2)CC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
Acetic acid (200 mL) was added to dioxane (500 mL) in a 3 L fixed double jacketed vessel and the solution was heated to 70° C. under nitrogen. (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)-piperidine-1-carboxylate (74.5 g, 152.80 mmol) was added portionwise to the warm mixture. After 10 minutes the temperature was increased to 100° C. (slight reflux). The reaction mixture was stirred at 100° C. for 1.5 hours (suspension) then held at 80° C. overnight (solution formed after overnight hold). The resulting solution was concentrated under reduced pressure, then diluted with toluene, evaporated to dryness, taken up with toluene and concentrated again. The residual oil was mixed with some ethyl acetate and concentrated to dryness. A solid crystallised from solution which was triturated with MTBE (200 mL) and isolated by filtration. The filter cake was washed with water and MTBE to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (50 g, 70%) as a grey solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH:8]1[CH2:11][O:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:6]=1
Reactant: BrC1COC1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2COC2)c1
Temperature: 130 °C

Procedure:
4-Bromo-1H-pyrazole (1.53 g, 10.7 mmol) is dissolved in anhydrous dimethylformamide (15 mL). 3-Bromooxetane (2.0 g, 14.6 mmol) and caesium carbonate (4.7 g, 14 mmol) are successively added thereto. The reaction mixture is heated for 8 hours at 130° C. in a sealed flask. At the end of the reaction, the solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel using dichloromethane containing diethylamine and methanol as eluants to yield the expected compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>[OH-].[Na+].CCOCC>[Cl:14][CH2:15][C:16]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)NCC(=O)NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CNC(=O)CNC(=O)CNC(=O)CCl
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.5 g (0.013 mol) of glycylglycylglycine in 75 ml of 1.0N NaOH in a 500 ml flask under nitrogen at 0° C., a solution of 13.0 g (0.115 mol) of chloroacetyl chloride in 100 ml of ether was added dropwise from one addition funnel while simultaneously 100 ml of 1.0N NaOH was added dropwise from another. After additions were complete, the reaction mixture was stirred for 1.5 hr. at 0° C. The mixture was then acidified with concentrated HCl while cooling. After stirring for an additional 30 min. the mixture was concentrated to one-third volume under reduced pressure at 40° C. The residue precipitated upon cooling in an ice bath. Isolation of the solid gave 2.75 g (78.5%) after two washings.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19](O)=[O:20])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]([NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:44]([O:43][CH:39]([O:40][CH2:41][CH3:42])[C@@H:38]([N:26]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:20])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH2:47][C:48](=[O:49])[NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH3:46])[CH3:45]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 67 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:3]1=2.[ClH:37]>CO.CCOCC>[ClH:37].[ClH:37].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 80 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.248 mmol) was dissolved in MeOH (1.5 mL) and 2 N HCl in Et2O (5 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et2O to provide the title compound (90 mg, 80%) as a yellow solid: mp 282-286° C.; 1H NMR (500 MHz, CD3OD) δ 7.70 (d, J=6.9 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.52 (s, 1H), 7.33-7.26 (m, 4H), 7.22 (t, J=7.2 Hz, 1H), 7.09 (dd, J=8.3, 1.6 Hz, 1H), 6.59-6.56 (m, 2H), 4.50 (s, 2H), 3.76 (s, 3H), 3.70 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.0 Hz, 2H), 3.04-3.01 (m, 2H), 2.98-2.95 (m, 2H); ESI MS m/z 384 [M+H]+; HPLC (Method B)>99% (AUC), tR=13.3 min.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)[Cl:5].[CH2:9]([O:16][NH:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[S:35][N:34]=[CH:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([O:16][N:17]([C:4]([Cl:5])=[O:3])[C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[S:35][N:34]=[CH:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncns1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1ncns1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diphosgene (360 mg, 1.8 mmol) was added to a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (468 mg, 1.2 mmol) in dry DCM (20 mL) at 0° C. followed by addition of TEA (360 mg, 3.6 mmol). The mixture was stirred at 0° C. for 2 hrs and then quenched with saturated NaHCO3 (20 mL). The reaction mixture was then extracted with DCM (3×) and the combined organic layer was dried over Na2SO4 and concentrated to afford (2S,5R)-tert-butyl 5-(benzyloxy(chlorocarbonyl)amino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate, which was directly used in the next step. ESI-MS (EI+, m/z): 445 [M+H]+.