Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[C:12]2=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53]O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][O:27][C:26]([C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][CH:29]=1)[CH2:22][N:13]1[C:12](=[O:32])[C:11]2([CH2:33][CH2:34][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14]1)=[O:28]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 43.4 %

Procedure:
To a solution of 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (0.34 g, 0.73 mmol), dicyclohexylcarbodiimide (0.18 g, 0.88 mmol) and 4-(dimethylamino)pyridine (0.011 g, 0.088 mmol) in dichloromethane (10 mL), was added N,N-dimethylethanolamine (0.065 mg, 0.73 mmol). After stirring at room temperature for 60 hours, the reaction mixture was filtered, concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain tert-butyl 3-(3-((2-(dimethylamino)ethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.17 g, 43%); MS for C30H40N4O5 m/z 537 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[CH2:9][CH2:10][C:11]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:12]=1[CH2:13]CS([O-])(=O)=O)(=O)=O.Cl>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:9][CH2:10][C:11]2[C:12](=[CH:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=2)[CH2:13]1)[CH3:2]
Reactant: CCN
Reactant: CS(=O)(=O)OCCc1cc([N+](=O)[O-])ccc1CCS(=O)(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN1CCc2cc([N+](=O)[O-])ccc2C1
Reaction time: 12 h

Procedure:
7.65 mL of ethylamine was dropwise added to a chloroform (15 mL) solution of 1.08 g of 2-{2-[(methylsulfonyl)oxyethyl}-4-nitrobenzylmethanesulfonate, which had been produced according to the method described in Journal of Organic Chemistry, Vol. 63, pp. 4116-4119, and stirred for 12 hours. 1 N hydrochloric acid was added to the reaction solution, and stirred, and then the aqueous layer was separated. Aqueous 5 N sodium hydroxide solution was added to the resulting aqueous layer, extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 210 mg of 2-ethyl-6-nitro-1,2,3,4-tetrahydroisoquinoline as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3=[O:24])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:34])[CH2:20][C:19]3=[O:24])=[CH:15][CH:16]=2)=[CH:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCNCC2=O)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1

Procedure:
To 200 mg of the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide was added 55 mg of Paraformaldehyde and 185 mg of Sodium Triacetoxyborohydride in 1 mL of 2% AcOH in DMF. After completion, the reaction is extracted once with bicarbonate and brine in Ethyl Acetate, dried over Magnesium Sulfate, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 435.3 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:15][C@H:14]([NH:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][N:11]1[C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38]I>COCCOC>[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([N:16]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:38])[CH2:13][CH2:12][N:11]1[C:28](=[O:37])[C:29]1[CH:30]=[C:31]([Cl:36])[CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
13.4 mg (0.446 mmol) of an 80% strength suspension of sodium hydride in mineral oil (suspended in hexane and decanted) are added in one portion to a solution of 150 mg (0.297 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine in 2 ml of 1,2-dimethoxyethane at 0° C. After 10 minutes at 0° C., the mixture is left to stir at RT for 30 minutes, again cooled to 0° C., and 22 μl (0.357 mmol) of methyl iodide are added. The mixture is then stirred at RT for 96 hours. The solvent is stripped off in a rotary evaporator, and the residue is chromatographed on silica gel with toluene/ethyl acetate (1:1). The title compound ##STR78## is obtained (20 mg, 13%) as white foam. TLC: toluene/ethyl acetate (1:1) Rf =0.45; FD-MS: M+ =517, 519.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([C:7](Br)([CH2:22]Br)[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:25])[CH:3]1[Br:26].[I-].[Na+]>CC(C)=O>[CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([C:7](=[CH2:22])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:25])[CH:3]1[Br:26]
Reactant: C[C@H]1C(Br)C(=O)C=C2C(Br)(CBr)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)C(Br)[C@@H]2C
Yield: 90.1 %

Procedure:
With a procedure similar to the one described in the Example 3, 2.5 g of 1α-methyl-2,6-dibromo-6-bromomethylandrost-4-ene-3,17-dione and 5.5 g of sodium iodide in acetone give 1.6 g of the crude title compound which is directly used for the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([N:34]5[CH2:35][CH2:36][N:31]([C:28](=[O:30])[CH3:29])[CH2:32][CH2:33]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 1-acetylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 52.5 mg of 124. MS (Q1) 492.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:1][C:2]=2[CH:7]=1
Reactant: COC(=O)CCCCCCC(=O)Nc1ccc(Br)cc1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CCCCCCc1nc2cc(Br)ccc2[nH]1
Temperature: 110 °C
Yield: 84.3 %

Procedure:
To a solution of methyl 8-(2-amino-4-bromophenylamino)-8-oxooctanoate (140 mg, 0.395 mmol) in toluene was added a drop of acetic acid. The reaction was heated to 110° C. overnight and concentrated. The residue was purified by biotage column chromatography to give methyl 7-(5-bromo-1H-benzimidazol-2-yl)heptanoate (113 mg)
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)=[C:5]([Cl:13])[S:4][C:3]=1[NH:14][C:15](=[O:32])[CH:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][NH:18]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:18][CH2:17][CH:16]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:15]([NH:14][C:3]1[S:4][C:5]([Cl:13])=[C:6]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[C:2]=1[Cl:1])=[O:32]
Reactant: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CNC(=O)OC(C)(C)C)c2ccccc2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CN)c2ccccc2)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl (3-{[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-phenylpropyl)carbamate (320 mg, 0.646 mmol) in dichloromethane (6.459 ml) at 25° C. was added TFA (0.498 ml, 6.46 mmol). After 30 min, the solution was dry loaded onto silica and neutralized through silica (0-20% MeOH in DCM (1% NH4OH) affording the free base of the title compound. The free base was then dissolved in MeOH (10 mL) and treated with excess 4M HCl in dioxane (2 mL) providing the HCl salt of 3-amino-N-[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]-2-phenylpropanamide (188 mg, 0.414 mmol, 64.0% yield) as an orange solid: LCMS (ES) m/e 395, 397 (M, M+2)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1 H) 8.18 (br. s., 3 H) 7.55 (d, J=1.77 Hz, 1 H) 7.28-7.51 (m, 1 H) 7.41 (d, J=5.05 Hz, 4 H) 6.36 (d, J=6.06 Hz, 1 H) 4.53 (dd, J=9.09, 5.31 Hz, 1 H) 3.81 (br. s., 3 H) 3.48-3.59 (m, 1 H) 3.01-3.17 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([N:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH:41]=O)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[C:35]([O:34][C:32]([N:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH2:41][NH:24][C:23]1[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:31])=[CH:16][CH:15]=2)=[N:19][C:20]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[N:21][CH:22]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Nc1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of Compound 11b (0.55 g; 1.3 mmol) in 1,2-dichloroethane (25 ml) was added Boc-L-prolinal (0.37 mL; 1.9 mmol). To the reaction mixture was then added NaBH(OAc)3 (0.4 g; 1.9 mmol) portionwise, and the reaction mixture was continually stirred at room temperature for 5 h. The resultant mixture was diluted with water. After stirring for 10 min the organic phase was isolated, washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo to afford Compound 11c. The compound was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8]C(C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K+].[Br-].[C:13]([OH:16])(=[O:15])[CH3:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:14]([C:13]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1
Yield: 86.5 %

Procedure:
The oxidation of 300 g of p-nitrotoluene in 2500 ml of glacial acetic acid, in the presence of 4 g KBr and 15 g Co(OA)2 . 4H2O, at a reaction temperature of 185° C and a reaction time of 3 hours, gave a yield of 86.5% of p-nitrobenzoic acid. The absorption of oxygen began at 165° C. During the reaction CO2 was detected qualitatively in the residual gas. After the addition of 500 ml of benzene, 103 g of water (240% of the theory) was distilled azeotropically from the mother liquor.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1)#[N:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:9][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A mixture of 5-cyano-2-nitro-phenol (3.0 g, 18.9 mmol), allyl bromide (1.82 ml, 21.0 mmol) and cesium carbonate (7.39 g, 22.7 mmol) in DMF (20 ml) was stirred at rt for 18 hrs under Ar. The reaction mixture was partitioned between t-butyl-methylether and water. The layers were separated and the aqueous portion was further extracted (×3). The combined organic extracts were washed twice with water, then brine and dried over MgSO4 and filtered. Removal of solvent at reduced pressure afforded the title compound (3.89 g, 100%). 1H NMR(400 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 1H), 7.35 (dd, J=8.4 Hz J=1.2 Hz 1H), 7.35 (d, J=1.5 Hz, 1H), 6.02 (m, 1H), 5.52 (d, 1H), 5.43 (d, 1H), 4.73 (dd, J=3.6 Hz J=1.2 Hz 2H);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:36](CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:26])[NH2:36])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
Acid compound 6 (1.5 g, 3.3 mmol) was dissolved in DCM (25 mL). Triethylamine (0.55 mL, 3.94 mmol) and BOP reagent (1.6 g, 3.61 mmol) were added and the reaction mixture stirred at room temperature for 15 min under an atmosphere of argon. Ammonia gas was then bubbled gently through the solution for 15-20 min to complete the reaction. Excess ammonia was degassed, the solvent was removed under reduced pressure and the residue was suspended in EtOAc (75 mL). The organic layer was washed with 0.5 N NaOH (2×10 mL), water (2×25 mL), and brine (1×30 mL), dried and concentrated under reduced pressure to yield the amide compound 11 (1.5 g, ˜99%). 1H NMR (DMSO-d6): 7.27 (br, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.75 (br, 1H), 4.53 (m, 1H), 2.91 (s, 3H), 2.75-2.83 (m, 7H), 2.33 (t, J=7.6 Hz, 2H), 1.32 (s, 9H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 4-fluoro-2-methoxy-1-nitrobenzene (15 g, 87 mmol), tert-butyl piperazine-1-carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethylformamide (150 mL) was heated at 80′C for 8 hours. After cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound. MS: 338 (M+H+).
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]C.C[O-].[Na+].CS(C)=O.[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32]Cl>O>[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32][O:12][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CCCCCCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC(=O)OCc1c(Cl)ccc2cc(Cl)cnc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
16 parts by weight of nonanecarboxylic acid, 20 parts by weight of 30% strength sodium methylate solution and 440 parts by weight of dimethylsulfoxide are stirred for 1 hour at 100° C. Thereafter, 24.5 parts by weight of 3,7-dichloro-8-chloromethylquinoline are introduced and the reaction mixture is stirred for a further 2 hours at 100° C. The reaction solution is then cooled, water is added and the precipitated solid is filtered off under suction and recrystallized from toluene. 32.5 parts by weight (89% of theory) of 3,7-dichloro-8-octylcarbonyloxymethylquinoline of melting point 92° C. are obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>ClCCl>[CH3:27][S:28]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[CH:10]=2)[CH2:3]1)(=[O:30])=[O:29]
Reactant: O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Reaction time: 8 h

Procedure:
(S)-3-Hydroxy-1-(3-pyrrolidinophenethyl)pyrrolidine (1.04 g, 4.00 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (0.76 ml, 5.49 mmol) and methanesulfonyl chloride (0.39 ml, 5.03 mmol) were added to the obtained solution at 0° C. and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with chloroform and methanol (95:5), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(3-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (1.30 g, 96%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].[OH-].[Na+]>C(O)(=O)C>[OH:12][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17](=[O:19])[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1cc(O)c2ccccc2n1-c1ccccc1
Temperature: 0 °C

Procedure:
A solution of N-phenyl anthranilic acid (30.1g.; 0.146 mole) and acetic anhydride (74 ml.) in glacial acetic acid (74 ml.) was refluxed for 4 hrs. The resulting red solution was cooled, poured onto crushed ice-water (600 ml) and brought to pH 9 with dilute sodium hydroxide solution. After filtration the clear liquid was taken to pH 5 with hydrochloric acid and the white solid filtered off and dried, m.p. (AcOH) 298°-300°C. (Found: C, 75.40; H, 4.58; N, 5.70; C15H11NO2 requires; C, 75.94; H, 4.67; N, 5.90%).
Reaction SMILES: [CH2:1]([N:8](C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1.CN(C=O)C>>[CH2:1]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](C(=O)O)N(Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NCc1ccccc1)C(=O)O
Reaction time: 0.33 h

Procedure:
Fmoc protected amino acid 48 (1.0 g, 1.79 mmol) was treated with a solution of piperidine/DMF (9 mL, 5% v/v) and stirred for 20 min then concentrated to dryness and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][C:10]=2[F:26])=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[F:26][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a solution of benzyl {4-[(6-aminopyridin-3-yl)oxy]-3-fluorophenyl}carbamate (28.2 g, 79.8 mmol) in pyridine (141 mL) was added p-toluenesulfonyl chloride (18.3 g, 98.5 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (29.2 g, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([O:23]C)=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.Cl>[OH-].[Li+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([OH:23])=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(CCc2ncc3ccc(C(=O)O)cc3n2)cc1
Reaction time: 0.5 h

Procedure:
0.3 g (0.94 mmol) of methyl 2-[2-(4-cyanophenyl)ethyl]quinazoline-7-carboxylate were dissolved in 4.7 mL of 1N lithium hydroxide solution and 4 mL of tetrahydrofuran and stirred for 3 hours at ambient temperature. Then 4.7 mL of 1N hydrochloric acid were added and the mixture was stirred for 30 minutes. The product precipitated was suction filtered, washed with water, and dried. Yield: 0.30 g (100% of theory); Rf value: 0.1 (silica gel, ethyl acetate/cyclohexane=1:1).