Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[NH:9])=[O:8])[CH3:2].[H-].[Na+].I[CH2:24][CH3:25]>CN(C)C=O.O>[CH2:24]([N:9]=[S:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8])[CH3:25]
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN=S(=O)(CCCN(CC)CC)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of S-(3-diethylaminopropyl)-S-(4-nitrophenyl)sulfoximine (10 mmol) in dimethylformamide is added to a stirred suspension of 60% sodium hydride-oil dispersion (10 mmol) at ambient temperature. After stirring for 30 min the mixture is warmed to 50° C. for 30 min and then cooled to ambient temperature. Iodoethane (10 mmol) is added dropwise to the reaction mixture and stirred at ambient temperature for 30 min and then warmed to 50° C. for 1 hr. The reaction mixture is diluted with water and extracted with methylene chloride. The methylene chloride extract is concentrated in vacuo and the residue partitioned between methylene chloride-1N hydrochloric acid. The acid layer is separated and basified with 50% sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is washed with water, dried, and concentrated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([CH3:12])[CH:5]=1.[CH2:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH:15]([CH3:17])[CH3:16].O[NH:28]C(=N)C1C=CC(CO)=CC=1.C(OC1C=CC(C2ON=C(C3C=CC(CO)=CC=3)N=2)=CC=1)(C)C>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:28]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=3)[O:23][N:11]=2)=[C:6]([CH3:12])[CH:5]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: COC(=O)c1ccc(C#N)c(C)c1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: CC(C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(CC(C)C)cc3)n2)c(C)c1

Procedure:
The title compound was prepared from 4-cyano-3-methyl-benzoic acid methyl ester and 4-isobutyl-benzoic acid by procedures analogous to those described in Preparations 8B and 10A for the preparation of N-hydroxy-4-hydroxymethyl-benzamidine and 4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-phenylmethanol, respectively.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23]>C(O)C>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[CH2:13][S:12]1
Reactant: O[C@H]1[C@H](O)CS[C@H]1n1cnc2c(Cl)ncnc21
Reactant: NCc1cccc(F)c1
Solvent: CCO
Product: O[C@@H]1[C@H](O)CS[C@H]1n1cnc2c(NCc3cccc(F)c3)ncnc21
Yield: 82 %

Procedure:
(2R,3S,4S)-2-(6-chloro-9H-purin-9-yl)tetrahydrothiophen-3,4-diol (1 equivalent), prepared in Step 2, and 3-fluorobenzylamine (1.5 equivalents) were dissolved in ethanol (5 ml) at room temperature for 2-3 hrs with stirring. The reaction mixture was concentrated in a vacuum and the concentrate was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (20:1, v/v) as an elution solvent to afford the object compound (0.11 g, 82%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])[CH3:3].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[C:20]([F:28])[CH:19]=1.CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[C:6]([C:12]([F:14])([F:13])[F:15])[CH:7]=2)=[O:26])=[C:20]([F:28])[CH:19]=1
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline, 2 hydrochloride (4 g, 13.74 mmol), 2-(4-bromo-2-fluorophenyl)acetic acid (3.20 g, 13.74 mmol) and Et3N (9.57 mL, 68.7 mmol) in DCM (100 mL) stirred under a N2 atmosphere at 20° C. were added EDC (2.63 g, 13.74 mmol) and HOBt (2.104 g, 13.74 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol, 66.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (br. s., 2H), 7.70 (d, J=5.02 Hz, 2H), 7.30 (br. s., 2H), 3.73 (s, 2H), 3.53 (s, 2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[C:6]1=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]2)[C:6]1=[O:20]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Cl)c(CC2CCN(C3CCC(=O)CC3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (6.5 g, 15.7 mmol) in acetone (100 mL), add p-toluenesulfonic acid hydrate (3 g, 15.7 mmol) and stir for 24 hr at room temp. Add 5N HCl (10 mL) and heat to 45° C. for 1 hr. Reaction progress can be monitored by TLC. Concentrate the reaction mixture, dilute with saturated aqueous sodium hydrogen carbonate (500 mL) and extract with ethyl acetate (3×150 mL). Wash the combined extracts with water (100 mL) and brine (100 mL), dry over anhydrous sodium sulfate, filtered, and concentrate to about 50 mL volume, dilute with hexanes (50 mL) and filter to give 5.5 g, 95%, as a white solid. 1H NMR (CDCl3) δ 6.78 (s, 2H), 4.44-4.52 (m, 1H), 3.78 (s, 3H), 3.37-3.47 (m, 1H), 3.29-3.36 (m, 1H), 3.15-3.23 (m, 2H), 2.39-2.62 (m, 4H), 1.80-2.11 (m, 6H). LCMS m+1 370.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.C(O)(=O)C(O)=O.N1C2(COC2)CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[C:23]3([CH2:28][O:25][CH2:24]3)[CH2:26][CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CC2(COC2)N1
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCC23COC3)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 6-oxa-1-azaspiro[3.3]heptane oxalate and isolated as light-yellow gum (12.5 mg, 65%). MS(m/e): 399.4 (MH+).
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.O.[NH2:23][NH2:24]>C(O)C>[CH3:20][N:18]1[CH:19]=[C:15]([C:12]2[CH:13]=[C:14]3[N:6]([CH2:5][C:4]([NH:23][NH2:24])=[O:21])[CH:7]=[CH:8][C:9]3=[N:10][CH:11]=2)[CH:16]=[N:17]1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc2ncc(-c3cnn(C)c3)cc21
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2cnc3ccn(CC(=O)NN)c3c2)cn1
Yield: 99 %

Procedure:
[6-(1-Methyl-1H-pyrazol-4-yl)-pyrrolo[3,2-b]pyridin-1-yl]-acetic acid ethyl ester (122 mg, 0.42 mmol) was dissolved in ethanol (1 mL) and hydrazine hydrate (500 uL). The solution was heated to reflux for 1 hour. Next the solution was concentrated down under vacuum and redissolved in a minimal amount of hot methanol. The product crystallized and was a collected by filtration to afford the title compound (114.8 mg, 99% yield). MS m/z=271 [M+H+]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:22])[CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:12]=[CH:13][CH:14]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzene sulfonylchloride (1.10 g, 4.32 mmol) in pyridine (5 mL) was added 8-quinolinamine (1, 623 mg, 4.32 mmol) and the reaction mixture was stirred overnight at 25° C. Ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated sodium carbonate (X 3), dried over magnesium sulfate, filtered and concentration under reduced pressure to afford a light brown solid (2, 1.57 g, 3.80 mmol). MS(ESI) [M+H+]+=363.1; 365.1 (1:1)
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:32][NH:31][C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:28][CH:29]=1)=[NH:2]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C#N)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
Prepared using General Procedure 19. To a stirred solution of tert-butyl 2-(N-(4-cyanobenzyl)-4-nitrobenzamido)acetate INT-56 (11.5 g, 29.2 mmol) and TEA (10.2 mL, 73.0 mmol) in DMF (50 mL) was added hydroxylamine hydrochloride (5.07 g, 73.0 mmol). After 24 h the reaction mixture was poured onto water (200 mL) and NaHCO3 (200 mL) and extracted into EA (2×250 mL). The organics were washed with brine (3×200 mL), dried over MgSO4 and concentrated in vacuo, evaporating from hexanes, to provide 12.1 g (97%) of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate INT-57 as an off-white powder. LCMS-ESI (m/z) calculated for C21H24N4O6: 428; found 429 [M+H]+, tR=1.42 min (Method 10).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:20]1([CH2:26][N:27]2[CH2:32][CH:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl.C(N(CC)CC)C>[C:20]1([CH2:26][N:27]2[CH2:28][CH:29]=[C:30]([C:33]3[CH:34]=[CH:35][C:36]([NH:39][C:15]([C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.12 mol) was added dropwise to a stirring mixture of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.095 mol) in DCM (300 ml) and triethylamine (50 ml). The mixture was stirred overnight, poured out into water and then stirred for 30 minutes. The organic layer Was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 43 g of N-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1F
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1F

Procedure:
To a slurry of 3-fluoro-4-methoxybenzoic acid (30.0 g) in toluene (100 ml) was added thionyl chloride (25 ml). The reaction was heated under reflux for 2 hrs and then distilled. The residue was dried under high vacuum to give 32 g of 3-fluoro-4-methoxybenzoyl chloride. To a solution of 2-amino-2-methyl-1-propanol (35 ml) in dichloromethane (200 ml) was added a solution of the 3-fluoro-4-methoxybenzoyl chloride in dichloromethane (150 ml). The reaction mixture was stirred for 1 hr at ambient temperature, dichloromethane (500 ml) was added, and washed with 2N hydrochloric acid (1 l). The layers were separated and the organic extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. To the residue was added thionyl chloride (25 ml) at 0° C. The reaction mixture was stirred for 30 min, diethyl ether (200 ml) was added, and the mixture was stirred for 10 min. The supernatant was decanted. 10% Sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 36 g (91%) of product, mp 59-60° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].CN(C)C=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:1](=[O:2])[O:25][C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(NNC(=O)C(C)(C)C)cc1
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)oc2=O)cc1

Procedure:
12 ml of a (20%) solution of phosgene in toluene are added dropwise, at room temperature, to a mixture of 50 ml of toluene, 0.1 ml of N,N-dimethylformamide and 2.3 g of N-(4-methoxyphenyl)-N′-pivaloyl-hydrazine. The reaction mixture is stirred at reflux for 7 hours and then concentrated. After purification of the residue on silica gel, 1-methoxy-4-(5-oxo-2-tert-butyl-3,4-diaza-1-oxa-cyclopent-2-en-4-yl)-benzene is obtained in the form of a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9](N)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=O)=[CH:15]1.C1CCC([N:32]=C=NC2CCCCC2)CC1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:32][C:23]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:14][CH:15]=3)=[O:25])=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2cccnc2)cc1)c1c[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
The crude 3-pyridine-3-yl-phenylamine (60 mg, 0.35 mmol) and indole-3-carboxylic acid (57 mg, 0.35 mmol) were dissolved in DMF (3 ml), DCC (73 mg, 0.35 mmol) was added to the solution, and then the mixture was stirred at 80° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (60 mg, 55%) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: [ClH:1].[N:2]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]=[CH:3]1.CS(O[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:32](=[NH:34])[NH2:33])[CH:28]=2)[CH:23]=1)(=O)=O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[ClH:1].[N:2]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:32](=[NH:33])[NH2:34])[CH:28]=4)[CH:23]=3)=[O:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5][N:4]=[CH:3]1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Yield: 63.6 %

Procedure:
Alternatively, 4 g of 4-(2-imidazolinyl)aminobenzoic acid hydrochloride, 4.67 g of 6-amidino-2-naphthol methanesulfonate and 0.2 g of DMAP were dissolved in 60 ml of anhydrous pyridine, 5.13 g of DCC was added to the solution and then the reaction mixture was treated as described above, via a carbonate salt, to yield 2.35 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dihydrochloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:7]([O:12][CH2:13][CH3:14])(=[O:8])[O:9][CH2:10][CH3:11]
Reactant: CCOP(=O)(Cl)OCC
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cccs1

Procedure:
A solution of 1.0 mmol 2-thienyl lithium in THF was treated with 1.0 mmol diethyl chlorophosphate at −78° C. for 1 h. Extraction and chromatography gave diethyl 2-thiophenephosphonate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[OH-].[Na+:23]>O>[Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[Na+:23]
Reactant: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 80 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
A 22 L, Pyrex glass, five-neck, round bottom flask was equipped with an overhead stirrer, thermocouple temperature read out, and heating mantle. The flask was charged with 2099.7 g of N-(5-chlorosalicyloyl)-8-aminooctanoic acid and 6000 mL water and stirred. To this slurry was added a solution of 265 g of sodium hydroxide dissolved in 2000 mL water. The mixture was heated to about 80° C. causing most of the solids to dissolve. The undissolved material was allowed to settle to the bottom of the flask and the supernate decanted. The resulting mixture was transferred to the pot flask of a large laboratory rotary evaporator. The rotary evaporator was operated with a bath temperature of about 60° C. and a pressure of about 70 mmHg. Water was removed from the disodium salt mixture until a solid mass was obtained in the rotary evaporator pot flask. The vacuum was released and pot flask removed from the rotary evaporator. The solids were scraped from the pot flask into trays. These trays were then placed in a vacuum oven and the solids dried at about 60° C. and full vacuum for about 48 hours. The dried solids were run through a laboratory mill until all the solids passed through a 35 mesh screen. The milled and seived disodium N-(5-chlorosalicyloyl)-8-aminooctanate was put into trays and placed back into the drying oven. Drying was continued at full vacuum to yield 2161.7 g of the desired product as a dry powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:19]#[N:20])[CH:5]([CH3:18])[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14]>C(O)=O.[Ni].C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[C:5]([CH3:18])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[NH:20][CH2:19]1)=[O:21]
Reactant: COC(=O)C(C#N)C(C)C(=O)c1ccccc1C(F)(F)F
Agent: [Ni]
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)C1CNC(c2ccccc2C(F)(F)F)=C1C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-cyano-3-methyl-4-oxo-4-(2-trifluoromethyl-phenyl)-butyric acid methyl ester (13.27 g, 44.4 mmol) in formic acid (100 mL) was added freshly prepared Raney nickel [Al—Ni (1:1), 117 g] and the mixture was heated to reflux with stirring for 2 h. After cooling, the catalyst was removed by filtration and washed with ethanol. The combined filtrates were concentrated to give an oil, which was re-dissolved in DCM and filtered to remove residual solids. Evaporation of solvent gave 4-methyl-5-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrrole-3-carboxylic acid methyl ester as an oil (10 g, 79%), which was used in the next step without purification. MS (ES): 286 (MH+).
Reaction SMILES: [Cl:1]CCCO[C:6]1[CH:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:7]=1[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:11]=1)=[O:9].Cl.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.[I-].[K+].Cl>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:29]2[CH:30]=[CH:6][C:7]([C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:11]=3)=[O:9])=[CH:27][C:28]=2[O:9][CH2:8][CH2:7][CH2:6][N:53]2[CH2:54][CH2:55][N:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][CH3:42])[CH2:51][CH2:52]2)=[CH:34][CH:35]=1)[CH3:40]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)cc2OCCCCl)c2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Yield: 142.6 %

Procedure:
Ethyl 4-{3-[3-chloropropoxy-4-(4-ethylphenyl)methylaminobenzoyl]indol-1-yl}butanoate (44.5 g) was dissolved in N,N-dimethylformamide (230 ml), and 1-(2-methoxyphenyl)piperazine hydrochloride (36.2 g), potassium iodide (52.5 g), and triethylamine (46 ml) were added to the solution. The resultant mixture was stirred at 90° C. for one hour. The reaction mixture was cooled and poured into ethyl acetate (230 ml) and 1N hydrochloric acid (460 ml) was added. Crystals so precipitated were collected by filtration and recrystallized from 90% ethanol, to thereby obtain 42.6 g of ethyl 4-{3-{4-(4-ethylphenyl)methylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy)benzoyl}indol-1-yl}butanoate hydrochloride as colorless crystals.