Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH2:32][C:33]1[CH:63]=[CH:62][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([CH2:44][NH:45][C:46](=[O:61])[CH2:47][NH:48][C:49](=[O:60])[C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH2:40][CH2:39]2)=[CH:35][CH:34]=1>C(Cl)Cl.CCN(CC)CC>[C:23]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([CH2:44][NH:45][C:46](=[O:61])[CH2:47][NH:48][C:49](=[O:60])[C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:51]=3)[CH2:40][CH2:39]2)=[CH:62][CH:63]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
EDCI (4.7 mg), 1-hydroxybenzotriazole hydrate (3.3 mg), Et3N (2.5 mg) and benzoic acid (3.0 mg) were added to a solution of 1-(4-aminobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (10.1 mg, 0.023 mmol) in CH2Cl2 (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2×2 mL) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford an yellow oil which was purified by preparative TLC (SiO3, 10% CH3OH—CH2Cl2) to give 1-{4-(benzoylamino)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 519) as a colorless oil (4.6mg, 36%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 553.2 (M++H, C30H31F3N4O3).
Reaction SMILES: [Br:1][C:2]1[C:10]([NH:11]N=C2CCCNC2=O)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:20]([OH:23])(=O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[O:8][CH2:7][CH2:6][C:5]2=[C:9]2[C:10]=1[NH:11][C:21]1[C:20](=[O:23])[NH:11][CH2:10][CH2:9][C:5]2=1
Reactant: CC(=O)O
Reactant: O=C1NCCCC1=NNc1cc2c(cc1Br)OCC2
Product: O=C1NCCc2c1[nH]c1c(Br)cc3c(c21)CCO3
Temperature: 115 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[(6-bromo-2,3-dihydro-1-benzofuran-5-yl)hydrazinylidene]piperidin-2-one (a mixture of E and Z isomers)(137 mg) and acetic acid (3.00 mL) was stirred at 115° C. for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 96:4) to obtain 5-bromo-1,2,6,8,9,10-hexahydro-7H-furo[3,2-e]pyrido[3,4-b]indol-7-one (40.0 mg) as a red solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>COCCOC.C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
N-Acetylphenylalanine methyl ester (4.2 g, 19 mmol) was dissolved in ethylene glycol dimethyl ether. The solution was cooled to −70° C. and diisobutylaluminum hydride (25.3 mL of a 1.5M solution in toluene, 39 mmol) was added. The resulting reaction mixture was stirred at −70° C. for 2 hours. The reaction was quenched by addition of 2N hydrochloric acid. The mixture was extracted 4 times with cold ethyl acetate and 4 times with toluene. The extracts were combined, washed with brine and dried over magnesium sulfate. Concentration in vacuo followed by silica gel chromatography furnished 2.7 g of a white solid. The NMR was identical to that reported in the literature, Biochemistry, 1979, 18, 921-926.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+].O>CCOC(C)=O>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (157 mg, 0.5 mmole) with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e (150 mg, 0.7 mmole) and Cs2CO3 (673 mg, 2.1 mmole) in a manner as previously described for example 1 to give 51 mg (39%) of a crisp foam. 1H NMR (DMSO-d6) δ8.54 (1H, dd, J=5.5, 1.13 Hz), 8.05 (1H, s), 7.84 (1H, d, J=8.6 Hz), 7.61-7.55 (1H, m), 7.54 (1H, d, J=2.1 Hz), 7.03 (1H, dd, J=2.1, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.12-3.51 (5H, m), 3.67 (3H, s), 3.27, 3.24 (3H, 2 s), 2.80 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.35-1.95 (2H, m). Anal. Calcd for C25H26N4O4S.0.9 H2O.0.2 EtOAc: C, 60.47; H, 5.78; N, 10.93; S, 6.26. Found: C, 60.46; H, 5.56; N, 10.81; S, 6.34.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[F:1])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (5.05 g, 0.0223 mol) and 4-bromoaniline (3.83 g, 0.0223 mol) in anhydrous dichloromethane (150 mL) was cooled to 0° C. and N,N-diisopropylethylamine (4.26 mL, 0.0245 mol) was added under nitrogen atmosphere dropwise. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and the residue was partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane (50 mL) and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (7.1 g, 0.0196 mol) as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12]2)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[ClH:23].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12]2
Reactant: COC(=O)c1cnc2ccc(NC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cnc2ccc(N)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-[(tert-butoxycarbonyl)amino]quinoline-3-carboxylate (Int-2, 1.28 g, 4.23 mmol) in methylene chloride (38 mL) was added hydrochloric acid in 1,4-dioxane (4.0 M, 10.6 mL, 42.3 mmol). The reaction was stirred at room temperature overnight then concentrated under reduced pressure. The crude reside was dried in vacuo and used as obtained. LC-MS: (FA) ES+ 203; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.14 (s, 1H), 9.08 (d, J=1.8 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 7.62 (dd, J=9.1, 2.4 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H), 3.96 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[C:5]([O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:32]([S:39][CH:40]([CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:32]([S:39][CH:40]([CH:43]([O:44][CH3:45])[O:46][CH3:47])[CH2:41][NH:42][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:3]=2[N:2]([CH3:1])[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:24])=[O:25])=[O:13])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)C(CNC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
A mixture of 7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylic acid (2.10 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.30 g), 1H-1,2,3-benzotriazol-1-ol (730 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.04 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:4-1:9, volume ratio) to give the title compound (2.70 g, yield 87%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([O:8][CH2:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: Cc1ccsc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1COc1cccnc1N
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-amino-3-hydroxypyridine (15.18 g) in N,N-dimethylformamide (150 ml) was added portionwise a 60% dispersion of sodium hydride in mineral oil (6.06 g) with ice-cooling and stirring over a period of 10 minutes. After being stirred at 0°-5° C. for 30 minutes and then at ambient temperature for 1 hour, a solution of 2-chloromethyl-3-methylthiophene (23.9 g) in N,N-dimethylformamide (10 ml) was added dropwise to the reaction mixture. The mixture was stirred at ambient temperature for 20 hours and poured into water. The resulting precipitate was collected by filtration and dissolved in methylene chloride. The solution was treated with activated charcoal and evaporated in vacuo. The residue was crystallized from diethyl ether to give 2-amino-3-(3-methyl-2-thienylmethoxy)pyridine (23.6 g).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[Li][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1>O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)CCBr
Reactant: [Li]c1cccs1
Solvent: O
Product: CC(C)CCc1cccs1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
Isopentyl bromide (Aldrich, 8 g, 53mmol) was added to 53 mL of an ice-cooled solution of lithiothiophene (1.0M in THF, 53 mmol). The reaction was stirred at 0° C. for 2 hours, at room temperature for 16 hours, and poured into water, then the mixture was extracted with hexane. The organic layer was dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with hexane, to give 7.2 g (88% yield) of the title compound as a colorless oil. NMR (CDCl3) δ:7.10 (dd, J=1, 6 Hz, 1H), 6.90 (dd, J=4, 6 Hz, 1H), 6.78 (dd, J=1, 4 Hz, 1H), 2.84 (t, J=8 Hz, 2H), 1.7-1.5 (m, 3H), 0.94 (d, J=6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][N:20]([CH2:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1)[CH3:21]>N1C=CC=CC=1>[CH3:19][N:20]([CH2:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1)[CH3:21]
Reactant: CN(C)CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CN(C)C)C3)cc21
Reaction time: 18 h
Yield: 15.7 %

Procedure:
A mixture of 480 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.0 g of 2-dimethylaminomethylpiperazine and 5 ml of pyridine in a sealed flask flushed with argon was stirred at 120°-130° C. for 18 hours. The solvent was removed in vacuo. The residue was evaporated twice from toluene, giving a gum. The gum was added to a silica gel column and flash chromatographed with methanol:chloroform (1.5:8.5 saturated with water). Fractions 61 and 62 were combined, evaporated and dried, giving 105 mg of the desired product as a white solid, mp 148°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[NH:10][C:4]=2[CH:3]=1.B.C1COCC1.O>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc2N1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)NCCCC2
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 8-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (500 mg, 2.082 mmol) in THF (20 mL) at RT was added borane-THF complex (1M solution in THF) (5.206 mL, 5.21 mmol). The reaction mixture was refluxed for 3 hours, after which the reaction mixture was cooled in an ice bath before the addition of a further amount of borane-THF complex (1M solution in THF) (7.290 mL, 7.29 mmol). The reaction mixture was once again refluxed overnight. The reaction mixture was cooled in an ice bath before the dropwise addition of water. The aqueous layer was then extracted with diethyl ether (3×25 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated. This residue was purified on silica column eluting with ethyl acetate in cyclohexane (0-15%) to afford the title compound (400 mg). LCMS (A): m/z (M+H)+ 226/228, C10H12BrN requires 225/227 (acidic).
Reaction SMILES: C1C=CC([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=CC=1.NN>C(O)C>[CH:13]1[C:8]([NH2:7])=[CH:9][CH:10]=[C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:12]=1
Reactant: Nc1ccc(Nc2ccc(Nc3ccc(Nc4ccccc4)cc3)cc2)cc1
Agent: NN
Solvent: CCO
Product: Nc1ccc(Nc2ccc(Nc3ccc(N)cc3)cc2)cc1
Reaction time: 2 h

Procedure:
About 5.0 g of the tetraaniline in the emeraldine oxidation state synthesized in Example 2 was dissolved in 250 ml ethanol. 10 ml of anhydrous hydrazine was added with constant magnetic stirring. The reaction system was stirred for about 2 hours. The blue precipitate was collected by vacuum filtration and washed with 100 ml cold ethanol in 3 portions. The precipitate was suspended in 700 ml ethanol containing 1 ml of phenylhydrazine which was heated to reflux for 0.5 hours. The heat was removed and about 2.5 g of active carbon was added. The suspension was heated to reflux for another 0.5 hours and then was filtered hot by vacuum filtration and the filtrate was cooled in an ice bath. The off white precipitate was collected by vacuum filtration and washed with 50 ml cold ethanol and dried under dynamic vacuum. This precipitate was readily oxidized to, or approaching, the emeraldine oxidation state by air, especially if wet or in solution. Hence, minimum exposure to air is necessary in order to obtain the tetramer in the leucoemeraldine oxidation state. The dried precipitate was ground and stored in a dark bottle under Argon in a refrigerator. The yield was 3.5 g or 70%. A typical analysis for the tetraaniline in the leucoemeraldine oxidation state C24H22N4 was C: 78.38; H: 6.02; N: 15.28, total 99.68%. Calculated, C: 78.68; H: 6.05; N: 15.29. Mass spectrum (CI): 367 (MH+ /e). 1H NMR (DMSO): 7.66 (s,1), 7.42 (s,1), 7.15 (s,1), 7.12 (t,2), 6.88 (m,12), 6.65 (t,1), 6.52 (d,2) and 4.63 (s,2). 13C NMR (DMSO): 145.7, 142.6, 139.9, 139.8. 135.1, 134.1, 133.5, 129.0, 121.0, 120.5, 119.6, 117.7, 116.3, 115.9, 114.9 and 114.4 (TMS std.). These data are in agreement with the proposed structure, and are presented in FIG. 3 where it is identified as "B."
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:11]([CH:14]=1)[C:12]#[N:13].FC(F)(F)C(O)=[O:35].S(=O)(=O)(O)O.[OH-].[Na+]>O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:21][CH2:22]2)=[O:16])=[C:11]([CH:14]=1)[C:12]([NH2:13])=[O:35]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3C#N)CC2)nc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3C(N)=O)CC2)nc1C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-(2-Oxoimidazolidin-1-yl)-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (418 mg) described in Example 445 was added to a solution of trifluoroacetic acid (1.12 mL) and concentrated sulfuric acid (0.28 mL) under cooling, and the mixture was stirred at 10° C. for 1 hr. Then, the reaction mixture was added to water under ice-cooling, neutralized with 4N aqueous sodium hydroxide solution and the to mixture was stirred for 1 hr. The obtained precipitate was collected by filtration to give the title compound (363 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Brc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3c2)cc1
Yield: 11.6 %

Procedure:
2-Bromonaphthalene (0.08 moles, 16.6 g), 4-nitrothiophenol (0.08 moles, 12.4 g), potassium carbonate (0.1 moles, 13.4 g), copper bronze (6.0 g) and cuprous chloride (0.02 moles, 2.0 g) were heated under reflux for 4 days in 300 ml pyridine. The solution was filtered hot, concentrated, dissolved in ethyl acetate and washed thoroughly with 2N HCl and water. The solution was dried over sodium sulfate, concentrated and purified by HPLC over silica gel eluted with 5% ethyl acetate in hexane. The product was recrystallized from ethyl acetate and hexane to yield 2-(4-nitrophenylthio)naphthalene 2.6 g, 12% in the first crop. Mass spec. (FD) 281.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:18][C:19]([C:21]1[CH:40]=[CH:39][C:24]2[N:25]=[C:26]([NH:29][C@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)[O:27][CH2:28][C:23]=2[CH:22]=1)=[NH:20]>O1CCCC1>[C@H:30]1([NH:29][C:26]2[O:27][CH2:28][C:23]3[CH:22]=[C:21]([C:19]4[N:20]=[C:1]([CH3:2])[O:4][N:18]=4)[CH:40]=[CH:39][C:24]=3[N:25]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: N=C(NO)c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)no1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a stirred solution of acetic acid (67 mg, 1.12 mmol) in tetrahydrofuran (7.5 ml) was added at room temperature 1,1′-carbonyl-diimidazole (193 mg, 1.19 mmol). The mixture was allowed to stir for 15 min at room temperature and afterwards for 90 min at 70° C. N-hydroxy-2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazine-6-carboxamidine (Example 130) (240 mg, 0.74 mmol) was added at room temperature. The mixture was allowed to stir for 1 h at room temperature, evaporated to dryness and diluted with acetic acid (10 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated sodium hydrogen carbonate solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (1×20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (137 mg, 53%). MS (ISP): m/e=347.1 (M+H+); m.p. 138° C.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([NH:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([C:33]2[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=2[CH3:38])=[O:32])[CH2:23][CH2:22]1>N1CCCCC1.C(O)C>[CH:21]1([NH:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([C:33]2[C:34]([CH3:41])=[C:35](/[CH:39]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:36][C:37]=2[CH3:38])=[O:32])[CH2:22][CH2:23]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (27 mg), 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (25 mg) and piperidine (1 drop) in ethanol (2mL) was stirred at rt for 4 hours, the precipitate was collected by vacuum filtration and purified on a silica gel column to give the titled compound.